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]

Pulmonary Hypertension Resident Survival Guide Microchapters
Overview
Causes
FIRE
Diagnosis
Treatment
Follow up
Do's
Don'ts

Overview

Pulmonary hypertension (PH) is defined by mean pulmonary artery pressure > 25, pulmonary capillary wedge pressure (PCWP), left atrial pressure, or left ventricular end diastolic pressure (LVEDP) ≤ 15 mm Hg; and a pulmonary vascular resistance (PVR) > than 3 Wood units.

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.

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.

Characterize the symptoms: ❑ Progressive dyspnea ❑ Exertional dizziness ❑ Syncope ❑ Edema of the extremities ❑ Angina ❑ 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) ❑ Conective 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 disorders

Inquire about risk factors ❑ Family history of pulmonary hypertension ❑ Family history of BMPR2 gene mutation ❑ Family history of 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 ❑ Hematology ❑ Complete blood count (to rule out myeloproliferative disorders) ❑ Periferal blood film (to rule out sickle cell disease) ❑ Biochemestry ❑ Free T4 and TSH (to rule out a thyroid disease) ❑ HIV serological test ❑ Connective tissue disease ❑ Anticentromere, anti-scl70 and U3-RNP (to rule out scleroderma) ❑ Anti-nuclear antibodies, dsDNA (to rule out SLE) ❑ Rheumatoid factor (to rule out rheumatoid arthritis) ❑ ABG (to assess lung function) ❑ Liver function tests (to rule out cirrhosis and portal hypertension) 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 AF (suggestive of severe disease) ❑ Echocardiogram ❑ Measure pulmonary artery pressure ❑ Assess valvular disease such as MR, MS, AS ❑ Left ventricle: evaluate possible systolic or diastolic dysfunction ❑ Rule out other obtructive conditions, such as: ❑ Supravalvular aortic stenosis ❑ Aortic coarctation ❑ Sub aortic membrane ❑ Cor triatriatum ❑ Search for congenital diseases with shunt such as ASD ❑ Thrombus in right chambers (suggestive of pulmonary embolism) ❑ Pulmonary stenosis ❑ Ventilation/perfusion scan to rule out chronic thromboemboelic pulmonary hypertension ❑ CT scan ❑ High-resolution ❑ Interstitial edema, ground-glass opacification and thickening of the interlobar septa (suggestive of pulmonary vein stenosis) ❑ Bilateral interlobar septal thickening (suggestive of capillary haemangiomatosis) ❑ Contrast angiography ❑ Irregularities of the intima and vein oclusion (suggestive of CTEPH) ❑ Right heart catherization confirmation test for PAH ❑ Confirmed PAH: mean PAP ≥ 25 mmHg and mean PCWP ≥ 15 mmHg and PVR ≥ greater than 3 Wood units ❑ Perform a vasoreactivity test to assess the possible benefit of long-term treatment with calcium channel blockers ❑ Use IV esoprostenol ❑ Reduction of the mean PAP in ≥ 10 mmHg to a mean PAP of ≤ 40 mmHg with an elevation or mantained cardiac output is considered a positive response ❑ The use of calcium channel blockers should be avoided for this test ❑ Abdominal ultrasound to rule out portal hypertension and cirrhosis

Findings suggestive of heart disease or pulmonary disease

Yes

No

Heart disease ❑ Congenital heart disease ❑ Left ventricular failure

Pulmonary disease ❑ COPD ❑ Interstitial lung disease ❑ Sleep apnea ❑ Asthma

Perform V/Q test

Perfusion defects

Normal V/Q test

Pulmonary hypertension due to chronic thromboembolism ❑ Patient with previous PE or DVT AND ❑ Dyspnea, fatigue, exercise intolerance OR ❑ Signs of right heart failure ❑ Pulmonary angiogram should be performed in patients with altered V/Q test

Perform right heart catherization ❑ Mean pulmonary arterial pressure ≥ 25 mmHg ❑ Pulmonary wedge pressure ≤ 15 mmHg

Yes

No

Pulmonary arterial hypertension

Consider other causes ❑ Haematological disorders: ❑ Myeloproliferative disorders ❑ Splenectomy ❑ 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

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

Associated pulmonary arterial hypertension ❑ Connective tissue disease ❑ Scleroderma ❑ Systemic lupus erythematosus ❑ Rheumatoid arthritis ❑ HIV infection ❑ Portal hypertension ❑ Chronic hemolytic anemia

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

Treatment

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 AND / OR ❑ Administer oxygen in patients with PaO2 < 60 mmHg (SatO2 <90%) AND / OR ❑ Administer warfarin in patients with IPAH titrated to a INR of 1.5-2.5 AND / OR ❑ Administer digoxin in patients with atrial arrhythmias or right heart failure and a low cardiac output

Acute vasodilator testing Agents ❑ Nitric oxide inhaled (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) ❑ 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 Avoid the use of verapamil due to its negative inotropic effect

Lower risk ❑ No clinical evidence of RV failure ❑ Gradual progression of symptoms ❑ WHO Class II and III ❑ 6 min walk distance > 400 meters ❑ Cardiopulmonary exercise testing: peak Vo2 > 10.4 mL/kg/min ❑ TTE: minimal RV dysfunction ❑ Right atrial pressure < 10 mmHg ❑ Cardiac index > 2.5 L/min/m² ❑ Normal or slight increased BNP

Higher risk ❑ Clinical evidence of RV failure ❑ Rapid progression of symptoms ❑ WHO Class IV ❑ 6 min walk distance < 300 meters ❑ Cardiopulmonary exercise testing: peak Vo2 < 10.4 mL/kg/min ❑ TTE: pericardial effusion, RV and RA enlargement ❑ Right atrial pressure > 20 mmHg ❑ Cardiac index < 2.0 L/min/m² ❑ Increased BNP

❑ Follow closely for efficacy and safety ❑ Did the patient responded to therapy?

Yes

No

First-line therapy ❑ Oral endothelin receptor antagonists: Bosentan 125 mg BID, OR ❑ Oral phospodiesterase-5 inhibitors: Sildenafil 20 mg TID Second-line therapy ❑ IV epoprostenol ❑ Start with 2 ng/Kg/min ❑ Adjust up to 25-40 ng/kg/min (based on the symptoms of PAH and side effects) OR ❑ IV treprostinil (83 ng/Kg/min) OR ❑ Iloprost inhaled 6 times/day OR ❑ Treprostinil (SC)

First-line therapy ❑ IV epoprostenol ❑ Start with 2 ng/Kg/min ❑ Adjust up to 25-40 ng/kg/min (based on the symptoms of PAH and side effects) OR ❑ IV treprostinil (83 ng/Kg/min) OR ❑ Iloprost inhaled 6 times/day Second-line therapy ❑ Oral endothelin receptor antagonists: Bosentan 125 mg BID, OR ❑ Oral phospodiesterase-5 inhibitors: Sildenafil 20 mg TID OR ❑ Treprostinil (SC)

Continue CCB

❑ Reassess

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

Unstable clinical course ❑ Signs of heart failure ❑ Functional class IV ❑ 6 minute walk distance <400 m ❑ RV enlargement on echocardiogram ❑ High right atrial pressure and low cardiac index ❑ Elevated/increasing BNP

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

In case of progress despite optimal medical treatment: ❑ Investigational protocols, OR ❑ Atrial septostomy, OR ❑ Lung transplant

The algorithm is based on Expert consensus document on pulmonary hypertension published by ACCF/AHA in 2009.

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.

Don'ts

• Do not perform vasospastic testing for those with overt heart failure or hemodynamic instability because calcium channel blocker will not be considered.

References