Pulmonary hypertension resident survival guide

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vidit Bhargava, M.B.B.S [2], Rim Halaby, M.D. [3], Alejandro Lemor, M.D. [4]

Pulmonary Hypertension Resident Survival Guide Microchapters
Overview
Causes
Classification Clinical Functional
FIRE
Diagnosis
Treatment IPAH Other Causes
Follow up
Do's
Don'ts

Overview

Pulmonary hypertension (PH) is defined as an at rest mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg measured using right heart catheterization. PH is clasified into five different ethiological groups and four functional classes according to WHO. Multiple causes and risk factors have been identified as responsible for the presentation of PH, with left heart diseases and lung diseases at the top of the list. Pulmonary arterial hypertension (PAH) is an exclusion diagnosis which requires common causes to be ruled out and a mPAP ≥ 25 mm Hg, a pulmonary artery wedge pressure (PAWP) ≤ 15 mm Hg and a pulmonary vascular resitance (PVR) > 3 Wood Unitis (WU). The treatment of pulmonary hypertension depends upon the underlying etiology. For PAH the treatment is based on oral endothelin receptor antagonists (ambrisentan, bosentan), oral phosphodiesterase-5 inhibitors (sildenafil), and/or prostanoids (epoprostenol, treprostinil). For other causes of pulmonary hypertension, the treatment would be addressed to the primary disease (eg. heart failure, COPD, interstitial lung disease)

Causes

Life Threatening Causes

Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated.

• Pulmonary embolism

Common Causes

• Congenital heart disease with left-to-right shunt (ASD, VSD, PDA)
• Congestive heart failure
• COPD
• Cor pulmonale
• Interstitial lung disease
• Obstructive sleep apnea
• Thromboembolism

Click here for the complete list of causes.

Classification

Clinical Classification of Pulmonary Hypertension

The classification below is based on the 5^th World Symposium on Pulmonary Hypertension Update from the 1998 World Health Organization Pulmonary Hypertension clinical classification.

Group 1. Pulmonary arterial hypertension (PAH)

• Idiopathic PAH
• Heritable PAJ
  • BMPR2
  • ALK-1, ENG, SMAD9, CAV1, KCNK3
  • Unknown
• Drug- and toxin-induced
• Associated with:
  • Connective tissue diseases
  • HIV infection
  • Portal hypertension
  • Congenital heart diseases
  • Schistosomiasis

Group 1'. Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH)

Group 1". Persistent pulmonary hypertension on the newborn (PPHN)

Group 2. Pulmonary hypertension due to left heart disease

• Left ventricular systolic dysfunction
• Left ventricular diastolic dysfunction
• Valvular disease
• Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies

Group 3. Pulmonary hypertension due to lung diseases and/or hypoxia

• Chronic obstructive pulmonary disease
• Interstitial lung disease
• Other pulmonary diseases with mixed restrictive and obstructive pattern
• Sleep-disordered breathing
• Alveolar hypoventilation disorders
• Chronic exposure to high altitude
• Developmental abnormalities

Group 4. Chronic thromboembolic pulmonary hypertension (CTEPH)

Group 5. Pulmonary hypertension with unclear multifactorial mechanisms

• Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy
• Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis
• Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
• Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH

Functional Classification of Pulmonary Hypertension

1998 WHO modified NYHA functional classification of pulmonary hypertension

Class I	Class II	Class III	Class IV
No limitation of physical activity Physical activity does not cause excessive dyspnea, fatigue, chest pain, or syncope	Mild limitation of physical activity Patients are comfortable at rest Physical activity causes excessive dyspnea, fatigue, chest pain, or syncope	Notable limitation of physical activity Patients are comfortable at rest Ordinary activity causes excessive dyspnea, fatigue, chest pain, or syncope	Inability to carry out any physical activity without symptoms. Signs of right heart failure Dyspnea and/or fatigue may even be present at rest Discomfort is increased by any physical activity

FIRE: Focused Initial Rapid Evaluation

A Focused Initial Rapid Evaluation (FIRE) should be performed to identify patients in need of immediate intervention.

