Cor Pulmonale Emedicine

7/27/2019 Cor Pulmonale Emedicine

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emedicine.medscape.com

eMedicine Specialties > Cardiology > Myocardial Disease and Cardiomyopathies

Cor Pulmonale

Al i A Sovar i, MD, Clinical and Research Fellow in Cardiovascular Medicine, Section of Cardiology, University of Illinois at ChicagoRavi H Dave, MD, Associate Professor of Medicine, University of California at Los Angeles David Geffen School of Medicine;Abraham G Kocheril , MD,FACC, FACP, FHRS, Professor of Medicine, Director of Clinical Electrophysiology, University of Illinois at Chicago

Updated: Jul 22, 2010

Introduction

Background

Cor pulmonale is defined as an alteration in the structure and function of the right ventricle caused by a primary disorder of the

respiratory system. Pulmonary hypertension is the common link between lung dysfunction and the heart in cor pulmonale. Right-sided

ventricular disease caused by a primary abnormality of the left side of the heart or congenital heart disease is not considered cor

pulmonale, but cor pulmonale can develop secondary to a wide variety of cardiopulmonary disease processes. Although cor

pulmonale commonly has a chronic and slowly progressive course, acute onset or worsening cor pulmonale with life-threatening

complications can occur.[1 ]

Pathophysiology

Several different pathophysiologic mechanisms can lead to pulmonary hypertension and, subsequently, to cor pulmonale. These

pathogenetic mechanisms include (1) pulmonary vasoconstriction due to alveolar hypoxia or blood acidemia, (2) anatomic

compromise of the pulmonary vascular bed secondary to lung disorders (eg, emphysema, pulmonary thromboembolism, interstitial

lung disease, adult respiratory distress syndrome, and rheumatoid disorders), (3) increased blood viscosity secondary to blood

disorders (eg, polycythemia vera, sickle cell disease, macroglobulinemia), (4) increased blood flow in pulmonary vasculature, and (5)

idiopathic primary pulmonary hypertension. The result is increased pulmonary arterial pressure.

The right ventricle (RV) is a thin-walled chamber that is more a volume pump than a pressure pump. It adapts better to changing

preloads than afterloads. With an increase in afterload, the RV increases systolic pressure to keep the gradient. At a point, a further

increase in the degree of pulmonary arterial pressure produces significant RV dilation, an increase in RV end-diastolic pressure, and

RV circulatory collapse. A decrease in RV output with a decrease in diastolic left ventricle (LV) volume results in decreased LV output.

Since the right coronary artery, which supplies the RV free wall, originates from the aorta, decreased LV output diminishes blood

pressure in the aorta and decreases right coronary blood flow. What ensues is a vicious cycle between decreases in LV and RVoutput.

Genetic investigations have confirmed that morphogenesis of the right and left ventricle originated from different sets of progenitor

cells and sites. This polymorphism could explain the differing rates of hypertrophy of the right and left ventricles.[2 ]

Right ventricular overload is associated with septal displacement toward the left ventricle. Septal displacement, which is seen on

echocardiography, can be another factor that decreases LV volume and output in the setting of cor pulmonale and right ventricular

enlargement. Several pulmonary diseases cause cor pulmonale, which may involve interstitial and alveolar tissues with a secondary

effect on pulmonary vasculature or may primarily involve pulmonary vasculature. Chronic obstructive pulmonary disease (COPD) is

the most common cause of cor pulmonale in the United States.

Cor pulmonale usually presents chronically, but 2 main conditions can cause acute cor pulmonale: massive pulmonary embolism

(more common) and acute respiratory distress syndrome (ARDS). The underlying pathophysiology in massive pulmonary embolismcausing cor pulmonale is the sudden increase in pulmonary resistance. In ARDS, 2 factors cause RV overload: the pathologic

features of the syndrome itself and mechanical ventilation. Mechanical ventilation, especially higher t idal volume, requires a higher

transpulmonary pressure. In chronic cor pulmonale, right ventricular hypertrophy (RVH) generally predominates. In acute cor

pulmonale, right ventricular dilatation mainly occurs. In the case of ARDS, cor pulmonale is associated with increased possibility of

right to left shunt through patent foramen ovale and caries poorer prognosis.[3 ]

