CONTENTS
- Symptoms of PH
- Diagnosis
- Causes of PH
- Treatment – array of available therapies
- Specific forms of PH
- Group 1 PH (PAH, pulmonary arterial hypertension)
- Group 2 PH (left heart failure)
- Group 3 PH (lung disease)
- Group 4 PH (chronic thromboembolic pulmonary hypertension)
- Group 5 PH (miscellaneous)
- Questions & discussion
abbreviations used in the pulmonary section: 9
- ABPA: Allergic bronchopulmonary aspergillosis 📖
- AE-ILD: Acute exacerbation of ILD 📖
- AEP: Acute eosinophilic pneumonia 📖
- AFB: Acid-fast bacilli
- AIP: Acute interstitial pneumonia (Hamman-Rich syndrome) 📖
- ANA: Antinuclear antibody 📖
- ANCA: Antineutrophil cytoplasmic antibodies 📖
- ARDS: Acute respiratory distress syndrome 📖
- ASS: Antisynthetase syndrome 📖
- BAL: Bronchoalveolar lavage 📖
- BiPAP: Bilevel positive airway pressure 📖
- CEP: Chronic eosinophilic pneumonia 📖
- CF: Cystic fibrosis 📖
- COP: Cryptogenic organizing pneumonia 📖
- CPAP: Continuous positive airway pressure 📖
- CPFE: Combined pulmonary fibrosis and emphysema 📖
- CTD-ILD: Connective tissue disease-associated interstitial lung disease 📖
- CTEPH: Chronic thromboembolic pulmonary hypertension 📖
- DAD: Diffuse alveolar damage 📖
- DAH: Diffuse alveolar hemorrhage 📖
- DIP: Desquamative interstitial pneumonia 📖
- DLCO: Diffusing capacity for carbon monoxide 📖
- DRESS: Drug reaction with eosinophilia and systemic symptoms 📖
- EGPA: Eosinophilic granulomatosis with polyangiitis 📖
- FEV1: Forced expiratory volume in 1 second 📖
- FVC: Forced vital capacity 📖
- GGO: Ground-glass opacity 📖
- GLILD: Granulomatous and lymphocytic interstitial lung disease 📖
- HFNC: High flow nasal cannula 📖
- HP: Hypersensitivity pneumonitis 📖
- IPAF: Interstitial pneumonia with autoimmune features 📖
- IPF: Idiopathic pulmonary fibrosis 📖
- IVIG: Intravenous immunoglobulin 📖
- LAM: Lymphangioleiomyomatosis 📖
- LIP: Lymphocytic interstitial pneumonia 📖
- MAC: Mycobacterium avium complex 📖
- MCTD: Mixed connective tissue disease 📖
- NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
- NSIP: Nonspecific interstitial pneumonia 📖
- NTM: Non-tuberculous mycobacteria 📖
- OHS: Obesity hypoventilation syndrome 📖
- OP: Organizing pneumonia 📖
- OSA: Obstructive sleep apnea 📖
- PAP: Pulmonary alveolar proteinosis 📖
- PE: Pulmonary embolism 📖
- PFT: Pulmonary function test 📖
- PLCH: Pulmonary Langerhans cell histiocytosis 📖
- PPFE: Pleuroparenchymal fibroelastosis 📖
- PPF: Progressive pulmonary fibrosis 📖
- PVOD/PCH Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis 📖
- RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease 📖
- RP-ILD: Rapidly progressive interstitial lung disease 📖
- TNF: Tumor necrosis factor
- UIP: Usual interstitial pneumonia 📖
(#1) initial symptoms
- Onset is typically insidious, often leading to delayed diagnosis.
- Dyspnea on exertion is the most frequent presentation.
- Fatigue.
(#2) right ventricular congestive symptoms
- Right ventricular failure causes peripheral edema and weight gain.
- Gastrointestinal symptoms:
- Bowel edema may cause malnutrition, anorexia/nausea.
- Hepatic congestion may cause abdominal fullness, discomfort.
- Ascites can occur.
(#3) impaired cardiac output (most worrisome)
- Exertional syncope or presyncope.
- Cool extremities.
- Prolonged capillary refill.
- Hypotension and tachycardia can be seen.
other symptoms:
- Palpitations.
- Anginal chest pain (due to subendocardial ischemia of the right ventricle, or dynamic compression of the left main coronary artery).
- Hoarseness due to Ortner syndrome: dilated pulmonary artery impairs the left recurrent laryngeal nerve, causing left vocal cord paralysis. Recurrent laryngeal nerve dysfunction may also result from dilation of the left atrium or aorta (cardiovocal syndrome). (31174660)
- Hemoptysis (rare, may be severe).
The NYHA functional assessment and the World Health Organization (WHO) functional status are essentially the same:
- Class I = Asymptomatic.
- Class II = Mild:
- Mild limitation, only with activity.
- Ordinary physical activity causes symptoms (abnormal dyspnea/fatigue, chest pain, or near syncope).
- Class III = Marked:
- Marked limitation with activity.
- Comfortable at rest, without rest symptoms.
- Class IV = Profound:
- Any activity causes symptoms.
- May have symptoms at rest.
- Signs of right ventricular failure.
dilated right atrium and right ventricle
- Frontal radiograph: Prominent bulge of the right atrium, to the right side of the spine.
- Lateral radiograph: Dilation of the right ventricle causes a reduction in the retrosternal air space. The right ventricle may contact >1/3 of the sternum.
enlarged central pulmonary arteries
- The convexity of the main pulmonary artery may be prominent.
- Prominent pulmonary arteries may mimic hilar lymphadenopathy. However, if arteries can be seen converging on the enlarged pulmonary artery, this confirms the presence of pulmonary artery enlargement (“hilum convergence sign”).
- Arteries may rapidly taper, with peripheral oligemia.
(#1) pulmonary artery diameter enlargement
- (Pulmonary artery)/(aorta) ratio >1.
- This ratio has a fairly high specificity for identifying pulmonary hypertension (~90%). (Walker 2019)
- The ratio is inaccurate among patients with aortic dilation (more likely in older patients).
- PA diameter above ~3 cm. (36017548)
- Specificity may be enhanced by using a cutoff of >32.5 mm. (Walker 2019)
(#2) chamber dilation and venous congestion
- Enlarged right heart chambers (right atrium, right ventricle).
- Inferior vena cava:
- Inferior vena cava dilation.
- Contrast reflux into the inferior vena cava and sometimes even hepatic veins.
other findings may include:
- Enlargement of segmental arteries >1.25 times the caliber of the adjacent bronchus.
- If 3 of the 4 segmental arteries are enlarged and the main pulmonary artery is >29 mm, this is highly specific for pulmonary hypertension. (Fishman 2023)
- This ratio may not be accurate in the presence of pulmonary pathology that affects bronchus caliber (e.g., bronchiectasis).
- RV outflow tract wall hypertrophy (>6 mm). (36017548)
- Pericardial effusion may be seen in some cases.
- Pulmonary cholesterol granulomas:
- Longstanding pulmonary hypertension may cause cholesterol granulomas to occur within alveolar spaces.
- Radiologically these may appear as diffuse centrilobular GGO (ground-glass opacities). (24791617) The differential diagnosis of this finding includes PCH (pulmonary capillary hemangiomatosis).
signs of the cause of pulmonary hypertension
- Parenchymal lung abnormalities suggest the possibility of Group III pulmonary hypertension.
- Dilation of the left atrium suggests the presence of left heart disease (i.e., Group II pulmonary hypertension).
- Pleural effusion is generally not caused by pulmonary hypertension, so this suggests the presence of another process (e.g., left heart disease or primary lung disease). (Murray 2022)
- Centrilobular ground-glass opacities:
- May be seen in severe idiopathic PAH (pulmonary atrial hypertension) due to repeated microhemorrhages.
- May occur in pulmonary capillary hemangiomatosis. 📖
- PCH/PVD (pulmonary capillary hemangiomatosis/pulmonary veno-occlusive disease) may cause features that resemble cardiogenic pulmonary edema. 📖
qualitative signs of pulmonary hypertension may be seen
- Chamber dilation:
- Dilated coronary sinus (although this may also be incidental, due to a persistent left superior vena cava, or due to congenital heart disease).
- Right atrial dilation.
- Right ventricular dilation (e.g., basal RV diameter greater than LV diameter in a long-axis view).
- Pulmonary artery dilation (either pulmonary artery diameter > aortic root diameter, or pulmonary artery diameter >25 mm).