Complete Diagnostic Approach

A complete diagnostic approach should be carried out after a focused initial rapid evaluation is conducted and following initiation of any urgent intervention. The algorithm below is based on the ACC/AHA 2009 Expert consenus document on pulmonary Hypertension and the ESC 2009 Guideles for the diagnosis and treatment of pulmonary hypertension.

Abbreviations: AS: Aortic stenosis; COPD: Chronic obstructive pulmonary disease; DVT: Deep venous thrombosis; EKG: Electrocardiogram; MR: Mitral regurgitation; MS: Mitral stenosis; PAP Pulmonary artery pressure; PAWP: Pulmonary artery wedge pressure; PE: Pulmonary embolism; PVR: Pulmonary vascular resistance; SLE: Systemic erythemotous lupus

Characterize the symptoms: ❑ Progressive dyspnea ❑ Exertional dizziness ❑ Syncope ❑ Edema of the extremities ❑ Chest pain ❑ Palpitations

Inquire about past medical history ❑ Cardiovascular disease ❑ Congenital heart disease ❑ Left ventricular failure ❑ Pulmonary disease ❑ Previous PE ❑ COPD ❑ Interstitial lung disease ❑ Sleep apnea ❑ Asthma ❑ Recent surgery (<3 months) (suggestive of PE) ❑ Connective tissue disease ❑ HIV infection ❑ Portal hypertension ❑ Chronic hemolytic anemia ❑ Myeloproliferative disorders ❑ Splenectomy ❑ Systemic diseases ❑ Sarcoidosis ❑ Pulmonary Langerhans histiocytosis ❑ Lung tumors ❑ Chronic kidney disease in dialysis ❑ Thyroid disease

Inquire about risk factors ❑ Family history of pulmonary hypertension ❑ BMPR2 gene mutation ❑ ACVRL1 gene mutation ❑ Drugs ❑ Anorectic drugs ❑ Amphetamines ❑ Cocaine ❑ Phenylpropanolamine ❑ Saint John's wort ❑ Chemotherapeutic agents ❑ Selective serotonin reuptake inhibitors

Examine the patient: Physical signs that reflect severity of PH: ❑ Loud pulmonary second heart sound (P2) ❑ Systolic murmur suggestive of tricuspid regurgitation ❑ Raised jugular venous pressure (JVP) ❑ Early systolic click ❑ Left parasternal heave ❑ Right ventricular S4 Physical signs suggestive of moderate to severe PH: ❑ Holosystolic murmur that increases with inspiration ❑ Increased jugular v waves ❑ Pulsatile liver ❑ Diastolic murmur ❑ Hepatojugular reflux Physical signs suggestive of advanced PH with right ventricular failure: ❑ Right ventricular S3 ❑ Distension of jugular veins ❑ Hepatomegaly ❑ Peripheral edema ❑ Ascites ❑ Hypotension Physical signs suggestive of possible underlying causes: ❑ Central cyanosis (Suggestive of an abnormal V/Q) ❑ Clubbing (Suggestive of congenital heart disease) ❑ Cardiac auscultatory findings (Suggestive of congenital or acquired heart disease) ❑ Rales, decreased breath sounds, dullness (Suggestive of pulmonary congestion) ❑ Fine rales, excessive muscle use, wheezing, protracted respiration, cough (Suggestive of pulmonary parenchymal disease) ❑ Obesity, kyphoscoliosis, enlarged tonsils (Suggestive of disordered ventilation) ❑ Sclerodactyly, arthritis, telengiectasia, Raynaud phenomenon, rash (Suggestive of connective tissue disorder) ❑ Peripheral venous insufficiency (Suggestive of venous thrombosis) ❑ Venous stasis ulcers (Suggestive of sickle cell disease) ❑ Pulmonary vascular bruits (Suggestive of chronic thromboembolic PH) ❑ Splenomegaly, spider angiomata, palmar erythema, icterus, caput medusae (Suggestive of portal hypertension)