Frequency

United States

z Cor pulmonale is estimated to account for 6-7% of all types of adult heart disease in the United States, with chronic obstructive

pulmonary disease (COPD) due to chronic bronchitis or emphysema the causative factor in more than 50% of cases.

z At present, cor pulmonale accounts for 10-30% of decompensated heart failure related admissions in the United States.[4 ]

z Although the prevalence of COPD in the United States is about 15 million, the exact prevalence of cor pulmonale is difficult to

determine because it does not occur in all cases of COPD, and the physical examination and routine tests are relatively

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insensitive for the detection of pulmonary hypertension.

z In contrast, acute cor pulmonale is usually secondary to massive pulmonary embolism.

z Acute massive pulmonary thromboembolism is the most common cause of acute life-threatening cor pulmonale in adults.

z In the United States, 50,000 deaths are estimated to occur per year from pulmonary emboli and about half occur within the first

hour due to acute right heart failure.

International

The incidence of cor pulmonale varies among different countries depending on the prevalence of cigarette smoking, air pollution, and

other risk factors for various lung diseases.

Mortality/Morbidity

Development of cor pulmonale as a result of a primary pulmonary disease usually heralds a poorer prognosis. For example, patients

with COPD who develop cor pulmonale have a 30% chance of surviving 5 years. However, whether cor pulmonale carries an

independent prognostic value or is simply reflecting the severity of underlying COPD or other pulmonary disease is not clear.

Prognosis in the acute setting due to massive pulmonary embolism or ARDS has not previously been shown to be dependent on the

presence or absence of cor pulmonale. However, a prospective, multicenter cohort study by Volschan et al indicates that in cases of

pulmonary embolism, cor pulmonale may be a predictor of inhospital mortality.[5 ]

The authors collected demographic, comorbidity, andclinical manifestation data on 582 patients admitted to emergency or intensive care units and diagnosed with pulmonary embolism.

Assessing the information using logistic regression analysis, the investigators built a prediction model. Their results indicated that in

hemodynamically stable patients with pulmonary embolism, the following factors may be independent predictors of inhospital

mortality:

z Age over 65 years

z Bed rest for longer than 72 hours

z Chronic cor pulmonale

z Sinus tachycardia

z Tachypnea

Clinical

History

Clinical manifestations of cor pulmonale generally are nonspecific. The symptoms may be subtle, especially in early stages of the

disease, and mistakenly may be attributed to the underlying pulmonary pathology.

z The patient may complain of fatigue, tachypnea, exertional dyspnea, and cough.

z Anginal chest pain also can occur and may be due to right ventricular ischemia (it usually does not respond to nitrates) or

pulmonary artery stretching.

z Hemoptysis may occur because of rupture of a dilated or atherosclerotic pulmonary artery. Other conditions, such as tumors,

bronchiectasis, and pulmonary infarction, should be excluded before attributing hemoptysis to pulmonary hypertension. Rarely,

the patient may complain of hoarseness due to compression of the left recurrent laryngeal nerve by a dilated pulmonary artery.

z A variety of neurologic symptoms may be seen due to decreased cardiac output and hypoxemia.

z In advanced stages, passive hepatic congestion secondary to severe right ventricular failure may lead to anorexia, right upper

quadrant abdominal discomfort, and jaundice.

z Syncope with exertion, which may be seen in severe disease, reflects a relative inability to increase cardiac output during

exercise with a subsequent drop in the systemic arterial pressure.

z Elevated pulmonary artery pressure can lead to elevated right atrial, peripheral venous, and capillary pressure. By increasing

the hydrostatic gradient, it leads to transudation of fluid and accumulation of peripheral edema. Although this is the simplest

explanation for peripheral edema in cor pulmonale, other hypotheses explain this symptom, especially in a fraction of patients

with COPD who do not show increase in right atrial pressure. A decrease in glomerular filtration rate (GFR) and filtration of

sodium and stimulation of arginine vasopressin (which decreases free water excretion) due to hypoxemia play important




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pathophysiologic roles in this setting and may even have a role for peripheral edema in patients with cor pulmonale who have

elevated right atrial pressure.[6 ]

Physical

Physical findings may reflect the underlying lung disease or pulmonary hypertension, RVH, and RV failure.

z On inspection, an increase in chest diameter, labored respiratory efforts with retractions of the chest wall, distended neck veins

with prominent a orv waves, and cyanosis may be seen.