- Right ventricular systolic failure: tricuspid annular plane systolic excursion (TAPSE) <18 mm.
- Interventricular septal flattening:
- Systolic flattening suggests pressure overload of the right ventricle, so this is especially suggestive of pulmonary hypertension.
- Diastolic flattening suggests volume overload of the right ventricle.
- Systemic congestion (e.g., dilated inferior vena cava with reduced collapsibility).
most basic quantitative approach: systolic Pulmonary Artery Pressure (sPAP)
- sPAP can be calculated based on the tricuspid regurgitant jet combined with an estimation of the right atrial pressure:
- PA systolic pressure = 4(tricuspid jet velocity squared) + right atrial pressure.
- sPAP may allow estimation of the likelihood of PH:
- sPAP <36 mm: PH is unlikely.
- sPAP 36-50 mm: Grey zone.
- sPAP >50 mm: PH is likely.
- Simply evaluating the sPAP is perhaps the least accurate method of utilizing echocardiographic data (figure below). However, this can be useful as a rough benchmark. Additionally, many echocardiographic reports will solely report the sPAP (without a more complete evaluation).
- ⚠️ Changes in sPAP over time don't necessarily track with disease improvement or deterioration. (36017548)
- ⚠️ Tricuspid regurgitation is often absent in patients with proven pulmonary hypertension. (Murray 2022) Thus, the absence of a measurable tricuspid regurgitant jet doesn't exclude pulmonary hypertension by any means.
tricuspid regurgitant velocity (TRV) might be superior to the systolic pulmonary artery pressure (sPAP)
- Systolic PA pressure calculation requires estimation of the right atrial pressure, a process which is relatively inaccurate. Thus, it may be more accurate to focus solely on the tricuspid regurgitant velocity. (36017548)
- TRV may be used to estimate the likelihood of PH:
- Peak tricuspid regurgitant velocity <2.8 m/s: PH is unlikely
- Peak tricuspid regurgitant velocity 2.9-3.4 m/s: Grey zone.
- Peak tricuspid regurgitant velocity >3.4 m/s: PH is likely
- TRV may underestimate the pulmonary pressures due to severe tricuspid regurgitation.
- TRV may overestimate the pulmonary pressures due to:
- High cardiac output.
- Misinterpretation of tricuspid valve closure artifact for the TR jet.
- Incorrect assignment of the peak TR velocity due to maximal velocity boundary artifacts.
integrated approach
- The 2022 ESC guidelines recommend a combination of tricuspid valve velocity plus additional signs of pulmonary hypertension, as shown above. (36017548)
- To increase the likelihood of pulmonary hypertension, signs from at least two of the following three categories should be present:
- (#1) Right ventricle:
- Right ventricular dilation (RV/LV diameter ratio >1).
- Flattening of the interventricular septum.
- TAPSE/sPAP ratio <0.55 mm/mm.
- (#2) Pulmonary artery:
- Pulmonary artery dilation (either pulmonary artery diameter > aortic root diameter, or pulmonary artery diameter >25 mm).
- Early diastolic pulmonary regurgitation velocity >2.2 m/s.
- Right ventricular outflow tract acceleration time <105 ms and/or mid-systolic notching (the latter may indicate pre-capillary pulmonary hypertension).
- (#3) Inferior vena cava and right atrium:
- IVC diameter >21 mm with decreased inspiratory collapse.
- Right atrial dilation (end-systolic area >18 cm2).
definition of pulmonary hypertension (PH)
- PH is defined as a mPAP (mean pulmonary artery pressure) >20 mm (at rest).
- Note that pulmonary hypertension has recently been redefined using a cutoff value of >20 mm (rather than the traditional value of >25 mm). Likewise, pulmonary arterial hypertension was redefined using a cutoff of 2 Wood units (rather than the traditional 3 Wood units).
- Patients with a mean PA pressure of 20-25 mm technically have pulmonary hypertension. However, such patients haven't been included in clinical trials on pulmonary hypertension, so there are no research-proven therapies for them. (Murray 2022)
hemodynamic evolution of PH over time
- Decompensated, advanced pulmonary hypertension is ultimately marked by a fall in cardiac output and pulmonary pressures (due to failure of the right ventricle).
- Consideration of disease severity must take into account both cardiac output and pulmonary artery pressures (not simply pulmonary artery pressures).
classification of PH
physiological basis of PH classification
- The mPAP (mean pulmonary artery pressure) is equal to the LVEDP (left ventricular end diastolic pressure) plus the pressure gradient between the pulmonary arteries and the left ventricle (which is equal to the cardiac output multiplied by the pulmonary vascular resistance):
- mPAP = PAWP + (CO)(PVR)
- This reveals mathematically that there are various reasons that the mPAP may be elevated: elevation of the PAWP, elevation of the CO, and/or elevation of the PVR.
- PH may be subcategorized based on its physiological cause:
pre-capillary PH
⬆mPAP = PAWP + (CO)(⬆PVR)
- Requirements:
- mPAP >20-25 mm.
- PA wedge pressure (PAWP) <15 mm.*
- PVR (pulmonary vascular resistance) >2-3 Wood units.
- Causes:
- PAH (pulmonary arterial hypertension).
- Group 3 PH (due to lung disease).
- Group 4 PH (CTEPH, chronic thromboembolic PH).
- Group 5 PH patients (miscellaneous).
isolated post-capillary
⬆mPAP = ⬆PAWP + (CO)(PVR)
- Requirements:
- mPAP >20-25 mm.
- PA wedge pressure (PAWP) >15 mm.*
- PVR (pulmonary vascular resistance) <2-3 Wood units.
- Causes:
- Early Group 2 PH (due to left heart disease).
- Group 5 PH patients (miscellaneous).
combined pre- & post-capillary PH
⬆mPAP = ⬆PAWP + (CO)(⬆PVR)
- Requirements:
- mPAP >20-25 mm.
- PA wedge pressure (PAWP) >15 mm.*
- PVR (pulmonary vascular resistance) >2-3 Wood units.
- Causes:
- More advanced Group 2 PH (due to left heart disease).
- Combined left heart and lung disease overlap. (37026538)
- Group 5 PH patients (miscellaneous).
unclassified PH
⬆mPAP = PAWP + (⬆CO)(PVR)
- Requirements:
- mPAP >20-25 mm.
- PA wedge pressure (PAWP) <15 mm.*
- PVR (pulmonary vascular resistance) <2-3 Wood units.
- Causes:
- Increased airway pressures.
- Elevated cardiac output, e.g.:
- Hyperthyroidism.
- Thiamine deficiency.
- Paget disease.
- AV (arteriovenous) fistula.
- Cirrhosis.
*PAWP cutoff of 15 mm is somewhat arbitrary. Pulmonary artery wedge pressure is an inaccurate measurement for the actual left ventricular end-diastolic pressure (figure below). Consequently, the binary division between pre-capillary and post-capillary pulmonary hypertension based on whether the pulmonary artery wedge pressure is <15 mm or >15 mm is a crude and frequently incorrect dichotomy. Additional factors should also be taken into account to distinguish pre- from post-capillary pulmonary hypertension (e.g., clinical features of PH due to left ventricular dysfunction, as discussed here: ⚡️). (36017548) Fluid challenge during the pulmonary artery catheterization may also help determine whether there is a component of left ventricular dysfunction.
Group 1: Pulmonary Arterial Hypertension (PAH)
- 1.1 Idiopathic.
- 1.1.1 Non-responders at vasoreactivity testing.
- 1.1.2 Acute responders at vasoreactivity testing.
- 1.2 Hereditary.
- 1.3 Drug and toxin induced (* = definite association):
- Anorexigens (e.g., aminorex*, benfluorex*, dexfenfluramine*).
- Tyrosine kinase inhibitors (dasatinib*, bosutinib, ponatinib). (32768078)
- Sympathomimetics: (amphetamines; cocaine; methamphetamine* especially may account for ~25% of idiopathic PH in the United States). (36017548)
- Alkylating agents (e.g., cyclophosphamide, mitomycin C, busulfan, BCNU, bleomycin). These are mostly associated with pulmonary veno-occlusive disease. 📖
- Selective proteasome inhibitors (carfilzomib).
- Direct-acting antiviral agents against hepatitis C virus (sofosbuvir).
- Interferon alpha and beta.
- Solvents (trichloroethylene).
- Miscellaneous (diazoxide, leflunomide, phenylpropanolamine, Saint John's Wort).
