Pulmonary Hypertension and Cor Pulmonale Diagnosis and Management



Pulmonary Hypertension and Cor Pulmonale Diagnosis and Management


Melvyn Rubenfire



The majority of patients with chronic heart and lung diseases associated with dyspnea and fatigue have some degree of pulmonary hypertension. The diagnosis, assessment of severity and prognosis, and treatment strategies for pulmonary hypertension can be made with a relatively high degree of certainty by experienced practitioners.

Pulmonary hypertension is defined by Doppler echocardiography as a tricuspid valve regurgitant velocity exceeding 3.0 to 3.5 m per second, corresponding to a right ventricular systolic pressure (RVSP) of 40 mm Hg or higher and a mean pulmonary artery pressure higher than 20 mm Hg (1). This chapter focuses on chronic pulmonary hypertension that is not attributable to left-sided heart disease and valvular disease.


USUAL CAUSES AND WORLD HEALTH ORGANIZATION CLINICAL CLASSIFICATION OF PULMONARY HYPERTENSION AND ASSOCIATED TRIGGERS

The World Health Organization (WHO) classification of pulmonary hypertension (PH), an expanded differential diagnosis, and definite and possible triggers for PH are summarized in Table 35.1 (1). It is helpful to think of the differential diagnosis as precapillary and postcapillary PH. The most common causes of PH and right-sided heart failure are postcapillary, such as left-sided heart failure and aortic and mitral valvular disease characterized by pulmonary venous hypertension and resistance to drainage. Because of therapeutic implications, pulmonary emboli, both central and peripheral, must always be the first consideration in precapillary PH. The term secondary pulmonary hypertension has been abandoned in the revised WHO classification, which categorizes PH by a shared pathologic process and treatment options (Table 35.1):



  • Pulmonary arterial hypertension (PAH).


  • Pulmonary venous hypertension.


  • Disorders of the respiratory system or hypoxemia or both.


  • Chronic thrombotic or embolic disease.


  • Disorder directly affecting the pulmonary vasculature.

Because pulmonary arterial hypertension (PAH) is insidious in onset but often rapidly progressive, it is important to have a high index of suspicion for persons at risk because of associated diseases and exposures. Patients at high risk include those with scleroderma-related disorders and lupus, congenital heart disease, sleep apnea, cirrhosis and portal hypertension, human immunodeficiency virus (HIV) infection, and a family history of primary pulmonary hypertension (PPH); chronic cocaine users; and those using anorexigens (2). An increased prevalence of PAH is found in
patients with anemia, including thalassemia and sickle cell disease; those with hyperthyroidism; and those who are obese. Each of these conditions is associated with a marked increase in pulmonary blood flow that could be a trigger, but the association is not clear.








TABLE 35.1. Classification, diseases, and triggers associated with pulmonary hypertension as modified from the WHO classification







































































































































1. Pulmonary arterial hypertension

1.1 Primary pulmonary hypertension


a. Sporadic


b. Familial

1.2 Related to


a. Collagen vascular diseases: scleroderma-related disorders, lupus, mixed connective tissue diseases, and less common Takayasu giant cell, ulcerative colitis, Wegener granulomatosis, rheumatoid arthritis, and juvenile rheumatoid arthritis


b. Congenital systemic-to-pulmonary shunts: high pressure or flow, left to right at atrial, ventricular, or pulmonary artery level


c. Portal hypertension (portopulmonary hypertension)


d. HIV infection


e. Drugs/toxins (L-tryptophan, toxic rapeseed oil, cocaine, heroin)


f. Anorexigens (amphetamines, fenfluramine, dexfenfluramine)


g. POEMS syndrome (myeloma variant)


h. Other possible triggers: obesity, anemia (thalassemia), hyperthyroidism

1.3 Persistent pulmonary hypertension of the newborn


2. Pulmonary venous hypertension with resistance to drainage

2.1 Left atrial and left ventricular disease (LV failure, diastolic dysfunction, atrial myxoma)

2.2 Left-sided valvular disease (mitral stenosis or insufficiency)

2.3 Extrinsic compression of pulmonary veins by fibrosing mediastinitis, lymph nodes, invasive tumors (breast, lung, lymphoma)

2.4 Pulmonary venoocclusive disease: primary PVOD, lupus, radiation, chemotherapeutic drugs (bleomycin, mitomycin C, cyclophosphamide, etoposide), tumor infiltration