z On auscultation of the lungs, wheezes and crackles may be heard as signs of underlying lung disease. Turbulent flow through

recanalized vessels in chronic thromboembolic pulmonary hypertension[7 ]may be heard as systolic bruits in the lungs. Splitting

of the second heart sound with accentuation of the pulmonic component can be heard in early stages. A systolic ejection

murmur with sharp ejection click over the region of the pulmonary artery may be heard in advanced disease, along with a

diastolic pulmonary regurgitation murmur. Other findings upon auscultation of the cardiovascular system may be third and

fourth sounds of the heart and systolic murmur of tricuspid regurgitation.

z RVH is characterized by a left parasternal or subxiphoid heave. Hepatojugular reflux and pulsatile liver are signs of RV failure

with systemic venous congestion.

z On percussion, hyperresonance of the lungs may be a sign of underlying COPD; ascites can be seen in severe disease.

z Examination of the lower extremities reveals evidence of pitting edema. Edema in cor pulmonale is strongly associated with

hypercapnia.[8 ]

Causes

Etiologies of cor pulmonale can mechanistically be categorized in 5 groups.

1. Pulmonary vasoconstriction due to alveolar hypoxia or blood academia: This can result in pulmonary hypertension and if the

hypertension is severe enough, it causes cor pulmonale.

2. Various lung disorders: Parenchymal or alveolar lung disorders may anatomically compromise the vasculature beds and cause

elevated pulmonary blood pressure. Chronic obstructive pulmonary disorder is the most common cause of cor pulmonale.

Other lung disorders that may cause cor pulmonale are pulmonary thromboembolism, interstitial lung disease, and adult

respiratory distress syndrome. Also, some connective tissue disorders with pulmonary involvement may result in pulmonary

hypertension and cor pulmonale.

3. Blood disorders that are associated with increased blood viscosity such as polycythemia vera, sickle cell disease,

macroglobulinemia

4. Increased blood flow in the pulmonary vasculature

5. Idiopathic primary pulmonary hypertension

Differential Diagnoses

Other Problems to Be Considered

Congestive (biventricular) heart failure

Primary pulmonic stenosis

Primary pulmonary hypertension

Right-sided heart failure due to congenital heart diseasesRight heart failure due to right ventricular infarction

Ventricular septal defect

Constrictive pericarditis

High-output heart failure

Infiltrative cardiomyopathies

Atrial myxoma

Workup

Laboratory Studies

z Laboratory investigations are directed toward defining the potential underlying etiologies as well as evaluating complications of

cor pulmonale. In specific instances, appropriate lab studies may include the following: hematocrit for polycythemia (which can

be a consequence of underlying lung disease but can also increase pulmonary arterial pressure by increasing viscosity),

serum alpha1-antitrypsin if deficiency is suspected, and antinuclear antibody level for collagen vascular disease such as

scleroderma. Hypercoagulability states can be evaluated by serum levels of proteins S and C, antithrombin III, factor V




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Leyden, anticardiolipin antibodies, and homocysteine.

z Arterial blood gas tests may provide important information about the level of oxygenation and type of acid-base disorder.

z Elevated brain natriuretic peptide (BNP) level alone is not adequate to establish presence of cor pulmonale, but it helps to

diagnose cor pulmonale in conjunction with other noninvasive tests and in appropriate clinical settings. An elevated BNP level

may actually be a natural mechanism to compensate for elevated pulmonary hypertension and right heart failure by promoting

diuresis and natriuresis, vasodilating systemic and pulmonary vessels, and reducing circulating levels of endothelin and

aldosterone.

Imaging Studies

A general approach to diagnose cor pulmonale and to investigate its etiology starts with routine laboratory tests, chest radiography,

and electrocardiography. Echocardiography gives valuable information about the disease and its etiology. Pulmonary function tests

may become necessary to confirm the underlying lung disease. Ventilation/perfusion (V/Q) scan or chest CT scan may be performed

if history and physical examination suggest pulmonary thromboembolism as the cause or if other diagnostic tests do not suggest other

etiologies. Right heart catheterization is the most accurate but invasive test to confirm the diagnosis of cor pulmonale and gives

important information regarding the underlying diseases. Any abnormal result in each of these tests may need further diagnostic

evaluation in that specific direction.

