What is the treatment for pediatric pulmonary hypertension?

Treatment of Pediatric Pulmonary Hypertension

For children with lower-risk pulmonary arterial hypertension (PAH), initiate oral therapy with either a phosphodiesterase type 5 (PDE5) inhibitor or an endothelin receptor antagonist (ERA), while children with higher-risk PAH require immediate initiation of intravenous or subcutaneous prostacyclin therapy. 1

Risk Stratification and Initial Therapy Selection

The treatment approach depends critically on disease severity at presentation:

Lower-Risk PAH (WHO Functional Class I-II)

• Start with oral monotherapy using either a PDE5 inhibitor (sildenafil 0.5-2 mg/kg three times daily, maximum 20 mg three times daily) or an ERA (bosentan, ambrisentan, or macitentan at weight-based dosing). 1
• This recommendation carries Class I evidence (Level of Evidence B) from the American Heart Association and American Thoracic Society guidelines. 1

Higher-Risk PAH (WHO Functional Class III-IV)

• Initiate intravenous or subcutaneous prostacyclin therapy without delay. 1
• Epoprostenol: Start at 2 ng/kg/min IV, titrate to stable dose typically 50-80 ng/kg/min. 1
• Treprostinil: Start at 2 ng/kg/min IV or subcutaneous, titrate to stable dose typically 50-80 ng/kg/min. 1
• This carries Class I evidence (Level of Evidence B). 1

Goal-Directed Therapy Escalation

Adopt a progressive treatment escalation strategy where PAH-specific drugs are added sequentially to achieve therapeutic targets (Class IIa, Level of Evidence C). 1

When to Escalate Therapy:

• Persistent WHO functional class III-IV symptoms despite initial therapy 1
• Worsening hemodynamics on serial echocardiograms 1, 2
• Elevated NT-proBNP levels suggesting inadequate response 1
• Declining six-minute walk distance in children >8 years 1

Combination Therapy Approach:

• Add a second oral agent from a different drug class (PDE5 inhibitor + ERA) if monotherapy insufficient 1
• Consider adding inhaled prostacyclin (iloprost 2.5-5 μg, 6-9 inhalations daily) for additional benefit 1
• Escalate to parenteral prostacyclin if oral combination therapy fails 1

Supportive Care Measures

Oxygen Therapy

• Provide supplemental oxygen for children with oxygen saturations <92%, particularly those with associated respiratory disease (Class IIa, Level of Evidence B). 1
• Maintain SpO2 between 92-95% to prevent hypoxemia without causing additional lung inflammation. 3

Diuretics and Cardiac Support

• Use loop diuretics, thiazides, or spironolactone cautiously for signs of right heart failure, as overdiuresis can reduce preload to the failing right ventricle (Class IIa, Level of Evidence C). 1
• Digoxin may be considered but is rarely used in modern pediatric PH management (Class IIb, Level of Evidence C). 1

Anticoagulation Considerations

• Consider warfarin (target INR 1.5-2.0) for children with idiopathic/heritable PAH, low cardiac output, indwelling central catheters, or hypercoagulable states (Class IIb, Level of Evidence C). 1
• Avoid anticoagulation in young children not yet walking or those with developmental/neurological problems due to bleeding risks. 1

Calcium Channel Blocker Testing

Calcium channel blockers should ONLY be given to children >1 year who demonstrate acute vasoreactivity during cardiac catheterization (Class I, Level of Evidence C). 1

Acute Vasoreactivity Testing (AVT):

• Perform during cardiac catheterization using inhaled nitric oxide, oxygen, or IV prostacyclin 1
• Positive response: ≥20% decrease in mean PAP with maintained or increased cardiac output 1
• Only 10-15% of pediatric PAH patients are responders 4, 5

CCB Dosing for Responders:

• Nifedipine: 0.1-0.2 mg/kg orally three times daily, titrate to 2-3 mg/kg/day (maximum 180 mg/day) 1
• Amlodipine or diltiazem are alternatives 1

CCBs are contraindicated in non-responders and those with right ventricular dysfunction due to negative inotropic effects (Class III, Level of Evidence C). 1

Special Populations

Bronchopulmonary Dysplasia with PH

• Inhaled nitric oxide (10-20 ppm initially, wean to 2-10 ppm maintenance) is effective for infants with established BPD and symptomatic PH (Class IIa, Level of Evidence C). 1, 2
• Sildenafil (0.5-2 mg/kg three times daily) is an alternative 2
• Monitor response with serial echocardiograms every 2-4 weeks initially, then every 4-6 months (Class I, Level of Evidence B). 1, 2

Congenital Heart Disease-Associated PAH

• Cardiac catheterization is essential to measure pulmonary vascular resistance index (PVRI) and determine operability before considering repair. 1
• Repair is indicated if PVRI <6 WU·m² or PVR/SVR <0.3 at baseline (Class I, Level of Evidence B). 1
• If PVRI ≥6 WU·m² and minimal AVT response, repair is contraindicated (Class III, Level of Evidence A). 1
• Consider PAH-targeted therapy for 4-6 months followed by repeat catheterization; repair may be reconsidered if PVRI decreases to <6 WU·m² (Class IIb, Level of Evidence C). 1

Transplant Evaluation

Refer children in WHO functional class III-IV on optimized medical therapy or with rapidly progressive disease to lung transplantation centers (Class I, Level of Evidence A). 1

Critical Pitfalls to Avoid

• Never start CCBs without documented vasoreactivity testing - this can precipitate acute right heart failure in non-responders. 1
• Never abruptly discontinue prostacyclin therapy - the short half-life (2-5 minutes for epoprostenol) causes rapid PH crises. 1
• Do not use PAH-targeted therapy in sickle cell disease patients with elevated pulmonary capillary wedge pressure - this can cause pulmonary edema. 1
• Avoid forced alkalosis or hyperventilation in neonatal PH - this may worsen cerebral blood flow and neurodevelopmental outcomes. 1
• Do not over-expand lungs with mechanical ventilation - maintain peak inspiratory pressure ≤30 cmH₂O to prevent worsening PH. 3

Monitoring Parameters

• Serial echocardiograms to assess right ventricular function and estimate pulmonary artery pressures 1, 2
• NT-proBNP or BNP levels as biomarkers of disease severity 1, 6
• Six-minute walk distance in children >8 years 1
• Repeat cardiac catheterization for clinical deterioration or consideration of therapy transition 2
• WHO functional class assessment at each visit 1, 6