- 1.4 Pulmonary Arterial Hypertension associated with:
- 1.4.1 Connective tissue disease:
- ~75% of patients in this category have scleroderma.
- Other causes include lupus and mixed connective tissue disease; rarely dermatomyositis and Sjogren syndrome). (37775164)
- 1.4.2 HIV.
- 1.4.3 Portal hypertension.
- 1.4.4 Congenital heart disease (especially right-to-left shunt, such as atrial septal defect).
- 1.4.5 Schistosomiasis.
- 1.4.1 Connective tissue disease:
- 1.5 PVOD/PCH (Pulmonary veno-occlusive disease / pulmonary capillary hemangiomatosis). 📖
- 1.6 Persistent PH of the newborn.
Group 2: PH associated with left heart disease 🫀🫀
- 2.1 Heart failure:
- 2.1.1 With preserved ejection fraction. (36017548)
- 2.1.2 With reduced (<40) or mildly reduced (41-49) ejection fraction.
- 2.2 Valvular heart disease.
- 2.3 Congenital/acquired cardiovascular conditions leading to post-capillary PH
Group 3: PH associated with lung disease and/or hypoxemia 🫁🫁🫁
- 3.1 COPD.
- 3.2 Restrictive lung disease.
- 3.3 Lung disease with mixed restrictive/obstructive pattern.
- 3.4 Hypoventilation syndromes (e.g., obesity hypoventilation syndrome).
- 3.5 Hypoxia without lung disease (e.g., high altitude).
- 3.6 Developmental lung disorders (e.g., kyphosis).
Group 4: Pulmonary artery obstruction
- 4.1 Chronic thromboembolic pulmonary artery hypertension (CTEPH).
- 4.2 Other pulmonary artery obstructions:
- Malignant obstruction: Angiosarcomas, other malignant tumors (e.g., renal carcinoma, uterine carcinoma, germ-cell tumors of the testis).
- Arteritis without connective tissue disease.
- Congenital pulmonary arterial stenoses.
- Hydatidosis.
- Foreign-body embolism.
Group 5: Unclear and/or multifactorial mechanisms
- 5.1 Hematologic disorders:
- Myeloproliferative disorders (e.g., chronic myelogenous leukemia, polycythemia vera, idiopathic myelofibrosis).
- Status post splenectomy.
- Sickle cell anemia.
- 5.2 Systemic disorders:
- Sarcoidosis. 📖
- Pulmonary Langerhans cell histiocytosis.
- Neurofibromatosis type 1.
- 5.3 Metabolic disorders:
- Glycogen storage diseases.
- Gaucher disease.
- 5.4 Chronic renal failure with or without hemodialysis.
- 5.5 Pulmonary tumor thrombotic microangiopathy.
- 5.6 Fibrosing mediastinitis.
family history
- ? Connective tissue disease.
- ? Pulmonary hypertension.
- ? Clotting disorder.
review of systems
- ? Rheumatologic symptoms (Raynaud phenomenon, arthritis/arthralgia, skin changes).
- ? Symptoms of obesity hypoventilation (snoring, daytime somnolence, morning headache).
past medical history
- ? History of venous thromboembolic disease.
- ? History of heart murmur or cardiac disease.
- ? Liver disease, alcohol intake.
- ? Exposure to chemotherapy.
- ? Splenectomy.
medications/exposures – review the list above 📖
laboratory tests
- Complete blood count & differential cell count (? myeloproliferative disease or evidence of splenectomy).
- Liver function tests (noting, however, that congestive hepatopathy due to pulmonary hypertension can cause some abnormalities).
- ANA (antinuclear antibody) for all patients. If connective tissue disease is suspected, then additional tests may also be obtained:
- If connective tissue disease suspected, also consider anticentromere antibody, anti-SCL70, anti-RNP, and anti-Ro.
- [[If scleroderma is suspected, test for anticentromere, anti-topoisomerase, anti-RNA polymerase III, and U1-RNP antibodies. (Murray 2022)]]
- HIV screen.
- TSH (thyroid stimulating hormone).
- ABG/VBG to exclude hypercapnia.
imaging studies
- Complete echocardiogram.
- Thoracic CT scan.
- Ventilation-perfusion scan (VQ scan):
- Should be obtained in any patient without an evident cause of pulmonary hypertension, to exclude chronic thromboembolic pulmonary hypertension (CTEPH).
- (More on the use of VQ scan to evaluate for CTEPH here: 📖)
other studies to consider
- PFTs (pulmonary function tests).
- Overnight oximetry or sleep study, to evaluate for obesity hypoventilation syndrome.
- Abdominal ultrasound should be performed to screen for portal hypertension.
supplemental oxygen
- Provide oxygen to achieve saturation >92%, if possible.
- Oxygen functions as a pulmonary vasodilator, so ideally hypoxemia should be avoided.
- Ambulatory oxygen may be considered when there is evidence of symptomatic benefit and correctable desaturation with exercise. (36017548)
- Some patients with right-to-left shunts (Eisenmenger syndrome) won't respond to supplemental oxygen, so oxygen supplementation may be futile in such patients.
diuretics
- Patients with PH tend to retain volume and become volume overloaded. Avoiding fluid retention is one of the key objectives in managing patients with PH. (36017548)
- Diuretic resistance may result from poor renal perfusion, renal venous congestion, and intense neurohormonal activation. Combination therapy may be needed, including loop diuretics, thiazides, and mineralocorticoid receptor antagonists.
medications to avoid
- Alpha-agonists increase pulmonary vascular resistance:
- Nasal decongestants.
- Vasodilators may reduce RV filling:
- Nitrates, ACE inhibitors, ARBs (angiotensin receptor blockers).
- Negative inotropes may impair RV contraction:
- Beta-blockers.
lung transplantation
- Lung transplantation may be a consideration for pulmonary arterial hypertension that fails to respond to therapy.
- Indications to refer for transplantation evaluation are listed here: 📖
(anticoagulation)
- Some registry data has suggested improved outcomes among patients with idiopathic pulmonary arterial hypertension (IPAH) who were anticoagulated. However, data is contradictory and of low quality (with anticoagulation carrying obvious risks).
- Currently guidelines make no recommendations regarding anticoagulation for pulmonary hypertension. (36017548)
when to perform vasoreactivity testing
- Vasoreactivity testing is performed only in patients with the following types of PH: (37026538)
- 1.1 (idiopathic pulmonary arterial hypertension).
- 1.2 (hereditary pulmonary arterial hypertension).
- 1.3 (drug-induced pulmonary arterial hypertension).
- Only patients in these groups may have a durable clinical response to calcium channel blockers. Consequently, these patients are the only ones where vasoreactivity testing would change clinical management. (Murray 2022)
contraindications to vasoreactivity testing
- Overt right ventricular failure (such patients aren't candidates for calcium channel blocker therapy).
- Vasoreactivity testing for identifying candidates for calcium channel blocker therapy is not recommended in patients known to have pulmonary arterial hypertension of other types (1.4-1.6), or PH groups 2-5. (Class III recommendation, 36017548)
how to perform vasoreactivity testing
- May use short-acting IV epoprostenol sodium or inhaled nitric oxide.
- Nitric oxide is the preferred pulmonary vasodilator (e.g., 20 ppm for 5-10 minutes). Inhaled nitric oxide is easier to use than IV epoprostenol, because nitric oxide titration may be performed more rapidly.
three criteria required to define a positive vasodilator response:
- mPAP falls by >10 mm.
- mPAP reaches a value <40 mm.
- Cardiac output is stable or increases. (36017548)
implications of positive vasoreactivity
- This is a favorable prognostic sign.
- Patients can be treated with calcium channel blockers.
indications for oral calcium channel blockers (CCBs)
- Calcium channel blockers are only for patients with idiopathic PAH, hereditary PAH, or drug/toxin-associated PAH -AND- who respond favorably to a vasodilator challenge.
- In other forms of PAH, even a favorable vasodilator challenge doesn't predict a durable, long-term response to calcium channel blockers. (36017548)
- In practice, very few patients may be treated with calcium channel blockers.
- At baseline, only 12% of patients have vasoreactivity. (37026538)
- Among patients with vasodilator responsiveness, only about half will obtain long-term benefit from calcium channel blockers (the other half of patients will lose responsiveness over time).
- At follow-up, a satisfactory response is defined by WHO functional class I or II and marked hemodynamic improvement (ideally mPAP <30 mm and PVR <4 Wood units). (36017548)
- ⚠️ If calcium channel blocker therapy doesn't improve the patient to NYHA functional class I or II, then additional therapy should be utilized.