Imaging studies may show evidence of underlying cardiopulmonary diseases, pulmonary hypertension, or its consequence, right

ventricular enlargement.

z Chest roentgenography: In patients with chronic cor pulmonale, the chest radiograph may show enlargement of the central

pulmonary arteries with oligemic peripheral lung fields. Pulmonary hypertension should be suspected when the right

descending pulmonary artery is larger than 16 mm in diameter and the left pulmonary artery is larger than 18 mm in diameter.

Right ventricular enlargement leads to an increase of the transverse diameter of the heart shadow to the right on the

posteroanterior view and filling of the retrosternal air space on the lateral view. These findings have reduced sensitivity in the

presence of kyphoscoliosis or hyperinflated lungs.

z Echocardiography: Two-dimensional echocardiography usually demonstrates signs of chronic RV pressure overload. As this

overload progresses, increased thickness of the RV wall with paradoxical motion of the interventricular septum during systole

occurs. At an advanced stage, RV dilatation occurs and the septum shows abnormal diastolic flattening. In extreme cases, the

septum may actually bulge into the left ventricular cavity during diastole resulting in decreased diastolic volume of LV and

reduction of LV output.

z Doppler echocardiography is now used to estimate pulmonary arterial pressure, taking advantage of the functional tricuspid

insufficiency that is usually present in pulmonary hypertension. Doppler echocardiography is considered the most reliable

noninvasive technique to estimate pulmonary artery pressure. The efficacy of Doppler echocardiography may be limited by the

ability to identify an adequate tricuspid regurgitant jet, which may be further enhanced by using saline contrast.

z Ventilation/perfusion (V/Q) lung scanning, pulmonary angiography, and chest CT scanning may be indicated to diagnose

pulmonary thromboembolism as the underlying etiology of cor pulmonale. These tests may be performed early in the

diagnostic workup if any evidence of pulmonary embolism appears in history and physical examination. The test may also be

considered later in the workup if other tests are not suggestive of any other etiology. Pulmonary thromboembolism has a wide

range of clinical presentations from massive embolism with acute and severe hemodynamic instability to multiple chronic

peripheral embolisms that may present with cor pulmonale.

z Ultrafast, ECG-gated CT scanning has been evaluated to study RV function. In addition to estimating right ventricular ejection

fraction (RVEF), it can estimate RV wall mass. I ts use is still experimental, but with further improvement, it may be used to

evaluate the progression of cor pulmonale in the near future.

z Magnetic resonance imaging (MRI) of the heart is another modality that can provide valuable information about RV mass,

septal flattening, and ventricular function. [9 ]

z Radionuclide ventriculography can determine RVEF noninvasively. Myocardial perfusion may also show a permanent increase

in brightness of the right ventricle.[10 ]

Other Tests

Electrocardiography (ECG) abnormalities in cor pulmonale reflect the presence of RVH, RV strain, or underlying pulmonary disease.

These electrocardiographic changes may include the following:

z Right axis deviation




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Medical therapy[12 ]for chronic cor pulmonale is generally focused on treatment of the underlying pulmonary disease and improving

oxygenation and RV function by increasing RV contractility and decreasing pulmonary vasoconstriction. However, the approach might

be different to some degree in an acute setting with priority given to stabilizing the patient.

Cardiopulmonary support for patients experiencing acute cor pulmonale with resultant acute RV failure includes fluid loading and

vasoconstrictor (eg, epinephrine) administration to maintain adequate blood pressure. Of course, the primary problem should be

corrected, if possible. For example, for massive pulmonary embolism, consider administration of anticoagulation, thrombolytic agents

or surgical embolectomy, especially if circulatory collapse is impending; consider bronchodilation and infection treatment in patients

with COPD; and consider steroid and immunosuppressive agents in infiltrative and fibrotic lung diseases.

Oxygen therapy, diuretics, vasodilators, digitalis, theophylline, and anticoagulation therapy are all different modalities used in the long-

term management of chronic cor pulmonale.

Oxygen therapy

Oxygen therapy is of great importance in patients with underlying COPD[13 ], particularly when administered on a continuous basis.

With cor pulmonale, the partial pressure of oxygen (PO2) is likely to be below 55 mm Hg and decreases further with exercise and

during sleep.