3. Pulmonary hypertension associated with disorders of the respiratory system and/or hypoxemia

3.1 Chronic obstructive lung disease

3.2 Interstitial lung diseases

3.3 Sleep apnea, obstructive or primary hypoventilation

3.4 Chronic high-altitude: “chronic mountain sickness”

3.5 Alveolar-capillary dysplasia

3.6 Lymphangioleiomyomatosis

3.7 Disorders of respiratory excursion: marked obesity, severe kyphoscoliosis, neuromuscular disorders


4. Pulmonary hypertension due to chronic thromboembolic or thrombotic disease

4.1 Thromboembolic obstruction of proximal or central pulmonary arteries

4.2 Obstruction of distal pulmonary arteries


a. Pulmonary embolism (thromboemboli, tumor, ova and/or parasites, foreign body)


b. In situ thrombosis


c. Sickle cell disease


5. Pulmonary hypertension due to disorders directly affecting the pulmonary vasculature

5.1 Inflammatory


a. Schistosomiasis


b. Sarcoidosis


c. Other

5.2 Pulmonary capillary hemangiomatosis


HIV, human immunodeficiency virus; LV, left ventricular; POEMS, polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes; WHO, World Health Organization.


From: Rich S, ed. Executive summary. From the World Symposium on Primary Pulmonary Hypertension, Evian, September 6-10, 1998. Cosponsored by the World Health Organization (http://www.who.int/ncd/cvd/pph.html), with permission.




COMMON SIGNS AND SYMPTOMS IN PULMONARY HYPERTENSION

The signs and symptoms associated with PH are summarized in Table 35.2. Mild PH (pulmonary artery systolic pressure less than 40 to 45 mm Hg, or mean pulmonary artery pressure of 20 to 25 mm Hg) is generally not associated with symptoms, except in active persons (who participate in, e.g., aerobic sport, dancing) who experience decreased energy and endurance. The WHO PH functional assessment classification (Table 35.3) is very useful for describing and risk-stratifying patients (1).








TABLE 35.2. Common presenting symptoms and signs in pulmonary hypertension, depending on related disease





































Symptoms


General: fatigue, weakness, Raynaud phenomenon, generalized swelling


Cardiac: chest pain consistent with angina, atypical chest pains, palpitations


Pulmonary: dyspnea, orthopnea, and hemoptysis (rare in PAH)


Gastrointestinal: nausea, anorexia, abdominal bloating and fullness, occasionally severe abdominal pains


Neurologic: lightheadedness with positional change: presyncope and syncope with effort, cough, and at rest


Signs


General: anxiety, depression


Blood pressure: normal to low (occasionally hypertension)


Jugular venous pulse: distension with prominent a and V waves, estimated RA pressure >5-20 mm Hg, giant V waves with tricuspid regurgitation


Carotid pulse: normal or low amplitude


Lungs: usually normal, rales with parenchymal disease


Cardiac: left parasternal RV lift, palpable pulmonic closure sound, increased split of S2 with increased P2 (heard at the apex); systolic murmur at left fourth ICS increasing with inspiration (tricuspid insufficiency), soft diastolic decrescendo murmur of pulmonic regurgitation in left third ICS, systolic ejection murmur at left second or third ICS, RV S4 and/or RV S3 gallop at lower left and/or right sternal border


Abdomen: pulsatile and enlarged liver, ascites, splenomegaly with portopulmonary hypertension and severe right-sided heart failure, distention


Extremities: peripheral edema, clubbing, Raynaud phenomenon, sclerodactyly, loss of digital pulp (scleroderma-related disorders)


Skin: pallor, plethora, cyanosis, telangectasias, livedo reticularis


ICS, intercostal space; PAH, pulmonary arterial hypertension; RA, right atrial; right ventricular.


Symptoms attributable to PH are similar to those in left-sided heart failure, valvular disease, and lung disease. PH should be suspected as the cause with risk factors, triggers, and associated diseases. The symptoms depend on the functional limitation and the degree of hemodynamic impairment.

Each of the symptoms has one or more hemodynamic correlates:



  • Dyspnea and fatigue are correlated with decrease in rest and exercise stroke volume, cardiac output, and oxygen transport.


  • Angina-like chest pains on exertion are correlated with increased right ventricular (RV) myocardial oxygen demand and pulmonary artery pressures in excess of aortic pressure.


  • Presyncope and syncope and postural, tussive, and exercise systemic hypotension are correlated with decreased RV filling, decreased left ventricular (LV) filling, and LV compression by the right ventricle.



