Diagnosis and Treatment of Pulmonary Hypertension
Diagnostic Approach
Echocardiography is the first-line screening test when pulmonary hypertension (PH) is suspected, but right heart catheterization is mandatory to confirm the diagnosis before initiating any PAH-specific therapy. 1, 2
Initial Screening and Clinical Evaluation
- Transthoracic echocardiography should be performed first when PH is suspected based on symptoms (dyspnea, exercise intolerance, chest pain) or physical findings 1, 3
- Look specifically for elevated tricuspid regurgitant velocity (TRV), right ventricular enlargement, and reduced tricuspid annular plane systolic excursion (TAPSE) 1
- Obtain routine blood work including complete blood count, comprehensive metabolic panel, thyroid function tests, HIV serology, and liver function tests to identify associated conditions 1
- Perform immunology testing (ANA, anti-Scl-70, anti-centromere) to screen for connective tissue diseases 1
- Order pulmonary function tests with DLCO and arterial blood gases to assess for underlying lung disease 1
Definitive Diagnostic Testing
Right heart catheterization must be performed to confirm PH diagnosis and establish hemodynamic classification before starting treatment. 1, 2, 4
- PH is defined as mean pulmonary arterial pressure ≥25 mmHg at rest 1, 5
- Pulmonary arterial hypertension (PAH, Group 1) specifically requires mean PAP ≥25 mmHg, pulmonary artery wedge pressure (PAWP) ≤15 mmHg, and pulmonary vascular resistance >3 Wood units 1
- The catheterization must include a full saturation run to detect intracardiac shunts 4
Distinguishing PH Subtypes
After confirming PH hemodynamically, perform ventilation/perfusion (V/Q) scanning to exclude chronic thromboembolic pulmonary hypertension (CTEPH), as this fundamentally changes management. 1
- V/Q scanning is more sensitive than CT angiography for detecting CTEPH and should be performed in all patients with unexplained PH 1
- If V/Q scan shows mismatched perfusion defects, proceed to contrast CT pulmonary angiography and consider pulmonary angiography 1
- High-resolution chest CT should be obtained to evaluate for interstitial lung disease, emphysema, or findings suggestive of pulmonary veno-occlusive disease (ground-glass opacities, septal thickening) 1
- Perform abdominal ultrasound to screen for portal hypertension in all PAH patients 1
Treatment of Pulmonary Arterial Hypertension (Group 1)
Vasoreactivity Testing and Calcium Channel Blockers
Vasoreactivity testing during right heart catheterization is mandatory in patients with idiopathic, heritable, or drug-induced PAH to identify the small subset who can be treated with high-dose calcium channel blockers. 1, 2, 6
- A positive response is defined as a fall in mean PAP of ≥10 mmHg to ≤40 mmHg with increased or unchanged cardiac output 6
- Only 10-15% of patients demonstrate acute vasoreactivity 1
- For vasoreactive patients, initiate high-dose calcium channel blockers (nifedipine 120-240 mg daily or diltiazem 240-720 mg daily) 2, 6
- Reassess these patients at 3-4 months; if they fail to achieve near-normalization of hemodynamics and functional class I-II, add PAH-specific therapy 1
Risk Stratification for Treatment Selection
All non-vasoreactive PAH patients require risk stratification using WHO functional class, 6-minute walk distance, BNP/NT-proBNP, right atrial pressure, and cardiac index to guide initial therapy. 2, 6
- Low-risk features: WHO FC I-II, 6MWD >440m, BNP <50 ng/L, RAP <8 mmHg, cardiac index ≥2.5 L/min/m² 2
- Intermediate-risk features: WHO FC III, 6MWD 165-440m, BNP 50-300 ng/L, RAP 8-14 mmHg 2
- High-risk features: WHO FC IV, 6MWD <165m, BNP >300 ng/L, RAP >14 mmHg, cardiac index <2.0 L/min/m² 2
Initial Therapy Based on Risk
For treatment-naïve low or intermediate-risk PAH patients, initial oral combination therapy with an endothelin receptor antagonist plus a phosphodiesterase-5 inhibitor is recommended over monotherapy. 1, 2, 6
- The combination of ambrisentan plus tadalafil has proven superior to monotherapy in delaying clinical failure 2
- Alternative initial combinations include other ERAs (bosentan, macitentan) with PDE-5 inhibitors (sildenafil) or soluble guanylate cyclase stimulators (riociguat) 1
For high-risk PAH patients, initial combination therapy including intravenous prostacyclin analogues (epoprostenol or treprostinil) should be prioritized. 2, 6
- Epoprostenol is initiated at 2 ng/kg/min and increased in 2 ng/kg/min increments every 15 minutes until dose-limiting effects occur 7
- Chronic dosing typically ranges from 20-40 ng/kg/min, adjusted based on clinical response 7
- Epoprostenol requires continuous intravenous infusion via central venous catheter using an ambulatory pump 7