- ⚠️ Long-term response to CCB therapy is uncommon, so patients need to be monitored for disease progression. (23809320)
adverse effects of calcium channel blockers
- Hypotension is common.
- Peripheral edema.
- Hypoxemia due to impaired ventilation-perfusion matching.
- Right ventricular failure (if diltiazem is utilized).
preferred agents & dose
- Agents: Amlodipine, felodipine, or nifedipine may be the best agents (since these provide vasodilation, without negative inotropic effects).
- Doses:
- Amlodipine: Start 5 mg daily, target dose 15-30 mg daily.
- Nifedipine: Start at 10 mg TID (or nifedipine XR 30 mg/daily), target dose 20-60 mg BID-TID (or nifedipine XR 120-240 mg daily).
- Felodipine: Start 5 mg daily, target dose 15-30 mg daily.
Endothelin-1 is a vasoconstrictor and smooth muscle mitogen that increases pulmonary vascular resistance. Similar effects seem to result from either selective inhibition of endothelin A, or nonselective inhibition of both endothelin A and B.
bosentan (nonselective endothelin A & B antagonist)
- Indications:
- Studied in patients with idiopathic PAH and connective tissue-associated PAH who were functional class III-IV.
- Improves exercise capacity, functional class, hemodynamics, and time to clinical worsening. (36017548)
- Cautions:
- Black box warning due to hepatotoxicity. Liver function tests should be followed closely, with discontinuation if AST/ALT >3 times upper limit normal with symptoms or elevated bilirubin. Roughly 10% of patients need to discontinue bosentan due to abnormal liver tests. (36017548)
- Avoid abrupt withdrawal.
- Can cause anemia (it usually decreases hemoglobin by about 1 g/dL). (Murray 2022)
- Metabolized by the CYP system (inducer and substrate of CYP 2C9 and 3A4). Interactions include reducing serum levels of sildenafil and tadalafil – which impairs the ability to combine bosentan with phosphodiesterase-5 inhibitors. (36017548)
- Teratogenic, cannot be used in pregnancy (class effect).
- Dose:
- Starting dose 62.5 mg BID.
- Target dose: 125 mg BID.
ambresartan (selective inhibitor of endothelin A)
- Indications:
- Cautions:
- Doesn't appear to be hepatotoxic.
- Can cause anemia.
- Teratogenic, cannot be used in pregnancy (class effect).
- Dose:
- Initial dose 5 mg daily.
- Target dose 10 mg daily.
macitentan (dual endothelin receptor antagonist)
- Indications:
- Shown to improve exercise capacity and reduce clinical worsening in pulmonary arterial hypertension. (36017548)
- Cautions/toxicity:
- Dose:
- Initial dose 10 mg daily, this is also the target dose.
basics
- Both phosphodiesterase-5 inhibitors (sildenafil, tadalafil) and guanylate cyclase stimulators (riociguat) act on the same molecular pathway, to cause vasodilation of the pulmonary vasculature. Phosphodiesterase-5 inhibitors enhance the activity of endogenous nitric oxide, whereas guanylate cyclase stimulators may directly cause pulmonary vasodilation in the absence of nitric oxide (allowing guanylate cyclase stimulators to be independently effective, regardless of prevailing nitric oxide levels).
- Phosphodiesterase-5 inhibitors and guanylate cyclase stimulators (riociguat) cannot be combined (since this may cause systemic hypotension). (36017548)
indications & side effects
- Sildenafil:
- Shown to improve exercise capacity, symptoms, and hemodynamics in patients with pulmonary arterial hypertension. (36017548)
- Side effects are generally mild/moderate (e.g., headache, flushing, and epistaxis).
- Tadalafil:
- Seems to be similar to sildenafil, but longer half-life may provide more sustained action.
- One RCT of patients with pulmonary arterial hypertension demonstrated improvements in exercise capacity, hemodynamics, symptoms, and time to clinical worsening. (19470885)
- Riociguat:
- An RCT of patients with pulmonary arterial hypertension demonstrated improvements in exercise capacity, hemodynamics, functional classification, and time to clinical worsening. (23883378)
- The REPLACE trial demonstrated that patients on phosphodiesterase-5 inhibitor therapy (mostly sildenafil) improved when switched to riociguat at 2.5 mg TID. (33773120)
- Side-effect profile is similar to that of phosphodiesterase-5 inhibitors.
contraindications/risks
- Impaired ventilation/perfusion matching may impair oxygenation.
- Avoid co-administration with nitrates (may cause severe hypotension).
- Riociguat is teratogenic.
dose & pharmacology
- Sildenafil:
- Initial dose and target dose are 20 mg TID. (However, higher doses were found to be more effective in the SUPER-1 trial. Such doses may occasionally be utilized in practice.)(16291984)
- Half-life is ~3-4 hours.
- Tadalafil:
- Starting dose is 20-40 mg daily, target dose is 40 mg daily.
- Half-life in pulmonary hypertension is ~35 hours.
- Riociguat:
- Starting dose is 1 mg TID, target dose is 2.5 mg TID.
- Half-life is 7 hours, but may be prolonged to 12 hours in patients with pulmonary artery hypertension.
basics – mechanism
- Epoprostenol and treprostinil are prostacyclin analogues, whereas selexipag is an orally available prostacyclin receptor agonist (which is chemically distinct from prostacyclin).
- All agents have the same mechanisms of action:
- Pulmonary vasodilation.
- May reduce pulmonary vascular remodeling due to antiplatelet aggregation effects.
indications
- IV epoprostenol (aka prostaglandin I2, prostacyclin):
- IV epoprostenol is generally considered to be the most powerful agent for PAH. It has been shown to improve hemodynamics, functional capacity, and survival (among patients with pulmonary arterial hypertension). (8532025)
- IV epoprostenol is often the preferred option for the highest risk patients.
- Treprostinil (either continuous IV or SC administration).
- Improves hemodynamic parameters, symptoms and exercise capacity in Group I PAH.
dosing
dosing of IV epoprostenol for chronic PH
- IV epoprostenol is commonly started in the hospital at a dose of 2 ng/kg/min with adjustment based on symptoms of PAH and side effects.
- May titrate hourly as tolerated to a target dose of ~12-20 ng/kg/min.
- The typical dose range after one year of therapy is 16-30 ng/kg/min, with wide individual variability. (36017548)
- Half-life is 3-5 minutes, so systemic levels will change almost immediately in response to dose adjustments. Metabolism occurs rapidly in the blood.
- Induced metabolism requires a continuous increase in dose to maintain symptom control. (Fishman 2023)
dosing of IV epoprostenol for acute right heart failure in the ICU
- IV epoprostenol may rarely be utilized for management of acute right heart failure in the ICU, for example:
- Acute-on-chronic deterioration in a patient with known Type 1 PH.
- Amniotic fluid embolism with refractory RV failure (if ECMO is unavailable). (33417901)
- ⚠️ This should generally be regarded as a last-line therapy, which ideally should be avoided. Specifically, either one or a combination of inhaled epoprostenol plus inhaled nitric oxide is generally safer and preferable.
- Side-effects of primary concern include:
- Systemic hypotension.
- Hypoxemia due to impaired ventilation-perfusion matching.
- Nausea and vomiting.
- Thrombocytopenia and impaired platelet function.
- Patients should be monitored with continuous pulse oximetry as well as an arterial catheter.
- Hypotension may occur due to the effect of epoprostenol on systemic vascular resistance. If there are no other treatment options, this may be alleviated with the use of a vasopressin infusion to increase the systemic vascular resistance.
- Hypoxemia may be dose-limiting if it is treatment refractory. (Note that patients would typically already be on an aggressive regimen of inhaled pulmonary vasodilators prior to initiation of intravenous epoprostenol.)
- Start at 2 ng/kg/min. The dose may be up-titrated by 2 ng/kg/min every 15 minutes until the patient stabilizes, or side-effects occur. (19332472)
- IV epoprostenol is preferable to treprostinil in this situation, because the short half-life of epoprostenol allows for more prompt titration. If epoprostenol causes destabilization, it may be discontinued with subsequent drug clearance within minutes.
dosing of treprostinil (SC or IV)
- Start at 1.25 ng/kg/min.
- Dose is determined by tolerability and effectiveness.