  • Abdominal pain, anorexia, edema, and ascites are correlated with gastric distention, increasing venous pressure, tricuspid insufficiency, and RV diastolic dysfunction.


  • Raynaud phenomenon is characteristically found in patients with scleroderma-related disorders and in 10% of patients with PPH.








TABLE 35.3. World Health Organization pulmonary hypertension functional assessment classification











Class I: Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope


Class II: Slight limitation of physical activity; ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope


Class III: Marked limitation of physical activity; comfortable at rest, but less-than-ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope; signs of right-sided heart failure may be present


Class IV: Inability to carry out any physical activity without symptoms; dyspnea and/or fatigue may even be present at rest; discomfort is increased by any physical activity; signs of right-sided heart failure are usually present


Physical findings depend on the cause and severity of PH. Most patients with a Doppler echocardiographic RVSP of more than 60 mm Hg or a pulmonary artery systolic pressure of more than 50 mm Hg obtained invasively have one or more cardiac findings. Patients with lung disease severe enough to cause more than moderate PH can be identified by decreased breath sounds, chest deformities, rales consistent with interstitial lung disease, abnormal jugular venous wave or pressure, a murmur of tricuspid insufficiency, and often clubbing of the fingers and toes and cyanosis.

Long-standing Eisenmenger syndrome (severe PH associated with congenital intracardiac shunt at the atrial, ventricular, or pulmonary artery level) with predominant right-to-left shunting is characterized by cyanosis at rest or with exercise, clubbing of the fingers and toes, and often murmurs of tricuspid insufficiency and pulmonic insufficiency. Because the right ventricle hypertrophies over a period of years, patients are often only mildly symptomatic until very late in the course. In patients with atrial septal defects and anomalous pulmonary venous drainage (about 2%), severe PH that resembles PPH and manifests without clubbing of the fingers and toes or without cyanosis can rapidly develop. Cyanosis can be due to intracardiac right-to-left shunting or to low cardiac output and decreased alveolar—capillary diffusion.


CLINICAL ALGORITHM FOR ASSESSMENT OF PULMONARY HYPERTENSION AND DIFFERENTIAL DIAGNOSIS

Figure 35.1 provides an algorithm for the assessment of PH. The algorithm provides a logical sequence in which to consider cost and therapeutic implications at each decision point that should be influenced by medical history and physical examination: for example, venous disease or pulmonary embolus, cirrhosis, evidence of sclerodactyly, telangiectasias, obesity or use of anorexigens, Raynaud phenomenon, and cyanosis. The clinical presentations of diseases associated with precapillary PH overlap. Diagnosis and management require a multidisciplinary approach and liberal referral to physicians experienced in evaluating and treating PH.


HELPFUL TESTS IN THE ASSESSMENT OF PULMONARY HYPERTENSION


Electrocardiogram

The electrocardiogram (ECG) has a high degree of sensitivity (more than 75% to 80%) for detecting right ventricular hypertrophy in symptomatic patients with severe PH. The sensitivity is less than 40% when the ECG is read without clinical information or when the ECG is unedited and computerized.
Frequent misdiagnoses include inferior, anterior, and septal infarction; inferior and anterior ischemia; and left posterior fascicular block. The ECG is not an effective screening tool in asymptomatic or mildly symptomatic persons. The most common ECG patterns in PH include a right-axis deviation of the QRS interval of more than 90 degrees, a qR in V1, a right-axis deviation, and increased voltage (more than 2.5 mm) of the p wave in lead II. The increased voltage is associated with a fourfold increase in mortality rate (3). Atrial premature beats occur frequently, but atrial fibrillation, atrial flutter, and serious ventricular arrhythmias are not common. The upper ECG tracing in Figure 35.2 demonstrates the typical ECG findings in PPH. It was obtained in a 37-year-old woman with WHO class IV PPH. Her pretreatment mean pulmonary artery pressure (mPA) was 75 mm Hg, and her pulmonary vascular resistance (PVR) was 24 Wood units. The lower ECG tracing is after 2 years of treatment with intravenous epoprostenol, at which point her disease was WHO class I, her mPA was 30 mm Hg, and her PVR was 6 Wood units. After treatment, less QRS right-axis deviation (120 degrees vs. 90 degrees), lower R-wave voltage in V1 to V3, and persistent but less ST-segment abnormality of RV strain or ischemia are seen.






FIGURE 35.1. Algorithm for pulmonary hypertension assessment in symptomatic individuals or those at high risk.