Sequential Combination Therapy
For patients with inadequate response to initial monotherapy or dual combination therapy, add a third agent from a different drug class. 1, 2
- Inadequate response is defined as failure to achieve or maintain low-risk status 2
- Triple combination therapy typically includes an ERA, PDE-5 inhibitor (or sGC stimulator), and prostacyclin pathway agent 1
Treatment Goals and Monitoring
The primary treatment goal is achieving and maintaining low-risk status, assessed every 3-6 months using WHO functional class, 6-minute walk distance, BNP/NT-proBNP, and echocardiography. 1, 2, 6
- Target WHO functional class I-II 2
- Target 6-minute walk distance >440 meters (though lower values may be acceptable in elderly patients with comorbidities) 2
- Target BNP <50 ng/L or NT-proBNP <300 ng/L 2
- Echocardiography should show no pericardial effusion, TAPSE >20mm, and normal right atrial size 2
Treatment of Other PH Groups
Group 2: PH Due to Left Heart Disease
PAH-specific therapies are not recommended for patients with PH due to left heart disease and may be harmful. 1, 2, 4
- Treatment focuses on optimizing management of the underlying left heart condition (heart failure, valvular disease) 1
- Diuretics are the mainstay for managing volume overload 2
Group 3: PH Due to Lung Disease
Long-term oxygen therapy to maintain saturations >90% is the primary treatment for PH associated with lung disease. 2
- PAH-specific therapies are not recommended for Group 3 PH 1
- Treat the underlying lung disease (COPD, interstitial lung disease) optimally 1
- Continuous oxygen is indicated when arterial oxygen pressure is consistently <60 mmHg 2
Group 4: Chronic Thromboembolic Pulmonary Hypertension
Surgical pulmonary endarterectomy in deep hypothermia with circulatory arrest is the treatment of choice for CTEPH and should be performed at expert centers. 1, 2, 4
- All CTEPH patients must be evaluated by a multidisciplinary team including surgeons, interventional cardiologists, and PH specialists to determine operability 1
- For inoperable or persistent/recurrent CTEPH, consider balloon pulmonary angioplasty or medical therapy with riociguat 1
- Lifelong anticoagulation is mandatory, targeting INR 2.0-3.0 2
Essential Supportive Care Measures
All PAH patients with signs of right ventricular failure and fluid retention require diuretics, typically furosemide, with monitoring of electrolytes and renal function. 2, 4
Supplemental oxygen should be provided continuously when arterial oxygen saturation falls below 90% or arterial oxygen pressure is <60 mmHg. 2, 4
Anticoagulation should be considered in idiopathic PAH, heritable PAH, and anorexigen-induced PAH, targeting INR 1.5-2.5. 2
Pregnancy must be avoided in all PAH patients due to high maternal mortality risk (30-50%). 1, 2
- Counsel all women of childbearing age on reliable contraception 1
- Avoid estrogen-containing contraceptives; prefer barrier methods, progesterone-only pills, or intrauterine devices 1
Immunizations against influenza and pneumococcus are recommended. 2
Supervised exercise training and pulmonary rehabilitation improve functional capacity and quality of life. 2, 6
Advanced Therapies and Transplantation
Consider lung transplantation eligibility after inadequate response to initial monotherapy or combination therapy. 2
- Refer for transplant evaluation soon after confirming inadequate response on maximal combination therapy 2
- Typical wait times are 1-2 years; early referral is critical 1
Balloon atrial septostomy may be considered as a palliative or bridging procedure in patients deteriorating despite maximal medical therapy. 2
Critical Pitfalls to Avoid
Never start PAH-specific drugs empirically without confirming diagnosis and hemodynamic classification via right heart catheterization. 2, 4
- This can delay appropriate treatment and cause harm, particularly in Group 2 PH where PAH therapies may worsen pulmonary edema 2, 4
Do not abruptly discontinue or reduce prostacyclin therapy, as this can cause rebound pulmonary hypertension and death. 7
Avoid ACE inhibitors, ARBs, and beta-blockers in PAH unless specifically required for comorbidities, as they lack proven benefit and may reduce cardiac output. 2
Do not rely on CT pulmonary angiography alone to exclude CTEPH; V/Q scanning is more sensitive and must be performed. 1
Management of Acute Decompensation
ICU hospitalization is required for PH patients with high heart rate (>110 bpm), systolic blood pressure <90 mmHg, low urine output, or rising lactate. 2, 4
Inotropic support with dobutamine or milrinone is recommended for hypotensive patients. 2, 4