Consider alternative diagnosis: ❑ Left sided heart failure ❑ Coronary artery disease ❑ Liver disease ❑ Budd-Chiari syndrome

Order tests: Labs ❑ Complete blood count and peripheral smear (to rule out): ❑ Chronic hemolytic anemia ❑ Sickle cell disease ❑ Thalassemia ❑ Spherocytosis ❑ Anticentromere antibody, anti-scl70 and U3-RNP (to rule out Scleroderma) ❑ Anti-nuclear antibody, anti-dsDNA antibody (to rule out SLE) ❑ Rheumatoid factor (to rule out rheumatoid arthritis) ❑ HIV serological test ❑ Liver function tests Other tests ❑ Chest X-ray ❑ Pulmonary artery dilation ❑ Loss of peripheral blood vessels ❑ Enlargement of the right chambers ❑ Pulmonary diseases ❑ Left heart abnormalities ❑ EKG ❑ Signs of right ventricle hypertrophy ❑ Right axis deviation ❑ Supraventricular arrhythmias such as atrial flutter and Atrial fibrillation (suggestive of severe disease) ❑ Echocardiogram ❑ Measure pulmonary artery pressure ❑ Assess valvular diseases such as MR, MS, AS ❑ Left ventricle: evaluate possible systolic or diastolic dysfunction ❑ Rule out other obstructive conditions, such as: ❑ Supravalvular aortic stenosis ❑ Aortic coarctatio ❑ Subaortic membrane ❑ Cor triatriatum ❑ Search for congenital diseases with shunt such as atrial septal disease ❑ Thrombus in right chambers (suggestive of pulmonary embolism) ❑ Pulmonary stenosis ❑ Abdominal ultrasound (to rule out portal hypertension)

Does the findings are suggestive of heart disease or pulmonary disease?

Yes

No

Heart disease ❑ Congenital heart disease ❑ Left ventricular failure

Pulmonary disease ❑ Pulmonary function tests ❑ Arterial blood gases ❑ Diffusion capacity for carbon monoxide (DLCO) ❑ Polysomnography (to rule out sleep apnea)

❑ Perform a Ventilation/perfusion scan to rule out chronic thromboembolic pulmonary hypertension

❑ COPD ❑ Interstitial lung disease ❑ Sleep apnea

Normal V/Q test

Perfusion defects

Does the patient presents any other conditions that can present with PH (Group 5)?

Pulmonary hypertension due to chronic thromboembolism ❑ Patient with previous PE or DVT AND ❑ Dyspnea, fatigue, exercise intolerance OR ❑ Signs of right heart failure ❑ A pulmonary angiography should be performed in patients with altered V/Q test ❑ Contrast CT angiography ❑ Irregularities of the intima and vein occlusion

No

Yes

Refer to a specialized center for a right heart catheterization ❑ Confirmed PAH: ❑ Mean PAP ≥ 25 mm Hg AND ❑ PAWP ≤ 15 mm Hg AND ❑ PVR > 3 Wood units ❑ Perform a vasoreactivity test to assess the possible benefit of long-term treatment with calcium channel blockers only in patients with Idiopathic PAH ❑ Administer: Inhalaed nitric oxide 10-20 parts per million (gold standard) ❑ Alternatives: IV epoprostenol, IV adenosine, inhaled iloprost ❑ Reduction of the mean PAP in ≥ 10 mm Hg to a mean PAP of ≤ 40 mm Hg with an elevation or maintained cardiac output is considered a positive response ❑ The use of calcium channel blockers should be avoided for this test ❑ Do not perform this tests in other types of PAH or PH

❑ Hematological disorders: ❑ Myeloproliferative disorders ❑ Splenectomy ❑ Chronic hemolytic anemia ❑ Systemic disorders: ❑ Sarcoidosis ❑ Metabolic disorders: ❑ Thyroid disease ❑ Others: ❑ Chronic kidney disease in dialysis ❑ Obstructing tumor ❑ Fibrous mediastinitis