Oxygen therapy relieves hypoxemic pulmonary vasoconstriction, which then improves cardiac output, lessens sympathetic

vasoconstriction, alleviates tissue hypoxemia, and improves renal perfusion. The Nocturnal Oxygen Therapy Trial (NOTT), a

multicenter randomized trial, showed that continuous low-flow oxygen therapy for patients with severe COPD resulted in significantreduction in the mortality rate.[14 ]In general, in patients with COPD, long-term oxygen therapy is recommended when PaO2 is less

than 55 mm Hg or O2 saturation is less than 88%. However, in the presence of cor pulmonale or impaired mental or cognitive

function, long-term oxygen therapy can be considered even if PaO2 is greater than 55 mm Hg or O2 saturation is greater than 88%.

Although whether oxygen therapy improves survival in patients with cor pulmonale due to pulmonary disorders other than COPD is

not clear, it may provide some degree of symptomatic relief and improvement in functional status. Therefore, oxygen therapy plays an

important role in both the immediate setting and long-term management, especially in patients who are hypoxic and have COPD.

Diuretics

Diuretics are used in the management of chronic cor pulmonale, particularly when the right ventricular filling volume is markedly

elevated and in the management of associated peripheral edema. Diuretics may result in improvement of the function of both the right

and left ventricles; however, diuretics may produce hemodynamic adverse effects if they are not used cautiously. Excessive volumedepletion can lead to a decline in cardiac output. Another potential complication of diuresis is the production of a hypokalemic

metabolic alkalosis, which diminishes the effectiveness of carbon dioxide stimulation on the respiratory centers and lessens

ventilatory drive. The adverse electrolyte and acid-base effect of diuretic use can also lead to cardiac arrhythmia, which can diminish

cardiac output. Therefore, diuresis, while recommended in the management of chronic cor pulmonale, needs to be used with great

caution.

Vasodilator drugs

Vasodilator drugs have been advocated in the long-term management of chronic cor pulmonale with modest results. Calcium channel

blockers, particularly oral sustained-release nifedipine[15 ]and diltiazem, can lower pulmonary pressures, although they appear more

effective in primary rather than secondary pulmonary hypertension.[16 ]Other classes of vasodilators, such as beta agonists, nitrates,

and angiotensin-converting enzyme (ACE) inhibitors have been tried but, in general, vasodilators have failed to show sustained

benefit in patients with COPD and they are not routinely used. A trial of vasodilator therapy may be considered only in patients withCOPD with disproportionately high pulmonary blood pressure.

Beta-selective agonists

Beta-selective agonists have an additional advantage of bronchodilator and mucociliary clearance effect. Right heart catheterization

has been recommended during initial administration of vasodilators to objectively assess the efficacy and detect the possible adverse

hemodynamic consequences of vasodilators.

The Food and Drug Administration (FDA) has approved epoprostenol, treprostinil, bosentan, and iloprost for treatment of primary

pulmonary hypertension. Epoprostenol, treprostinil, and iloprost are prostacyclin (PGI2) analogues and have potent vasodilatory

properties.[17 ]Epoprostenol and treprostinil are administered intravenously and iloprost is an inhaler. Bosentan is a mixed endothelin-A

and endothelin-B receptor antagonist indicated for pulmonary arterial hypertension (PAH), including primary pulmonary hypertension

(PPH). In clinical trials, it improved exercise capacity, decreased rate of clinical deterioration, and improved hemodynamics.[17 ]

The PDE5 inhibitor sildenafil has been intensively studied[18,19,20 ]and approved by the FDA for treatment of pulmonary hypertension.

Sildenafil promotes selective smooth muscle relaxation in lung vasculature.[21 ]Tadalafil, another PDE5 inhibitor, was also recently




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approved by the FDA for the treatment of PAH to improve exercise ability.[22 ]

Not enough data are available regarding the efficacy of these drugs in patients with secondary pulmonary hypertension such as in

patients with COPD.

Cardiac glycosides

The use of cardiac glycosides, such as digitalis, in patients with cor pulmonale has been controversial, and the beneficial effect of

these drugs is not as obvious as in the setting of left heart failure. Nevertheless, studies have confirmed a modest effect of digitalis on

the failing right ventricle in patients with chronic cor pulmonale.[23 ]It must be used cautiously, however, and should not be used during

the acute phases of respiratory insufficiency when large fluctuations in levels of hypoxia and acidosis may occur. Patients with

hypoxemia or acidosis are at increased risk of developing arrhythmias due to digitalis through different mechanisms including

sympathoadrenal stimulation.

