What are the diagnostic and treatment approaches for a patient with suspected pulmonary hypertension?

Pulmonary Hypertension: Diagnostic and Treatment Approach

Immediate Diagnostic Confirmation

Right heart catheterization is mandatory to confirm the diagnosis of pulmonary hypertension, which is defined as mean pulmonary arterial pressure ≥25 mmHg at rest. 1 This invasive procedure is essential not only for diagnosis but also for establishing the specific classification, determining severity, and guiding therapy decisions. 1, 2

Initial Clinical Suspicion and Screening

Clinical suspicion should arise in any patient presenting with:

• Progressive dyspnea without obvious heart or lung disease 3
• Unexplained exercise intolerance or fatigue 3
• Physical examination findings including left parasternal lift, accentuated pulmonary component of S2, pansystolic murmur of tricuspid regurgitation, jugular venous distension, hepatomegaly, or peripheral edema 3

Transthoracic Doppler echocardiography is the essential first-line screening tool to estimate right ventricular systolic pressure, assess right atrial/ventricular enlargement, evaluate for pericardial effusion, and identify left heart disease or intracardiac shunting. 1 However, echocardiography alone cannot make a definitive diagnosis—it only estimates probability. 3

Systematic Diagnostic Workup Algorithm

Step 1: Basic Non-Invasive Testing

• Electrocardiogram to detect right ventricular hypertrophy and strain patterns 3
• Chest radiograph to exclude moderate-to-severe lung disease or pulmonary venous hypertension, though a normal chest X-ray does not exclude mild post-capillary pulmonary hypertension 3
• Pulmonary function tests with DLCO to evaluate for underlying lung disease 1
• Arterial blood gas analysis to assess oxygenation status 3

Step 2: Critical Exclusion of CTEPH

Ventilation-perfusion (V/Q) lung scan is mandatory to exclude chronic thromboembolic pulmonary hypertension (CTEPH). 1, 3 This is the primary screening test for CTEPH—a normal V/Q scan rules out CTEPH, while segmental or larger perfusion defects warrant further investigation. 3 In pulmonary arterial hypertension, V/Q scans may be entirely normal or show only small peripheral non-segmental defects. 3

If V/Q scanning shows abnormalities suggestive of CTEPH, proceed to CT angiography to delineate complete obstructions, bands, webs, and intimal irregularities. 3 Traditional pulmonary angiography is required in most CTEPH patients to determine operability for pulmonary endarterectomy. 3

Step 3: Identify Underlying Etiology

• Serological testing for connective tissue disease (antinuclear antibodies, anti-centromere, anti-Ro, U3-RNP), HIV, and hepatitis 3
• Thrombophilia screening in CTEPH patients (antiphospholipid antibodies, anticardiolipin antibodies, lupus anticoagulant) 3
• Abdominal ultrasound to evaluate for portal hypertension 3
• NT-proBNP or BNP for prognostic assessment and monitoring 3

Step 4: Hemodynamic Confirmation

Right heart catheterization must be performed to confirm diagnosis and classify the type of pulmonary hypertension:

• Pulmonary arterial hypertension (PAH) requires mean PAP ≥25 mmHg, pulmonary artery wedge pressure ≤15 mmHg, AND pulmonary vascular resistance >3 Wood units 1
• This distinguishes pre-capillary from post-capillary pulmonary hypertension 3

Risk Stratification for Treatment Planning

All patients must be risk-stratified using a comprehensive panel including clinical assessment, exercise capacity (6-minute walk distance), biomarkers (BNP/NT-proBNP), and echocardiographic/hemodynamic parameters. 3, 2

Low-risk patients have estimated 1-year mortality <5% and present with WHO Functional Class I-II, 6-minute walk distance >440 meters, and normal or near-normal right ventricular function. 3, 1

High-risk patients present with WHO Functional Class IV, 6-minute walk distance <165 meters, elevated BNP/NT-proBNP, and severe right ventricular dysfunction. 3

Treatment Approach Based on Classification

For Pulmonary Arterial Hypertension (PAH)

All PAH patients must be referred immediately to specialized pulmonary hypertension centers with multidisciplinary expertise. 1, 2, 4

Vasoreactivity Testing

Acute vasoreactivity testing with short-acting agents is mandatory for all patients with idiopathic PAH, heritable PAH, and drug-induced PAH. 1, 2 This identifies the small subset (approximately 10-15%) who may respond to calcium channel blockers.