Idiopathic

Heritable ❑ Family history of BMPR2 gene mutation ❑ Family history of ACVRL1 gene mutation

Pulmonary vein stenosis

Associated pulmonary arterial hypertension ❑ Connective tissue disease ❑ HIV infection ❑ Portal hypertension ❑ Hematological disorders ❑ Sickle cell disease ❑ Thalassemia ❑ Spherocytosis

Drug induced ❑ Anorectic drugs ❑ Amphetamines ❑ Cocaine ❑ Phenylpropanolamine ❑ Saint John's wort ❑ Chemotherapeutic agents ❑ Selective serotonin reuptake inhibitors

Findings Symptoms: ❑ Exertion dyspnea ❑ Fatigue Signs: ❑ Clubbing ❑ Rales in lung bases Chest X-ray: ❑ Kerley B lines ❑ Ground-glass centrolubular lines CT scan: ❑ Thickened septal subpleural lines ❑ Ground-glass centrolubular lines ❑ Lymphadenopathy in the mediastinum ❑ Pulmonary edema with epoprostenol administration ❑ Search alveolar hemorrhage: perform a bronchoscopy with bronchoalveolar lavage ❑ Gold standard: lung biopsy ❑ PAWP is normal

Treatment

Idiopathic Pulmonary Arterial Hypertension

Shown below is an algorithm of the treatment approach for Idiopathic PAH based on the ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension and JACC 2013 Updated Treatment Algorithm of Pulmonary Arterial Hypertension.

Abbreviations: BID: two times a day; TID: three times a day; RV: Right ventricle; mPAP: mean pulmonary artery pressure; BNP: Brain natriuretic peptide ; TTE: Transthoracic echocardiography

General recommendations ❑ Avoid pregnancy (30% to 50% maternal mortality rate) ❑ Consider physical therapy for physically deconditioned patients ❑ Administer vaccines against influenza and pneumococcal infections ❑ Offer psychosocial support ❑ Avoid excessive physical activity ❑ For elective surgeries, epidural anesthesia should be considered before general anesthesia ❑ Avoid exposure to high altitudes

Supportive therapy ❑ Administer diuretics in patients with signs of RV failure and fluid retention ❑ Administer oxygen in patients with PaO2 < 60 mm Hg (SatO2 <90%) ❑ Administer warfarin (titrated to a INR of 1.5-2.5) in patients with IPAH, hereditable PAH, and PAH due to anorexigens ❑ Administer digoxin in patients with atrial arrhythmias or right heart failure and a low cardiac output

Referral to an expert center for vasodilator testing

Acute vasodilator testing Agents ❑ Nitric oxide inhaled 10 - 20 p.p.m (preferred vasodilator) OR ❑ Epoprostenol IV 2ng/kg/min every 10 to 15 min OR ❑ Adenosine IV 50 mcg/Kg/min every 2 min

Is there a decrease in mPAP of at least 10 mm Hg to an absolute mPAP of less than 40 mm Hg without a decrease in cardiac output?

YES Positive

NO Negative

❑ Administer an oral calcium channel blocker (CCB): Avoid the use of verapamil due to its negative inotropic effect ❑ Nifedipine ❑ Start with 30mg bid ❑ Increase slowly to 120–240 mg/day OR ❑ Diltiazem ❑ Start with 60mg TID ❑ Increase slowly to 240–720 mg/day OR ❑ Amlodipine ❑ Start with 2.5 mg/day ❑ Increase slowly to 20 mg/day ❑ Follow closely for efficacy and safety

Low risk ❑ No clinical evidence of RV failure ❑ Gradual progression of symptoms ❑ WHO functional class II and III ❑ 6 min walk distance > 400 meters ❑ Cardiopulmonary exercise testing: peak Vo2 > 15 mL/kg/min ❑ TTE: minimal RV dysfunction ❑ Right atrial pressure < 8 mm Hg ❑ Cardiac index > 2.5-3.0 L/min/m² ❑ Normal or slight increased BNP

High risk ❑ Clinical evidence of RV failure ❑ Rapid progression of symptoms ❑ WHO functional class IV ❑ 6 min walk distance < 300 meters ❑ Cardiopulmonary exercise testing: peak Vo2 < 10 mL/kg/min ❑ TTE: pericardial effusion, RV and RA enlargement ❑ Right atrial pressure > 20 mm Hg ❑ Cardiac index < 2.0 L/min/m² ❑ Increased BNP

Does the patient responded to therapy?

