What are the current pediatric guidelines for diagnosing and managing a child with suspected pulmonary arterial hypertension, including recommended diagnostic tests, acute vasoreactivity assessment, medication selection, and follow‑up care?

Pediatric Pulmonary Arterial Hypertension: Current Guidelines

Diagnostic Approach

Right heart catheterization (RHC) is mandatory to confirm the diagnosis of pediatric PAH before initiating any therapy, and must be performed at expert centers experienced in pediatric pulmonary hypertension. 1

Initial Screening and Non-Invasive Assessment

• Transthoracic echocardiography serves as the first-line screening tool to estimate pulmonary artery pressure, assess right ventricular function, and detect structural heart disease 2, 3, 4
• Measure tricuspid regurgitant velocity (TRV), tricuspid annular planar excursion (TAPSE), and assess ventricular septal position and right ventricular size 1, 4
• Obtain arterial blood gas measurements and oxygen saturation to assess for hypoxia and acidosis, which are potent pulmonary vasoconstrictors in children 1
• Perform chest radiograph, pulmonary function tests, and exercise testing (6-minute walk test when age-appropriate) 1
• Ventilation-perfusion (V/Q) scan is mandatory in all suspected PAH patients to exclude chronic thromboembolic pulmonary hypertension 5
• Obtain chest CT, abdominal ultrasound, serological studies for connective tissue disease, hypercoagulability studies, and HIV testing 1

Cardiac Catheterization Protocol

• Perform catheterization under either general anesthesia or conscious sedation, depending on developmental stage and institutional expertise 1
• Use fentanyl, ketamine, or propofol for sedation as these have minimal effects on pulmonary artery pressure and pulmonary vascular resistance index (PVRI) in children 1
• Measure pressures at end-expiration for spontaneously breathing patients and at end-inspiration for ventilated patients 1
• Obtain oxygen saturation measurements ("saturation run") from superior vena cava, inferior vena cava, right atrium, right ventricle, pulmonary artery, pulmonary veins, left atrium, left ventricle, and ascending/descending aorta to detect shunts 1
• Measure right atrial, right ventricular, pulmonary artery (proximal and distal), pulmonary artery wedge, left atrial, and systemic arterial pressures 1
• Calculate PVRI and pulmonary-to-systemic vascular resistance ratio (PVR/SVR) 1

Diagnostic criteria for pediatric PAH: mean pulmonary artery pressure (mPAP) >20 mmHg, pulmonary artery wedge pressure (PAWP) ≤15 mmHg, and PVR >3 Wood units 1, 5

Acute Vasoreactivity Testing (AVT)

Indications and Contraindications

Vasoreactivity testing should ONLY be performed in children with idiopathic PAH (IPAH), heritable/familial PAH (HPAH), or drug-induced PAH. 1, 5

Vasoreactivity testing is contraindicated (Class III) in: 1, 5, 6

• PAH associated with congenital heart disease (including ventricular septal defects, atrial septal defects)
• PAH associated with connective tissue disease
• HIV-associated PAH
• Portopulmonary hypertension
• Pulmonary veno-occlusive disease
• All Group 2 (left heart disease), Group 3 (lung disease), Group 4 (chronic thromboembolic), and Group 5 PH

Testing Protocol

• Inhaled nitric oxide (20-80 ppm) is the preferred agent for acute vasoreactivity testing 1, 5
• Alternative agents include intravenous epoprostenol, intravenous adenosine, or inhaled prostacyclin analogs (iloprost) 1
• Some studies suggest synergy between inhaled nitric oxide and 100% oxygen 1
• Never use oral or intravenous calcium channel blockers for acute testing (Class III recommendation) 1, 5

Definition of Positive Response

A positive acute vasoreactivity response requires ALL three criteria: 1, 5

1. Decrease in mPAP ≥10 mmHg
2. Absolute mPAP ≤40 mmHg
3. Cardiac output increased or unchanged

• Approximately 30-50% of pediatric IPAH patients demonstrate acute vasoreactivity in North American registries, though European data suggest <10% (similar to adults) 1
• The higher prevalence of acute vasoreactivity in children with IPAH suggests vasoconstriction may predominate over fixed obstructive vascular changes in this subset 1

Special Considerations for Congenital Heart Disease

For children with congenital heart disease and borderline operability, AVT assesses whether PVR will decrease sufficiently for surgical repair 1

Positive AVT for CHD-associated PAH is defined as: 1

• Decrease in PVRI to <6-8 Wood units·m² OR
• PVR/SVR ratio <0.3

However, AVT is only one measure used to define operability; the entire clinical picture, patient age, and lesion type must be considered. 1

Management and Medication Selection

Calcium Channel Blocker Therapy (for Vasoreactive IPAH/HPAH Only)