Chest Radiograph

The magnitude of lung disease (emphysema, fibrosis, masses, and skeletal deformity) needed to induce significant PH is
usually detectable on the chest radiograph. Chest radiographic indicators of PH include enlargement of the right ventricle, the right atrium, the superior vena cava, and the main pulmonary artery and its major branches. The criteria for PH are found in 95% of patients with PPH and only 4% of controls matched for age, gender, and bodysurface area. Figure 35.3 demonstrates the baseline and on-treatment chest radiograph in the 37-year-old woman with PPH described previously.






FIGURE 35.2. Electrocardiographic tracings in a 37-year-old woman with primary pulmonary hypertension. Top: Tracing shows right ventricular hypertrophy and right ventricular strain, a qR in lead V1, peaked enlarged p wave in lead II, and a right-axis deviation of 120 degrees. Bottom: Tracing obtained after 2 years of treatment with intravenous epoprostenol.


Doppler Echocardiography

Doppler echocardiography is an effective screening tool for detecting PH and for monitoring progression. The tricuspid regurgitant velocity (TRV) is proportional to the gradient between the RV and RA and is used to calculate the RVSP with the Bernoulli equation:


RVSP = 4 × TRV2 + estimated RA pressure in millimeters of mercury.







FIGURE 35.3. Top: Posteroanterior and lateral chest radiograph in the 37-year-old woman with World Health Organization class IV pulmonary artery hypertension with shortness of breath, demonstrating enlarged pulmonary artery and major branches, enlarged right atrium and right ventricle, and decreased pulmonary vascularity. Bottom: Film taken after 1 year of treatment with intravenous epoprostenol.

Some authorities estimate the RA pressure from the size of the inferior vena cava and its response to respiration, and others use a fixed value (range, 10 to 14 mm Hg). The TRV (in meters per second) should be provided to allow the clinician to add an estimate of the RA. Doppler echocardiography is sensitive for PH, but the TRV should be viewed in the context of clinical parameters, the size of the right atrium, and the size and function of the right ventricle (e.g., a mild increase in RVSP with dilated right atrium and right ventricle should prompt further studies). Agitated saline contrast material should be used to facilitate the measure of the TRV, particularly when the clinical estimate is mild PH, and to identify intracardiac shunts and a patent foramen ovale. A patent foramen ovale can be the explanation for rest and exercise arterial desaturation. The common anatomic findings in severe PH include dilated right atrium and right ventricle, flattened or D-shaped septum, and often a small, compressed left
ventricle (4). Pericardial effusions are not common but may be predictive of a poor outcome. Doppler findings include significant tricuspid and pulmonic regurgitation, from which the RVSP and pulmonary artery diastolic pressures can be calculated.

The WHO recommendations for Doppler echocardiography in persons at risk for PH are presented in Table 35.4 (1). The RVSP on screening Doppler echocardiography is often normal or mildly increased; a TRV of 3.0 to 3.5 m per second on Doppler echocardiography corresponds to an RVSP of 40 to 50 mm Hg. Under these circumstances, patients at high risk (first-degree relatives of patients with sporadic or familial PPH, those with scleroderma-related disorders) or with portal hypertension should be considered for a right-sided heart catheterization supplemented by exercise if the resting study is inconclusive. Although it is a very effective screening tool and is useful for detecting response to therapy in moderately severe PH, Doppler echocardiography is less useful in monitoring progress and prognosis in severe PH, for which it adds little to clinical parameters.


Computed Tomography and the Ventilation/Perfusion Lung Scan

The ventilation/perfusion (V/Q) lung scan is the “gold standard” for the diagnosis of acute pulmonary embolus, and a normal or low-probability V/Q scan can be used to exclude chronic thromboemboli when the PH is moderate to severe. However, the best tool for assessing chronic thromboembolic PH is helical computed tomographic (CT) contrast-enhanced pulmonary angiography. The advantage of helical CT is the ability to screen for chronic central pulmonary thromboemboli that may be amenable to thromboendarterectomy (5). When PH is moderate or more severe and the helical CT pulmonary angiogram is “normal” or indicates low probability, the V/Q scan is needed to exclude third- and fourth-order pulmonary branch embolus. When the V/Q scan is normal or indicates low probability, the algorithm shown in Fig. 35.1 is continued. In severe PH, it may be necessary to exclude central thromboemboli confidently by performing pulmonary angiography.