YES

NO

Continue with CCB

First-line therapy ❑ Oral endothelin receptor antagonist ❑ Ambrisentan 5 mg/day, OR ❑ Bosentan 125 mg BID OR ❑ Oral phospodiesterase-5 inhibitor ❑ Sildenafil 20 mg TID

First-line therapy ❑ Epoprostenol (central IV infusion) ❑ Initial dose: 2 ng/kg/min ❑ Titrate in increments of 2 ng/kg/min q ≥15 min based on the symptoms and side effects ❑ Optimal dose range: 25–40 ng/kg/min (when used as monotherapy) OR ❑ Treprostinil (SC or central IV infusion) ❑ Initial dose: 1.25 ng/kg/min (0.625 ng/kg/min if intolerable) ❑ Titrate in increments of 1.25–2.5 ng/kg/min per week OR ❑ Iloprost (inhalation) ❑ Initial dose: 2.5 mcg ❑ If tolerated, increase dose to 5 mcg x 6–9 times per day ❑ Maximum dose: 45 mcg/day

Second-line therapy ❑ Epoprostenol (central IV infusion) ❑ Initial dose: 2 ng/kg/min ❑ Titrate in increments of 2 ng/kg/min q ≥15 min based on the symptoms and side effects ❑ Optimal dose range: 25–40 ng/kg/min (when used as monotherapy) OR ❑ Treprostinil (SC or central IV infusion) ❑ Initial dose: 1.25 ng/kg/min (0.625 ng/kg/min if intolerable) ❑ Titrate in increments of 1.25–2.5 ng/kg/min per week OR ❑ Iloprost inhaled 6 times/day

Second-line therapy ❑ Oral endothelin receptor antagonist ❑ Ambrisentan 5 mg/day, OR ❑ Bosentan 125 mg BID OR ❑ Oral phospodiesterase-5 inhibitor ❑ Sildenafil 20 mg TID OR ❑ Treprostinil (SC or inhaled)

Does the patient responded to therapy?

YES Stable clinical progress ❑ No evidence of right heart failure on physical exam ❑ Functional class I/II ❑ No syncope ❑ 6 minute walk distance >400 m ❑ Normal RV size on echocardiogram ❑ Normal right atrial pressure and cardiac index ❑ Near normal or stable BNP

NO Unstable clinical progress ❑ Signs of right heart failure ❑ Functional class IV ❑ Presence of syncope ❑ 6 minute walk distance <300 m ❑ RV enlargement on echocardiogram ❑ High right atrial pressure and low cardiac index ❑ Elevated and increasing BNP

Continue with monotherapy

❑ Consider combination therapy ❑ Oral endothelin receptor antagonist ❑ Oral phospodiesterase-5 inhibitor ❑ Prostanoid (epoprostenol, treprostinil)

Consider the following in case of inadequate response to therapy ❑ Atrial septostomy, OR ❑ Lung transplant, OR ❑ Investigational protocols

Treatment for other causes of Pulmonary Hypertension

Classify the pulmonary hypertension (PH)

Group 1

Group 1' Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH)

Group 2 Pulmonary hypertension due to left heart disease

Group 3 Pulmonary hypertension due to lung diseases and/or hypoxia

Group 4 Chronic thromboembolic pulmonary hypertension (CTEPH)