Theophylline

In addition to bronchodilatory effect, theophylline has been reported to reduce pulmonary vascular resistance and pulmonary arterial

pressures acutely in patients with chronic cor pulmonale secondary to COPD.[24 ]Theophylline has a weak inotropic effect and thus

may improve right and left ventricular ejection. Low doses of theophylline have also been suggested to have anti-inflammatory effects

that help to control underlying lung diseases such as COPD.[25 ]As a result, considering the use of theophylline as adjunctive therapy

in the management of chronic or decompensated cor pulmonale is reasonable in patients with underlying COPD.

Warfarin

Anticoagulation with warfarin is recommended in patients at high risk for thromboembolism. The beneficial role of anticoagulation in

improving the symptoms and mortality in patients with primary pulmonary arterial hypertension has been demonstrated in several

studies.[26,27,28,29 ]The evidence of benefit, however, has not been established in patients with secondary pulmonary arterial

hypertension. Therefore, anticoagulation therapy may be used in patients with cor pulmonale secondary to thromboembolic

phenomena and with underlying primary pulmonary arterial hypertension.

Surgical Care

Phlebotomy is indicated in patients with chronic cor pulmonale and chronic hypoxia causing severe polycythemia, defined as

hematocrit of 65 or more. Phlebotomy results in a decrease in mean pulmonary artery pressure, a decrease in mean pulmonary

vascular resistance,[30 ]and an improvement in exercise performance in such patients. However, no evidence suggests improvement

in survival. Generally, phlebotomy should be reserved as an adjunctive therapy for patients with acute decompensation of cor

pulmonale and patients who remain significantly polycythemic despite appropriate long-term oxygen therapy. Replacement of the

acute volume loss with a saline infusion may be necessary to avoid important decreases in systemic blood pressure.

No surgical treatment exists for most diseases that cause chronic cor pulmonale. Pulmonary embolectomy is efficacious for

unresolved pulmonary emboli, which contribute to pulmonary hypertension. Uvulopalatopharyngoplasty in selected patients with sleep

apnea and hypoventilation[31 ]may relieve cor pulmonale. Single-lung, double-lung, and heart-lung transplantation are all used to

salvage the terminal phases of several diseases (eg, primary pulmonary hypertension, emphysema, idiopathic pulmonary fibrosis,

cystic fibrosis) complicated by cor pulmonale. Lung transplantation may lead to a reversal of right ventricular dysfunction from the

chronic stress of pulmonary hypertension. However, strict selection criteria for lung transplant recipients must be met because of the

limited availability of organ donors.

Medication

Diuretics are used to decrease the elevated right ventricular filling volume in patients with chronic cor pulmonale. Calcium channel

blockers are pulmonary artery vasodilators that have proven efficacy in the long-term management of chronic cor pulmonale

secondary to primary pulmonary arterial hypertension. New FDA-approved prostacyclin analogues and endothelin-receptor

antagonists are available for treatment of PPH. The beneficial role of cardiac glycosides, namely digitalis, on the failing right ventricle

are somewhat controversial; they can improve right ventricular function but must be used with caution and should be avoided during

acute episodes of hypoxia.

In the management of cor pulmonale, the main indication for oral anticoagulants is in the setting of an underlying thromboembolic

event or primary pulmonary arterial hypertension. Methylxanthines, like theophylline, can be used as an adjunctive treatment for

chronic cor pulmonale secondary to COPD. Besides the moderate bronchodilatory effect of methylxanthine, it improves myocardial

contractility, causes a mild pulmonary vasodilatory effect, and enhances diaphragmatic contractility.

Diuretics

Are used to decrease the elevated right ventricular filling volume in patients with chronic cor pulmonale.




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Furosemide (Lasix)

Example of diuretic agents used in the management of chronic cor pulmonale. Furosemide is a powerful loop diuretic that works on

thick ascending limb of Henle loop, causing a reversible block in reabsorption of sodium, potassium, and chloride.