- Typical dose range at one year is 25-60 ng/kg/min, with wide individual variability. (36017548)
- Half-life is ~4 hours, so titration will take much longer to reach steady state (as compared to epoprostenol). Metabolism occurs in the liver, predominantly by CYP2C8.
side effects & risks of epoprostenol/treprostinil
- Hypoxemia may result from diffuse pulmonary vasodilation, which impairs ventilation-perfusion (V/Q) matching. (32654737)
- Hypotension.
- Thrombocytopenia and reduced platelet function.
- Side effects related to chronic infusion:
- Catheter-related sepsis.
- Deep vein thrombosis.
- Pump dysfunction or kinking may lead to abrupt discontinuation (which may cause hemodynamic decompensation).
- Numerous side effects can occur that are dose-dependent (and often respond to cautious reduction in dose):
- Headache, jaw pain, musculoskeletal aches and pains (mostly in the legs and feet).
- Flushing.
- Diarrhea, nausea, vomiting.
- Blotchy erythematous rash.
- Overdose:
- Acute overdose may cause systemic hypotension.
- Chronic overdose may cause development of a hyperdynamic state with high-output heart failure.
basics
- Selexipag is an oral prostacyclin receptor agonist.
evidence
- When given alone or combined with an endothelin receptor antagonist and/or phosphodiesterase-5 inhibitor, selexipag reduced the risk of composite morbidity or mortality events in one Phase III RCT by 40%. (GRIPHON trial, 26699168) Most subjects in this trial were already on background medication (including 15% with an endothelin-receptor agonist, 32% with a phosphodiesterase-5 inhibitor, and 33% on both an endothelin-receptor agonist and a phosphodiesterase-5 inhibitor).
- Unfortunately, the addition of selexipag failed to cause any improvement when given on top of dual therapy with macitentan plus tadalafil. (TRITON trial, 34593120)
side effects & risks
- The most common side effects are headache, diarrhea, nausea, and jaw pain (similar to those of prostacyclin analogs).
dosing
- Dose is initially 200 ug BID, with gradual up-titration as high as can be tolerated (up to 1600 ug BID).
PAH which is idiopathic, hereditary, drug/toxin-associated, or associated with connective tissue disease
PAH which is idiopathic, hereditary, drug/toxin-associated, or associated with connective tissue disease
The initial approach to patients depends on risk stratification. Patients can be divided into three groups:
Very occasional patients in groups 1.1-1.3 (idiopathic, inheritable, or drug-associated pulmonary arterial hypertension) have a positive response to vasodilation therapy during PA catheterization. Such patients may be treated with oral calcium channel blockers as described above: 📖
Most patients will not be candidates for calcium channel blocker therapy. Such patients are managed using the algorithm shown below.
additional considerations based on the specifics of PAH
PAH with cardiopulmonary comorbidities
- PAH is increasingly being diagnosed among older patients with medical comorbidities, which can make it challenging to differentiate between type-2 and type-3 PH. For example: (36017548)
- Left heart phenotype: Elderly patients with clinical features suggestive of Group 2 PH (such features are discussed further here: ⚡️).
- Cardiopulmonary phenotype: Elderly, mostly male patients with hypoxemia, smoking history, and risk factors for left heart disease.
- Older patients with comorbidities are less likely to benefit from pulmonary vasodilator medications. Such patients are often excluded from trials of pulmonary vasodilators, rendering management challenging.
- Monotherapy with an oral phosphodiesterase-5 inhibitor or endothelin receptor antagonist should be considered. However, among patients with comorbidities, these agents may have increased risks of precipitating left heart failure or exacerbating hypoxemia (due to impaired ventilation/perfusion matching).
PAH associated with drugs and toxins
- In patients with a low-risk profile, the initial management may be to discontinue the causative agent and follow for 3-4 months. In patients with intermediate or high-risk profile, treatment for pulmonary arterial hypertension should start immediately.
- Some patients may improve over time, allowing for de-escalation of therapy.
PAH associated with connective tissue disease
- Patients with connective tissue disease may have pulmonary hypertension for a variety of reasons:
- Pulmonary arterial hypertension.
- Left heart dysfunction.
- Interstitial lung disease.
- Pulmonary emboli.
- Thus, every patient must be evaluated to determine the components of their pulmonary hypertension.
- Treatment depends on a judgement regarding which etiology(ies) are contributing predominantly to the pulmonary hypertension. (34366049) For example:
- If the interstitial lung disease is severe and felt to the cause of pulmonary hypertension, then treatment may resemble that of Group 3 PH. 📖
- If the interstitial lung disease is mild in comparison to the pulmonary hypertension and no other etiology of pulmonary hypertension is discovered, this implies predominantly Group 1 PH. Such patients may benefit from PAH-specific treatment (as discussed in the section above).
basics
- HIV may cause a form of Group I pulmonary artery hypertension (PAH) that is pathologically indistinguishable from idiopathic PAH.
- Clinical features are similar to non-HIV idiopathic PAH.
- Among patients with PAH and HIV, PAH is a common cause of death (this isn't merely an incidental finding).
epidemiology
- The annual incidence PAH in HIV might be ~0.25-0.5%. Echocardiographic data suggest that the prevalence could be on the order of 5-10%. (Murray 2022)
- There is no correlation between the severity of PAH and the stage of HIV, or the level of immunodeficiency. (36017548)
differential diagnosis includes
- Sympathomimetic use (especially methamphetamine).
management
- Antiretroviral therapy will reduce HIV replication and immune dysregulation, which may delay progression. Additionally, antiretroviral therapy may actually have a beneficial effect on hemodynamics.
- Treatment is generally similar to that of idiopathic PAH. However, there may be increased risks of drug interactions (e.g., with antiretroviral medications). Consequently, initial monotherapy is generally recommended, with individualized escalation to combination therapy if patients don't respond adequately. (36017548)
basics
- Portopulmonary hypertension seems to occur due to impaired hepatic metabolism of vasoconstrictive agents (e.g., thromboxanes, serotonin, bradykinin, and neuropeptide Y).
- Pulmonary arterial lesions in portopulmonary hypertension are histologically indistinguishable from those seen in idiopathic pulmonary arterial hypertension. (30526986)
epidemiology: causes of pulmonary hypertension
- [1] Cirrhosis:
- PH occurs in ~2% of patients with cirrhosis.
- PH is detected in ~5% of patients undergoing liver transplantation evaluation. (Murray 2022)
- PH is usually diagnosed ~4-7 years after the diagnosis of portal hypertension.
- Portopulmonary hypertension doesn't correlate with the severity of the liver disease. (Murray 2022)
- [2] Portosystemic shunt of other etiologies: Portopulmonary hypertension may rarely develop in the absence of any liver disease (e.g., congenital extrahepatic cavoportal shunts). (36017548)
symptoms
- Initially, symptoms are often related to portal hypertension.
- Eventually, symptoms may relate increasingly to pulmonary hypertension:
- Exertional dyspnea.
- Syncope, chest pain.
- Features of right heart failure may be difficult to distinguish from features of cirrhosis (e.g., edema, abdominal distension). (Murray 2022)
definition of portopulmonary hypertension & evaluation
- Portopulmonary hypertension is defined as pre-capillary pulmonary hypertension in patients with portal hypertension or a portosystemic shunt, in the absence of alternative explanations (i.e., sPAP >20 mm, PVR >2 Wood units, and PA wedge pressure <15 mm).
- Patients with cirrhosis tend to have chronically elevated cardiac output. This may cause confusion with two entities that mimic portopulmonary hypertension:
- (1) Elevated cardiac output may increase the tricuspid regurgitant jet velocity, which may lead to overestimation of pulmonary artery pressures on echocardiography. PA catheterization may demonstrate that the sPAP is not actually elevated – so there isn't any pulmonary hypertension at all.
- (2) Many patients with cirrhosis do have truly elevated sPAP >20 mm. However, this elevation is due to increased cardiac output, rather than an elevation of their PVR (pulmonary vascular resistance). Such patients do not have portopulmonary hypertension, but instead they are regarded as having “unclassified PH.” Management involves follow-up, but not treatment with medications for pulmonary arterial hypertension.
management of portopulmonary hypertension
- In patients with portopulmonary hypertension and mild liver disease, pulmonary hypertension may be a major cause of death.
- The pathophysiology of portopulmonary hypertension is generally similar to idiopathic pulmonary artery hypertension (iPAH). However, patients with cirrhosis were excluded from many studies on PAH. Treatment in cirrhosis may be a bit different, due to other hemodynamic perturbations caused by cirrhosis.