Group 5 Pulmonary hypertension with unclear multifactorial mechanisms

❑ Click here for idiopathic PAH and hereditable PAH ❑ Treat the underlying cause: Connective tissue diseases HIV infection Portal hypertension Congenital heart diseases Schistosomiasis

❑ There is no established medical therapy ❑ Patients should be referred to a transplant center for evaluation ❑ Lung transplantation is the only curative therapy

❑ Treatment should be aimed to treat the heart failure ❑ There are no contraindications for any heart failure drugs because of PH Systolic heart failure ❑ Sildenafil has demonstrated some benefit for patients with systolic heart failure Diastolic heart failure ❑ Treat hypertension with ACE inhibitors or ARBs ❑ Strict volume control achieved with diuretics and sodium restriction ❑ Consider beta-blockers and calcium channel blockers to prevent tachyarrhythmias and control the heart rate to improve diastolic filling

❑ In COPD patients, long-term O2 administration may reduce the progression of PH ❑ Do not use conventional vasodilators as they may impair gas exchange ❑ Patients with sleep apnea should use CPAP during the night to prevent hypoxia ❑ The use of PAH-specific therapy† is not recommended

❑ Administer vitamin K antagonists, titrated to INR of 2.0-3.0 ❑ Pulmonary thromboendarterectomy (PTE) is the treatment of choice ❑ PAH-specific therapy† is indicated for: ❑ Patients not candidates for surgery ❑ Patients with a residual PH after PTE ❑ Epoprostenol may be considered as a therapeutic bridge to PTE in high risk patients ❑ Possible treatment alternatives include: ❑ Lung transplantation ❑ Balloon pulmonary dilation

The treatment is orientated based on the underlying cause Hematologic disorders: myeloproliferative disorders, splenectomy Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis: lymphangioleiomyomatosis, neurofibromatosis, vasculitis Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis

† PAH-specific therapy refers to the use of CCBs, oral endothelin receptor antagonists (ambrisentan, bosentan), oral phosphodiesterase-5 inhibitors (sildenafil), and/or prostanoids (epoprostenol, treprostinil).

Follow Up Testing

Shown below is a table depicting the follow up testing after etiology for pulmonary hypertension is established.

Condition	Follow up testing
BMPR2 mutation	❑ Yearly echocardiogram ❑ Right heart catheterization if evidence of PH
1st degree relative of patient with BMPR2 mutation or with 2 or more relatives with PH	❑ Genetic counseling for BMPR2 testing ❑ Proceed as above if positive
Systemic sclerosis	❑ Yearly echocardiogram ❑ Right heart catheterization if evidence of PH
HIV infection	❑ Do echocardiogram if signs & symptoms are suggestive of PH ❑ Right heart catheterization if evidence of PH on echocardiography
Portal hypertension	❑ If considering liver transplant perform echocardiogram ❑ Right heart catheterization if evidence of PH
Congenital heart disease with shunt	❑ Echocardiogram and right heart catheterization at the time of diagnosis ❑ Repair any significant defect
Recent acute pulmonary embolism	❑ If symptomatic 3 months after event, perform ventilation perfusion scintigraphy ❑ Do a pulmonary angiogram if positive
Prior fenfluramine use (appetite suppressant)	❑ Echocardiogram only if symptomatic
Sickle cell disease	❑ Yearly echocardiogram ❑ Right heart catheterization if evidence of PH

Do's

• Monitor liver function tests monthly in patients being treated with endothelin receptor antagonists.
• Follow up on patients with advanced symptoms, right heart failure, advanced hemodynamics and those on parenteral or combination therapy every 3 months.
• Perform an echocardiogram 6 weeks after an acute pulmonary embolismto screen for persistent pulmonary hypertension that may predict the development of CTEPH.

Don'ts

• Do not perform pulmonary vasoreactivity test in patients with other types of PAH or PH different of Idiopathic pulmonary arterial hypertension as the effectiveness of calcium channel blockers in those groups is very low.
• Do not administer calcium channel blockers for the pulmonary vasoreactivity test as risk of life-threatening complication exist.

References