For vasoreactive patients: High-dose calcium channel blockers are first-line therapy. 1, 2, 4 These patients must demonstrate a significant hemodynamic response (reduction in mean PAP ≥10 mmHg to reach an absolute mean PAP ≤40 mmHg with increased or unchanged cardiac output).

For Non-Vasoreactive Patients

High-risk patients require intravenous epoprostenol as first-line therapy—it is the only medication proven to reduce mortality in PAH. 1, 2 Epoprostenol is administered by continuous intravenous infusion via a central venous catheter, starting at 2 ng/kg/min and titrated based on clinical response. 5

Low-risk and intermediate-risk patients should receive initial oral combination therapy targeting multiple pathways (phosphodiesterase-5 inhibitors, endothelin receptor antagonists, or prostacyclin analogues). 2, 4 Sequential combination therapy is recommended for patients with inadequate response to initial therapy. 2

For Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

Surgical pulmonary endarterectomy in deep hypothermia circulatory arrest is the treatment of choice for operable CTEPH patients—it is potentially curative. 3, 4 The decision on operability must be made at an experienced center (performing ≥20 procedures annually with <10% mortality) through interdisciplinary discussion among internists, radiologists, and expert surgeons. 3

All CTEPH patients require lifelong anticoagulation with vitamin K antagonists (target INR 2.0-3.0). 3, 4

For inoperable CTEPH or persistent/recurrent pulmonary hypertension after surgery, riociguat is the only licensed targeted therapy. 4, 6

Essential Supportive Care Measures

Diuretics are recommended for fluid overload with careful monitoring of electrolytes and renal function to avoid excessive volume depletion. 1, 2

Oxygen supplementation must maintain arterial oxygen saturation >90% at all times. 1, 4

Anticoagulation with warfarin is recommended for idiopathic PAH patients to prevent in situ thrombosis. 1

Supervised exercise training should be considered for physically deconditioned patients who are stable on medical therapy, as it improves functional capacity without adverse effects. 1, 4

Monitoring and Follow-Up Strategy

Regular follow-up assessments every 3-6 months are mandatory in stable patients to evaluate treatment response and adjust therapy. 3, 2, 4 Each visit should include:

• Functional class assessment 3
• 6-minute walk test with Borg dyspnea score 3
• BNP/NT-proBNP measurement 3
• Echocardiography every 6-12 months 3
• Right heart catheterization should be considered at regular intervals, particularly 3-6 months after therapy changes 3

The primary treatment goal is achieving and maintaining low-risk status (WHO Functional Class I-II, 6-minute walk distance >440 meters, preserved right ventricular function). 1, 2, 4 Achievement of intermediate-risk status should be considered inadequate for most patients and warrants treatment escalation. 3

Critical Contraindications and Warnings

Pregnancy must be avoided in all PAH patients—it carries 30-50% mortality risk. 1, 4 Effective contraception counseling is mandatory, and pregnancy termination should be discussed if it occurs. 1

Epoprostenol dosing must never be abruptly withdrawn or significantly reduced as this can cause rebound pulmonary hypertension, right heart failure, and death. 5 All dosing changes require close monitoring.

Excessive physical activity that leads to distressing symptoms is contraindicated, though supervised rehabilitation is beneficial. 1

Common Pitfalls to Avoid

• Do not rely on echocardiography alone for diagnosis—right heart catheterization is mandatory for confirmation and classification 1
• Do not miss CTEPH—always perform V/Q scanning as it is the only form of pulmonary hypertension that may be curable with surgery 3, 1
• Do not delay referral to specialized centers—early expert evaluation is critical for optimal outcomes, particularly in PAH and CTEPH 1, 2, 4
• Do not use angiotensin-converting enzyme inhibitors, angiotensin-2 receptor antagonists, or beta-blockers in PAH patients unless required for specific comorbidities, as they are not beneficial and may be harmful 2
• Do not overlook associated conditions—screen for connective tissue disease, HIV, portal hypertension, and congenital heart disease in all PAH patients 3