- Initial monotherapy should be considered more often, followed by combination therapy if necessary. (31178422)
- An RCT dedicated to portopulmonary hypertension involved macitentan, which demonstrated improvement in pulmonary vascular resistance but no differences in functional class, 6-minute walk distance, or NT-BNP levels. (PORTICO trial 31178422) A single-arm observational study likewise found benefit from ambrisartan. (32008947)
- Uncontrolled series have consistently found that prostacyclin infusions improve hemodynamics among patients with portopulmonary hypertension. This is probably the most powerful approach to optimize patients and bridge them to liver transplantation (discussed further below). (Fishman 2023)
- Diuretics are especially important, because both portopulmonary hypertension and cirrhosis may promote sodium retention. (Fishman 2023)
- ⚠️ Calcium channel blockers should be avoided, because they can worsen splanchnic vasodilation. (27326810)
- ⚠️ Beta-blockers are often used in cirrhosis, but beta-blockers should be avoided as these can worsen cardiac output. (27326810)
- ⚠️ TIPS placement is contraindicated in severe pulmonary hypertension. TIPS may reduce liver perfusion, causing reduced metabolism of endogenous pulmonary vasoconstrictors (e.g., endothelin).
portopulmonary hypertension & liver transplantation
- The response of pulmonary hypertension to liver transplantation is variable. Pulmonary hypertension may gradually improve following transplantation, but severe pulmonary hypertension can be progressive.
- Uncontrolled pulmonary hypertension is a contraindication to liver transplantation. In a historic series from the Mayo Clinic: (10915166)
- mPAP >50 mm correlated with 100% perioperative mortality.
- mPAP 35-50 mm with PVR >3 Wood unit correlated with 50% perioperative mortality.
- Current guidelines suggest that in order to undergo liver transplantation, at least one of the following criteria should be met: (36017548, 27326810)
- (#1) mPAP <35 mm with PVR <5 Wood units.
- (#2) mPAP 35-45 mm with PVR <3 Wood units.
- ⚠️ mPAP >45 mm is regarded as an absolute contraindication to liver transplantation.
- If pulmonary hypertension precludes a liver transplantation, medical therapy should be utilized to control pulmonary hypertension. If hemodynamics respond well to therapy, then transplantation may be reconsidered.
clinical classification of pulmonary arterial hypertension associated with congenital heart disease
- (1) Eisenmenger syndrome:
- Eisenmenger syndrome includes all patients with systemic-to-pulmonary shunts that progress to severely elevated PVR and undergo subsequent reversal of the shunt (or bidirectional shunting). Eisenmenger syndrome is an ominous sign overall, but it implies that the right ventricle has preserved systolic function (as required to generate the pressure required to shunt blood towards the left side of the heart).
- Clinical manifestations may include:
- Cyanosis, hypoxemia.
- Secondary erythrocytosis.
- Hemoptysis.
- Coagulation abnormalities, including thrombocytopenia.
- Brain abscess, ischemic stroke.
- (2) PAH associated with systemic-to-pulmonary shunts:
- PVR is mild-moderately increased, and systemic-to-pulmonary shunting is still prevalent.
- Eisenmenger syndrome has not occurred (there is no reversal of the shunt), so there is not cyanosis at rest.
- Some patients may be eligible for shunt correction.
- (3) PAH with small/coincidental defects:
- Markedly elevated PVR in the presence of cardiac defects considered to be nonsignificant (usually ventricular septal defect <1 cm or atrial septal defects <2 cm).
- Clinical picture and therapy may be similar to that of idiopathic pulmonary arterial hypertension.
- Closure of shunts is contraindicated.
- (4) PAH after defect correction:
- Congenital heart disease is repaired, but PAH either persists or recurs.
diagnosis and evaluation
- PA catheterization with compartmental oximetry is required to calculate the ratio of blood flow through the pulmonary circulation in comparison to the systemic circulation (Qp/Qs).
- Thermodilution should be avoided in the presence of intracardiac shunts.
management
- Shunt closure may be considered in patients with lower pulmonary pressures (e.g., PVR <3-5 Wood units). However, once significant pulmonary arterial hypertension has developed, it's generally too late to close the defect. Precise indications for closure are beyond the scope of this chapter.
- There should be a low threshold to consider infection, since these patients are at increased risk of endocarditis and brain abscess.
- Supplemental oxygen should be utilized in patients where it causes significant improvement. However, patients with shunt physiology may not respond to supplemental oxygen.
- In Eisenmenger syndrome, medications for pulmonary arterial hypertension are generally similar to those for other forms of pulmonary arterial hypertension, although less evidence is available.
- Endothelin receptor antagonist bosentan has been shown to improve exercise capacity in patients with Eisenmenger syndrome. (16801459) It's conceivable that endothelin receptor antagonists could constitute a preferred oral therapy for these patients.
- In patients with pulmonary-to-systemic shunting, placement of an indwelling line for epoprostenol infusion may create a risk of cerebral embolic events. Consequently, there may be some advantages to subcutaneous treprostinil.
- (Closing the shunt is contraindicated, since this would precipitate volume overload of the right ventricle).
- For patients with prevalent systemic-to-pulmonary shunting (prior to the development of Eisenmenger syndrome), the benefit of PAH therapies is less well established. (36017548) Reduction of the pulmonary vascular resistance could increase the shunt fraction.
basics
- Historically, pulmonary vaso-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) were considered as separate entities. However, clinically they are largely identical (e.g., sharing the same genetic substrate and clinical presentations). Consequently, it is useful to consider them as a single entity (PVOD/PCH).
- Pulmonary capillary hemangiomatosis may represent a secondary phenomenon that results from capillary congestion, as a result of pulmonary veno-occlusive disease.
- PVOD/PCH involves:
- Obstruction of post-capillary venules with fibrous tissue that may cause complete occlusion (PVOD).
- Capillary dilation and proliferation (PCH).
- When to consider PVOD/PCH:
- 💡 CT scan reveals features of cardiogenic pulmonary edema, but there is no left ventricular dysfunction.
- 💡 Patient with PAH develops cardiogenic pulmonary edema after initiation of pulmonary vasodilators.
epidemiology
general epidemiology
- PVOD/PCH is ~1/10th as common as idiopathic PAH, so it is quite rare.
- PVOD/PCH may occur in siblings (due to recessive genetics involving the EIF2AK4 gene).
- Inheritable cases tend to present earlier (~25 years old), whereas acquired cases often present later (~60 years old). (34295399)
most cases are idiopathic, but PVOD/PCH may be associated with:
- Hematopoietic stem cell transplantation:
- PVOD/PCH may tend to present ~3-4 months following transplantation. (Murray 2022)
- The incidence seems to be rare, largely limited to case reports. (Fishman 2023) However, the diagnosis may be under-recognized, since evidence of PVOD/PCH is found in ~1/3 of autopsies performed >1 year after transplantation. (Murray 2022)
- Alkylating agents, including cyclophosphamide, mitomycin C, bleomycin, busulfan, gemcitabine, and carmustine (BCNU).
- Scleroderma 📖 (and perhaps also lupus).
- HIV.
- Organic solvents (e.g., trichloroethylene).
clinical presentation
- Dyspnea is the most common symptom.
- Compared to other forms of pulmonary hypertension, the following features may be more common (possibly related to fragile capillary walls):
- If PVOD/PCH isn't recognized initially, ~50% of patients may develop cardiogenic pulmonary edema after initiation of a pulmonary vasodilator.
radiology
radiologic features suggestive of PVOD/PCH:
- (1) Radiographic features of a left heart failure mimic: 📖
- (a) Features of heart failure:
- Interlobular septal thickening.
- Pleural effusions.
- Ground-glass opacification (may be diffuse, mosaic, or patchy).
- (b) Normal left atrial size.
- (a) Features of heart failure:
- (2) Centrilobular ground-glass micronodules (although these may also be seen in idiopathic pulmonary arterial hypertension).
- (3) Mediastinal lymphadenopathy may be caused by vascular congestion. (36017548)
differential diagnosis of PH plus centrilobular nodules:
- PVOD/PCH (as discussed above).
- Pulmonary tumor emboli. 📖
- Intravenous talcosis 📖 (aka excipient lung disease).
- Nodules may be better defined than in PVOD/PCH.
- There is an absence of associated interlobular septal thickening or pleural effusion.
VQ scan
- VQ scan may be normal.
- VQ scan may reveal multiple small areas of hypoperfusion. These shouldn't be misinterpreted as evidence of CTEPH (chronic thromboembolic pulmonary hypertension).
