Pulmonary Hypertension Due to Chronic Lung Disease and Hypoxia

Pulmonary hypertension due to chronic lung disease and hypoxia (group 3) is an elevated pulmonary artery pressure (mean over 20 mmHg, with pulmonary vascular resistance over 2 Wood units). It occurs in patients with chronic obstructive pulmonary disease, interstitial lung disease, combined pulmonary fibrosis and emphysema, sleep related hypoventilation, or chronic exposure to high altitude.

It is the second commonest form of pulmonary hypertension after left heart disease. It occurs in 30 to 50% of patients with advanced COPD (mostly mild to moderate, with a mean pressure of 20 to 35 mmHg), and in 30 to 85% of patients with advanced interstitial lung disease. Severe pulmonary hypertension (mean over 35 mmHg, or over 25 mmHg with a cardiac index below 2.0 L/min/m2) is found in 1 to 5% and has a poor outlook.

Pathophysiology. Hypoxic pulmonary vasoconstriction, destruction of the capillary bed (emphysema, fibrosis), vascular remodelling with intimal and medial hypertrophy, endothelial dysfunction, inflammation, and raised intrathoracic pressure combine to raise pulmonary vascular resistance. Chronic right ventricular pressure overload leads to cor pulmonale. Hypoxaemia, hypercapnia and polycythaemia worsen it.

Breathlessness out of proportion to lung function, fatigue, reduced exercise tolerance, exertional chest pain and syncope. Signs of right heart strain: loud pulmonary second heart sound, parasternal heave, tricuspid regurgitation murmur, raised jugular venous pressure, peripheral oedema and ascites. Hypoxaemia and cyanosis. Features of the underlying lung disease dominate.

Syncope, worsening right heart failure or falling saturation despite oxygen needs urgent assessment.

• Suspected from disproportionate dyspnoea, low DLCO (under 40% predicted in COPD or ILD), exertional desaturation, enlarged pulmonary arteries on CT (main pulmonary artery diameter over 29 mm, or ratio to aorta over 1), and raised NT-proBNP.
• Echocardiography: estimated pulmonary artery systolic pressure from tricuspid regurgitation velocity, right ventricular dilatation, hypertrophy and function (tricuspid annular plane systolic excursion under 17 mm), and left heart assessment.
• Right heart catheterisation: the definitive test, to confirm mean pressure, pulmonary artery wedge pressure (15 mmHg or less), and pulmonary vascular resistance, and to define severity. Used when it would change treatment (for example, transplant or specific therapy).
• Arterial blood gas, overnight oximetry, sleep study for hypoventilation, full pulmonary function with DLCO, and six minute walk test.
• Exclude other causes: ventilation perfusion scan (for chronic thromboembolic disease), left heart disease, connective tissue disease serology, liver disease, HIV and thyroid disease.

Differential diagnosis.

• Pulmonary arterial hypertension (group 1) with coincident lung disease
• Left heart disease (group 2)
• Chronic thromboembolic pulmonary hypertension
• Pulmonary veno occlusive disease
• Obstructive sleep apnoea or obesity hypoventilation without parenchymal disease

• Optimise treatment of the underlying disease. Bronchodilators: tiotropium 5 micrograms, two inhalations daily, with a long acting beta agonist. Inhaled corticosteroid in COPD with eosinophilia.
• Antifibrotic treatment in fibrosis: nintedanib 150 mg twice daily with food, or pirfenidone titrated to 801 mg three times daily.
• Treatment of exacerbations, vaccination, smoking cessation and pulmonary rehabilitation.
• Long term oxygen therapy for at least 15 hours daily (or 24 hours) in chronic hypoxaemia, with PaO2 7.3 kPa or less (or 7.3 to 8.0 kPa with pulmonary hypertension, polycythaemia or oedema), aiming for saturation over 90% and PaO2 over 8 kPa. It slows the rise in pulmonary pressure and improves survival in COPD.
• Non-invasive ventilation for chronic hypercapnic failure (nocturnal bilevel), and treatment of sleep disordered breathing (continuous positive airway pressure).
• Inhaled treprostinil in pulmonary hypertension with interstitial lung disease: start 3 breaths (18 micrograms) four times daily and increase by 3 breaths every 1 to 2 weeks as tolerated, to a target of 9 to 12 breaths (54 to 72 micrograms) four times daily. It improves walk distance and slows deterioration. Adverse effects are cough, headache and flushing.
• Other pulmonary vasodilators (sildenafil 20 mg three times daily, tadalafil 40 mg daily, bosentan, ambrisentan) are not used routinely in COPD or mild disease because of worsening ventilation perfusion matching and little benefit.
• In interstitial lung disease, endothelin receptor antagonists and riociguat can be harmful.
• Pulmonary vasodilators are considered only for severe pulmonary hypertension at an expert centre, after individual review.
• Diuretics for right heart failure (furosemide 20 to 80 mg daily, with spironolactone 25 to 50 mg), with monitoring of electrolytes and renal function. Venesection for symptomatic polycythaemia (haematocrit over 55 to 60%).
• Anticoagulation is not routinely used, and digoxin or calcium channel blockers are not indicated.
• Lung transplantation referral for advanced disease with severe pulmonary hypertension, and palliative care for symptom control.

Complications and prognosis. Right heart failure, exacerbations, hospitalisation and death. Survival is shorter than in lung disease with normal pressures, with 3-year mortality of 40 to 50% in severe pulmonary hypertension.

Monitoring. Review every 3 to 6 months with oxygen saturation, six minute walk, natriuretic peptide and echocardiography, and blood gas for oxygen titration. Repeat catheterisation if therapy changes.

Referral and escalation. Refer to a pulmonary hypertension centre for severe disease, to a transplant service, and to palliative care when appropriate.