High-dose calcium channel blockers should ONLY be initiated in children with documented positive acute vasoreactivity testing. 1, 5

• Drug selection based on resting heart rate: 5

  • Heart rate <70-75 bpm: Extended-release nifedipine (target 120-240 mg daily) or amlodipine (up to 20 mg daily)
  • Heart rate >75-80 bpm: Diltiazem (target 240-720 mg daily)

• Children tolerate and require higher doses per kilogram than adults 1

• Mandatory reassessment: Repeat RHC at 3-4 months after CCB initiation to identify non-responders 5

• Approximately 50% of acute responders lose efficacy over time and require escalation to PAH-specific therapy 5

Long-term response criteria (all must be met): 5

• WHO functional class I-II
• Marked hemodynamic improvement approaching near-normalization
• Mean PAP ideally <25 mmHg

PAH-Specific Therapy (Non-CCB)

For children who are not vasoreactive or who fail calcium channel blocker therapy:

• Prostacyclin analogs: Intravenous epoprostenol is considered first-line therapy for severely ill children, though data are limited 1, 7
• Endothelin receptor antagonists: Bosentan has been studied in children 4-17 years with PAH (BREATHE-3 study), showing significant hemodynamic improvement after 12 weeks 1
• Phosphodiesterase-5 inhibitors: Sildenafil has been described in children, but data are limited to small case series 1
• Combination therapy (e.g., endothelin receptor antagonists plus prostanoids) may be considered for patients who fail to improve or deteriorate with first-line treatment 1

Supportive Care

• Diuretics should be used in cases of right heart failure 1
• Supplemental oxygen is controversial and should only be used when it produces consistent increase in arterial oxygen saturation and/or improved clinical well-being 1
• Anticoagulation practices vary; some centers anticoagulate Eisenmenger syndrome patients similarly to other PAH subjects in the absence of contraindication, while others avoid this due to hemorrhagic diathesis risk 1

Surgical Repair Considerations for Congenital Heart Disease

Recommendations for Structural Heart Defects (ASD, VSD, PDA)

For children with significant structural heart disease who have not undergone early repair (generally defined by age 1-2 years): 1

1. Cardiac catheterization should be considered to measure PVRI and determine operability (Class II recommendation) 1

2. Repair should be considered if: 1

   • PVRI <6 Wood units·m² OR
   • PVR/SVR <0.3 at baseline (Class I recommendation)

3. If cardiac catheterization reveals PVRI ≥6 Wood units·m² or PVR/SVR ≥0.3 with minimal responsiveness to AVT: 1

   • Repair is NOT indicated (Class III recommendation)
   • It is reasonable to implement PAH-targeted therapy followed by repeat catheterization with AVT after 4-6 months
   • Consider repair if PVRI decreases to <6 Wood units·m² (Class IIb recommendation)

Follow-Up Care

Monitoring Schedule

• Repeat cardiac catheterization should be performed: 1

  • At clinical worsening
  • 3-12 months after significant therapy change
  • Every 1-2 years during follow-up

• Clinical assessment every 3-6 months in stable patients should include: 5

  • WHO functional class
  • 6-minute walk distance (when age-appropriate)
  • ECG
  • BNP/NT-proBNP levels
  • Basic laboratory tests

• Serial echocardiography using standardized approach to assess right ventricular function, estimate pulmonary artery pressure, and evaluate treatment response 2, 4

Treatment Goals

The goal is to achieve and maintain a low-risk profile: 5

• WHO functional class I-II
• 6-minute walk distance >440 meters (when age-appropriate)
• BNP <50 ng/L

Critical Pitfalls to Avoid

• Never perform vasoreactivity testing in CHD-associated PAH, connective tissue disease-associated PAH, or any Group 2-5 PH – it provides no clinically useful information and adds unnecessary risk 5, 6
• Never start calcium channel blockers without documented positive vasoreactivity testing – this can cause life-threatening hypotension, reflex tachycardia, and right ventricular ischemia 5
• Never omit the 3-4 month repeat RHC in patients treated with CCBs – failure to identify non-responders delays necessary therapy escalation 5
• Avoid acidosis and hypoxia during catheterization – blood pH has potent effects on pulmonary vascular tone in children; acidosis causes vasoconstriction while alkalosis causes vasodilation 1
• Do not rely on a single echocardiographic variable – overreliance detracts from the overall diagnostic potential of comprehensive assessment 2
• Recognize that pulmonary hypertensive crises (PHCs) are potentially lethal – sudden increases in PAP and PVR cause acute right heart failure with systemic hypotension and can be triggered by pain, anxiety, tracheal suctioning, hypoxia, and acidosis 1
• Resuscitation of pediatric patients with PH is poor by conventional techniques alone – close collaboration between cardiologist and anesthesiologist is essential 1