PA catheterization
- PVOD/PCH causes precapillary pulmonary hypertension (mPAP >20 mm, PAWP <15 mm, PVR <2 Wood units).
- This may tend to mimic idiopathic pulmonary arterial hypertension (iPAH).
- Vasodilator testing may induce cardiogenic pulmonary edema. If PVOD/PCH is suspected, this is contraindicated. (34295399)
confirmation of the diagnosis
- Genetic studies revealing biallelic EIF2AK4 mutations confirms the diagnosis of inheritable PVOD/PCH.
- Lung biopsy is high-risk and not generally recommended. (36017548)
management
- General supportive measures for pulmonary hypertension may be utilized.
- Treatments for PAH are often ineffective and may cause deterioration (by precipitating pulmonary edema). Nonetheless, some experts may favor a very cautious trial of vasodilator therapy as a bridge to lung transplantation. (34022029)
- Lung transplantation is the only definitive treatment. Any patients who are potentially transplant candidates should be referred urgently. (34022029) The disease course of PVOD/PCH is generally more aggressive than idiopathic pulmonary arterial hypertension, with a one-year mortality of ~70%. (34743853)
epidemiology
- Group 2 PH is the most common form of PH (accounting for ~75% of cases).
clinical features that suggest PH is due to left heart disease
- Risk factors for left heart disease:
- Age >60-70 years old.
- Obesity.
- Hypertension.
- Dyslipidemia.
- Glucose intolerance / diabetes mellitus.
- Known history of left heart disease, including:
- Atrial fibrillation.
- Coronary artery disease.
- Prior cardiac intervention.
- EKG abnormalities, including:
- LAD (left axis deviation).
- LVH (left ventricular hypertrophy).
- LBBB (left bundle branch block).
- CT scan findings:
- Echocardiography findings:
hemodynamic forms of group 2 PH
- (#1) Isolated post-capillary PH:
- Hemodynamics:
- mPAP >20 mm.
- PA wedge pressure (PAWP) >15 mm.
- PVR (pulmonary vascular resistance) <2-3 Wood units.
- Summary of hemodynamics:
- ⬆mPAP = ⬆PAWP + (CO)(PVR)
- This occurs initially in the course of left heart failure. It is the most common form of PH due to left heart disease.
- PH is simply due to passive congestion.
- Hemodynamics:
- (#2) Combined pre- and post-capillary PH:
- Hemodynamics:
- mPAP >20 mm.
- PA wedge pressure (PAWP) >15 mm.
- PVR (pulmonary vascular resistance) >2-3 Wood units.
- Summary of hemodynamics:
- ⬆mPAP = ⬆PAWP + (CO)(⬆PVR)
- This represents disease progression from isolated post-capillary PH (due to pulmonary vascular remodeling).
- Hemodynamics:
- (Further discussion of hemodynamic profiles in PH above: 📖)
evaluation of pulmonary hypertension
- In the presence of predominant left heart disease and mild pulmonary hypertension, further evaluation may be unnecessary.
- Otherwise, a full evaluation should be undertaken – especially if right ventricular dysfunction seems disproportionately severe in comparison to the degree of left heart disease.
- Evaluation may help exclude additional causes of PH (e.g., chronic thromboembolic pulmonary hypertension). (36017548)
management
- The cornerstone is treatment of the left ventricular failure:
- Medication therapy for PAH is contraindicated, because pulmonary vasodilation may increase the venous return to the left heart and thereby worsen cardiogenic pulmonary edema:
- Prostacyclins are contraindicated (increased mortality in the FIRST trial). (9266782)
- Endothelin antagonists contraindicated. For example, bosentan increased heart failure exacerbations in the ENABLE trial. Even among patients with combined pre- and post-capillary pulmonary hypertension, macitentan worsened fluid retention and functional class in the MELODY-1 trial. (29437943)
basics
- Group 3 includes PH caused by the following:
- 3.1 COPD.
- 3.2 Restrictive lung disease.
- 3.3 Lung disease with mixed restrictive/obstructive pattern.
- 3.4 Hypoventilation syndromes (e.g., obesity hypoventilation syndrome).
- 3.5 Hypoxia without lung disease (e.g., high altitude).
- 3.6 Developmental lung disorders (e.g., kyphosis).
epidemiology
- Severe PH here is defined as PVR (pulmonary vascular resistance) >5 Wood units. (36017548)
- Severe PH occurs in ~1-5% of patients with COPD and <10% of patients with advanced ILD. (36017548)
diagnosis
- Exacerbations of lung disease may transiently increase pulmonary pressure, so evaluation should ideally be performed when patients are clinically stable.
- Initial evaluation includes echocardiography and contrast-enhanced CT scan.
- Indications for PA catheterization include:
- Assessment for lung transplantation.
- Suspicion of pulmonary artery hypertension (PAH) as the etiology of pulmonary hypertension (rather than underlying lung disease).
differential diagnosis
- Chronic pulmonary disease (e.g., COPD, IPF) often occurs in elderly patients with significant comorbidity. Age and comorbidity increase the rate of pulmonary hypertension due to left heart failure (Group 2 pulmonary hypertension).
- Connective tissue disorders cause a variety of etiologies of pulmonary hypertension, as discussed further above. 📖
- 💡 Even in patients with a seemingly obvious cause of PH, complete evaluation should be performed to evaluate for alternative etiologies (as explored above).
management
the cornerstone is treating the underlying lung disease
- Supportive care:
- Hypoxemia management: Supplemental oxygen sufficient to prevent hypoxemia may substantially improve pulmonary pressures.
- Hypercapnia management: Noninvasive ventilation may be beneficial for some patients (e.g., obesity hypoventilation syndrome).
- Disease-specific therapies should be optimized.
- Lung transplantation may be considered for selected patients.
inhaled prostacyclin analogues
- General concept:
- Since inhaled prostacyclins are distributed via inhalation to the best ventilated alveoli, they may improve ventilation-perfusion matching (V/Q matching), thereby improving oxygenation and ventilation. Inhaled prostacyclins may also simultaneously improve pulmonary pressures.
- Inhaled prostacyclins may be especially useful for patients with lung disease (e.g., Group III pulmonary hypertension), in whom systemic prostacyclins cause impaired ventilation-perfusion matching and thus worsened hypoxemia.
- Inhaled prostacyclins may also theoretically avoid systemic side effects.
- Evidence & role in therapy for Group III PH:
- Role of inhaled prostacyclins in other patients with PH?
- The TRIUMPH-1 trial demonstrated that inhaled treprostinil improved 6-minute walk distance and quality of life among patients on a background of therapy with either an endothelin-receptor antagonist or phosphodiesterase 5-inhibitor. (20430262)
- However, current treatment algorithms don't generally recommend the addition of inhaled prostacyclin analogues in this fashion.
other advanced therapies for PAH
- These should not be utilized, since generalized pulmonary vasodilation will impair ventilation/perfusion matching and thereby may exacerbate hypoxemia. This may cause deterioration among patients with substantial underlying hypoxemia and/or hypercapnia.
- For example, bosentan was demonstrated to worsen hypoxemia and quality of life among patients with COPD. (18448495) Riociguat appeared to increase mortality among patients with idiopathic interstitial pneumonia. (RISE-IIP study, 31416769)
basics
- Definitions:
- Chronic thromboembolic pulmonary disease (CTEPD): Patients with symptoms attributed to post-thromboembolic obstructions within the pulmonary arteries.
- Chronic thromboembolic pulmonary hypertension (CTEPH): A subset of patient with CTEPD who have pulmonary hypertension.
- CTEPH is the only form of PH that can potentially be cured without lung transplantation. Therefore, it is important to always consider the possibility of CTEPH whenever evaluating for the etiology of pulmonary hypertension.
- Elevated pulmonary pressures lead to further vascular remodeling and worsening of pulmonary pressures – thus forming a vicious spiral that leads to ongoing deterioration.
epidemiology
- CTEPH might occur in ~2% of patients with PE, but estimates vary widely.
- Conditions associated with CTEPH: (36017548)
- Permanent intravascular devices (pacemaker, long-term central lines, especially veno-arterial shunts).
- Recurrent venous thromboembolic disease.
- Splenectomy.
- Antiphospholipid syndrome.
- Inflammatory bowel disease.
- Essential thrombocythemia, polycythemia vera.
- Thyroid hormone replacement.
- Malignancy.
clinical presentation
- About half of CTEPH patients have no known history of pulmonary embolism.