TABLE 35.4. Recommended schedule for Doppler echocardiography for the detection of pulmonary hypertension in persons at high risk







































CONDITIONS PRESENT

SCHEDULE


High risk

Familial PPH: all first-degree relatives

When symptoms appear or at 3- to 5-year intervals if asymptomatic

Sporadic PPH: all first-degree relatives

When symptoms appear

Scleroderma spectrum of diseases

Annually with or without symptoms


Intermediate and low risk


Liver disease/portal hypertension

When symptoms appear or at time of liver-transplant listing

Murmur or congenital heart disease

At least once; repeat if symptoms or signs of PH appear

HIV infection

When symptoms appear

History of cocaine or anorexigen use

When symptoms appear


HIV, human immunodeficiency virus; PH, pulmonary hypertension; PPH, primary pulmonary hypertension.


With mild to moderate PH, the differential diagnosis includes hypoxic/parenchymal, thromboembolic, and intrinsic vascular occlusive disease (scleroderma-related disorders, vasculitis, PPH). Depending on the clinical findings, chest radiograph, and probability of parenchymal lung disease, a high-resolution CT scan (1-mm cuts) may be obtained first or at the time of a helical CT pulmonary angiogram. A high-resolution CT scan is recommended for patients with PH associated with collagen vascular disease, to detect interstitial fibrosis, inflammatory pneumonitis, and alveolitis that may be
amenable to immunosuppressive therapy. The CT scan can detect PH in parenchymal lung disease. A main pulmonary artery diameter larger than 29 mm has a sensitivity of 87%, a specificity of 89%, and a positive predictive value of 0.97 for identifying patients with an mPA of more than 20 mm Hg (6).


Magnetic Resonance Angiography

Magnetic resonance studies can be used to characterize both anatomy and physiology in PH (7,8). Estimates of RVSP and mPA can be obtained from flow velocities with the Bernoulli equation, as with Doppler echocardiography. Magnetic resonance imaging and magnetic resonance angiography can be used to assess RV and LV chamber volume and ejection fraction, detect intracardiac shunts, and image both acute and chronic central and peripheral pulmonary emboli (9). The resources for these studies, particularly software, are, however, not widely available.


Serologic and Hepatic-function Studies

After excluding hypoxemia, parenchymal lung disease, systemic-to-pulmonary shunts, and pulmonary emboli, the remaining differential diagnosis (Fig. 35.1) consists of entities associated with PAH or intrinsic pulmonary vascular occlusive disease (Table 35.1). Serologic studies are necessary to screen for the collagen vascular diseases: sedimentation rate, C-reactive protein, antinuclear antibody, and SCL-70 antibody. Distinguishing the scleroderma-related disorders and other collagen vascular disease from PPH has clinical implications and often requires specialty consultation.

Portopulmonary hypertension, found in nearly 1% of patients with chronic liver disease and 10% of those referred for liver transplantation, can be excluded in the absence of a history of alcohol abuse, blood transfusions, or hepatitis and in the presence of normal liver function. Because of the clinical implications, HIV screening should be considered in PAH. Hepatitis C is a suspected trigger for PAH, but because of its frequency in the population, the relation is unclear.


Pulmonary-function Studies and Arterial Blood Gas Measurements

Pulmonary-function testings are useful in the assessment of dyspnea but are not indicated in severe PH unless clinical evidence for structural lung disease is found on examination or chest radiograph. The usual pattern in severe PH without lung disease is a moderate decrease in diffusion capacity, mild reduction in ventilatory capacity, and no significant obstructive or restrictive physiologic processes (10). In scleroderma-related disorders with PH, pulmonary fibrosis, and hypoxemia, often a marked reduction in diffusion capacity and a restrictive ventilation pattern are seen.


Functional Assessment with Exercise

Assessment of exercise capacity in patients with mild to severe forms of PH is recommended for risk stratification, for selection of a treatment strategy, to measure the response to therapy, and to assist in determining eligibility for more aggressive therapies. The two most useful measures are a standardized 6-minute walk test with continuous measurement of cutaneous oxygen saturation and a submaximal or symptom-limited bicycle or treadmill exercise test with or without direct measurement of oxygen consumption. Because symptom-limited stress testing is poorly tolerated in patients with worse PH than WHO class II, our institution prefers the 6-minute walk. The walk is easily tolerated, and results correlate highly with PH class and prognosis. The inability to walk at least 300 m and a decrease in oxygen saturation by 10 or more units are associated with a marked increase in mortality rate and can be used to select patients for lung transplantation (10).

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