- The most common symptoms are fatigue and dyspnea on exertion.
echocardiogram
- Pulmonary embolism with estimated systolic PA pressure >60 mm should raise suspicion of CTEPH (acute PE shouldn't cause this degree of pulmonary hypertension without precipitating cardiovascular collapse; this degree of pulmonary hypertension implies chronicity with right ventricular hypertrophy). (36017548)
CT scan findings
pulmonary arteries
- Most patients have multiple, bilateral arterial abnormalities. (Walker 2019)
- [1] Clot is more plaque-like, with a tendency to hug the arterial wall. Clot may have a crescent-shaped configuration that forms obtuse angles with the pulmonary arterial wall. (Shepard 2019)
- [2] Recanalization:
- (#1) Initially, a central “dot” of contrast may be surrounded by circumferential thrombus.
- (#2) Ongoing recanalization may cause the walls of the artery to appear irregularly thickened.
- [3] Intravascular web or flap (linear filling defect).
- [4] Stenosis: It is a sign of CTEPH if the vessel is contracted, causing it to be smaller than corresponding arteries in the contralateral lung. (Shepard 2019) Complete vessel occlusion may occur. Post-stenotic dilation may occur.
- [5] Calcification of the thrombus may occur.
mosaic perfusion
- Mosaic perfusion (although this may also be seen in ~10% of patients with pulmonary artery hypertension due to other etiologies).
- Areas of hypoattenuated lung are associated with reduced pulmonary artery size.
- Enlarged bronchial arteries (>1.5 mm in diameter).
other findings
- Peripheral lung opacities due to prior pulmonary infarction.
- Bronchial dilation may occur in areas with severely stenotic or occluded pulmonary arteries. (Shepard 2019)
- Bronchial arteries may be unusually prominent.
performance of CT scan for CTEPH
- Performance of CTA for CTEPH is limited. It is reported as sensitivity of 76% and specificity of 96%. (36017548) Distal disease may be missed by CT scan.
- However, performance may be superior with modern, multi-detector CT scanners.
VQ scan
- VQ scan is the test of choice for the diagnosis of CTEPH (sensitivity ~90-100%, specificity of 94-100%). VQ scan has a higher performance than CT angiography.
- However, VQ abnormalities in CTEPH may be less dramatic than those seen in acute PE (due to partial recanalization of pulmonary arteries). (Murray 2022)
- Differential diagnosis of an abnormal V/Q scan includes:
- IPAH (idiopathic pulmonary arterial hypertension) or PVOD/PCH (pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis) may cause multiple small, subsegmental perfusion defects.
- Extrinsic vascular compression due to lymphadenopathy, fibrosing mediastinitis, or tumor.
- Pulmonary vasculitis.
- Pulmonary artery sarcoma.
- Prior PE with residual thrombus, in the absence of pulmonary hypertension.
management
- Lifelong anticoagulation.
- A retrospective case series found an increased rate of recurrent thromboembolism rates among patients treated with DOACs. (31557382, 35305871)
- Evaluation for antiphospholipid syndrome should be performed at the time of CTEPH diagnosis. (36017548) Patients with antiphospholipid syndrome require anticoagulation with warfarin, rather than direct oral anticoagulants. (36813291)
- Surgical thromboendarterectomy may be curative. This is the treatment of choice, if possible. Consultation should be obtained with a CTEPH surgical center of excellence (e.g., University of California at San Diego). CTEPH surgery should ideally be performed at a high-volume center (>50 surgical procedures per year). (36017548)
- Medical therapy:
- Treatments for pulmonary arterial hypertension may be beneficial for patients who aren't candidates for surgery, or patients with persistent pulmonary hypertension despite surgery.
- Available studies support the use of riociguat, s.c. treprostinil, or macitentan. Riociguat may be the single preferred oral agent at this point in time. (36017548) Although off-label, severe PH can be treated with combination therapies (e.g., combination therapy involving a phosphodiesterase-5 inhibitor or riociguat, plus an endothelin receptor antagonist). The pathophysiology of arteriole changes in CTEPH is similar to idiopathic PAH, so a similar treatment regimen may make sense.
- Balloon pulmonary angioplasty is an interventional option, although long-term outcomes remain unclear.
- Lung transplant may be considered if emboli are too distal to remove surgically.
epidemiology
- PH may occur in ~10% of patients with stable sickle cell disease (using a cutoff of mPAP >25 mm). These patients seem to be roughly divided between pre-capillary and post-capillary pulmonary hypertension.
- Common risk factors for PH include:
- Increased age.
- History of renal or cardiovascular complications.
- Renal insufficiency.
- Hypertension.
- Severity of hemolytic anemia (e.g., lower hemoglobin, higher lactate dehydrogenase; higher bilirubin). Hemolysis seems to be mechanistically related to pulmonary hypertension. (Fishman 2023)
evaluation
screening echocardiography & NT-proBNP
- Adults with Sickle cell disease should be screened with echocardiography and measurement of NT-proBNP values.
- Screening should be done when patients are at steady state (not during a vaso-occlusive crisis).
right heart catheterization
- A general approach to PH on echocardiography is shown above (with further discussion here: 📖).
- Within the context of sickle cell disease, indications for right heart catheterization may include: (Fishman 2023)
- (1) Tricuspid regurgitation velocity >3 m/s.
- (2) Tricuspid regurgitation velocity >2.5 m/s plus NT-proBNP >16 pg/ml AND 6-minute walk distance <333 meters.
- Pulmonary artery catheterization may confirm or refute the diagnosis of pulmonary hypertension, as well as determine the type of pulmonary hypertension. 📖
evaluation for other etiologies of PH
- Patients found to have PH should undergo a complete evaluation for alternative causes of PH (discussed above: 📖).
- Patients often have multifactorial pulmonary hypertension:
- Pulmonary thromboemboli may be a significant contributor. Patients should be evaluated for chronic thromboembolic pulmonary hypertension (CTEPH).
- Diastolic heart failure is common.
treatment
basic supportive measures:
- Sickle cell-specific therapy should be maximized, e.g.:
- Hydroxyurea.
- Exchange transfusions.
- Chronic hypoxemia should be treated with oxygen supplementation.
- Any contributory factors to PH should be treated as able, e.g.:
- Nocturnal hypoxemia.
- Thromboembolic disease.
- Left ventricular disease.
PAH medications for patients with precapillary PH:
- There is a lack of evidence to support these in sickle cell disease.
- Sildenafil was found to be ineffective among patients with sickle cell disease and elevated tricuspid regurgitant velocity. Sildenafil appeared to increase hospitalization rates for painful crises. (21527519)
- Nonetheless, PAH drugs can be considered on an individual basis, for a subset of patients with precapillary pulmonary hypertension. (Murray 2022)
To keep this page small and fast, questions & discussion about this post can be found on another page here.
Guide to emoji hyperlinks
- = Link to online calculator.
- = Link to Medscape monograph about a drug.
- = Link to IBCC section about a drug.
- = Link to IBCC section covering that topic.
- = Link to FOAMed site with related information.
- 📄 = Link to open-access journal article.
- = Link to supplemental media.
References
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Books:
- Shah, P. L., Herth, F. J., Lee, G., & Criner, G. J. (2018). Essentials of Clinical pulmonology. In CRC Press eBooks. https://doi.org/10.1201/9781315113807
- Shepard, JO. (2019). Thoracic Imaging The Requisites (Requisites in Radiology) (3rd ed.). Elsevier.
- Walker C & Chung JH (2019). Muller’s Imaging of the Chest: Expert Radiology Series. Elsevier.
- Palange, P., & Rohde, G. (2019). ERS Handbook of Respiratory Medicine. European Respiratory Society.
- Rosado-De-Christenson, M. L., Facr, M. L. R. M., & Martínez-Jiménez, S. (2021). Diagnostic imaging: chest. Elsevier.
- Murray & Nadel: Broaddus, V. C., Ernst, J. D., MD, King, T. E., Jr, Lazarus, S. C., Sarmiento, K. F., Schnapp, L. M., Stapleton, R. D., & Gotway, M. B. (2021). Murray & Nadel’s Textbook of Respiratory Medicine, 2-Volume set. Elsevier.
- Fishman's: Grippi, M., Antin-Ozerkis, D. E., Cruz, C. D. S., Kotloff, R., Kotton, C. N., & Pack, A. (2023). Fishman’s Pulmonary Diseases and Disorders, Sixth Edition (6th ed.). McGraw Hill / Medical.