Dosing

Adult

20-80 mg/d PO/IV/IM; may titrate to maximum dose of 600 mg/d

Pediatric

1-2 mg/kg/dose PO; not to exceed 6 mg/kg/dose; do not administer more frequent than q6h

1 mg/kg IV/IM slowly under close supervision; not to exceed 6 mg/kg

Interactions

Metformin decreases furosemide concentrations; furosemide interferes with hypoglycemic effect of antidiabetic agents and

antagonizes muscle-relaxing effect of tubocurarine; auditory toxicity appears to be increased with coadministration of aminoglycosides

and furosemide; hearing loss of varying degrees may occur; anticoagulant activity of warfarin may be enhanced when taken

concurrently with this medication; increased plasma lithium levels and toxicity are possible when taken concurrently with this

medication

Contraindications

Documented hypersensitivity; hepatic coma; anuria; concurrent severe electrolyte depletion

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Perform frequent serum electrolyte, carbon dioxide, glucose, creatinine, uric acid, calcium, and BUN determinations during first few

months of therapy and periodically thereafter

Calcium channel blockers

These agents inhibit movement of calcium ions across the cell membrane, depressing both impulse formation (automaticity) and

conduction velocity.

Nifedipine (Procardia)

Especially in the sustained-release form, nifedipine is a calcium channel blocker that has proven to be fairly effective in the

management of chronic cor pulmonale caused by primary pulmonary hypertension. Modifies the entry of calcium into the cells by

blocking the slow or voltage-dependent calcium channels, resulting in vasodilation, which improves myocardial oxygen delivery.

Sublingual administration generally is safe, despite theoretical concerns.

Dosing

Adult

10-30 mg SR cap PO tid; not to exceed 120-180 mg/d

30-60 mg SR tab PO qd; not to exceed 90-120 mg/d

Pediatric

Not recommended

Interactions

Monitor oral anticoagulants when used concomitantly; coadministration with any agent that can lower BP, including beta-blockers and

opioids, can result in severe hypotension; H2 blockers (cimetidine) may increase toxicity

Contraindications

Documented hypersensitivity

Precautions




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Pregnancy


Precautions

Aortic stenosis; angina; congestive heart failure; pregnancy; nursing mothers; may cause lower extremity edema; allergic hepatitis

has occurred but is rare

Cardiac glycosidesThese agents decrease AV nodal conduction primarily by increasing vagal tone.

Digoxin (Lanoxin)

Has a positive inotropic effect on failing myocardium. Effect is achieved via inhibition of the Na+/K+-ATPase pump, leading to

increase in intracellular sodium concentration along with concomitant increase in intracellular calcium concentration by means of

calcium-sodium exchange mechanism. Net result is augmentation of myocardial contractility.

Dosing

Adult

0.125-0.375 mg PO qd; may be administered qod; available in PO/IV/IM preparations

Pediatric

8-10 mcg/kg/d PO/IV/IM; maximum dose 100-150 mcg/kg/d

Interactions

Medications that may increase digoxin levels include alprazolam, benzodiazepines, bepridil, captopril, cyclosporine, propafenone,

propantheline, quinidine, diltiazem, aminoglycosides, oral amiodarone, anticholinergics, diphenoxylate, erythromycin, felodipine,

flecainide, hydroxychloroquine, itraconazole, nifedipine, omeprazole, quinine, ibuprofen, indomethacin, esmolol, tetracycline,

tolbutamide, and verapamil; medications that may decrease serum digoxin levels include aminoglutethimide, antihistamines,

cholestyramine, neomycin, penicillamine, aminoglycosides, oral colestipol, hydantoins, hypoglycemic agents, antineoplastic treatment

combinations (eg, carmustine, bleomycin, methotrexate, cytarabine, doxorubicin, cyclophosphamide, vincristine, procarbazine),

aluminum or magnesium antacids, rifampin, sucralfate, sulfasalazine, barbiturates, kaolin/pectin, and aminosalicylic acid

Contraindications

Documented hypersensitivity; beriberi heart disease; idiopathic hypertrophic subaortic stenosis; constrictive pericarditis; carotid sinus

syndrome

Precautions

Pregnancy


Precautions

Hypokalemia may reduce positive inotropic effect of digitalis; IV calcium may produce arrhythmias in digitalized patients;

hypercalcemia predisposes patient to digitalis toxicity; hypocalcemia can make digoxin ineffective until serum calcium levels are

normal; magnesium replacement therapy must be instituted in patients with hypomagnesemia to prevent digitalis toxicity; patients

diagnosed with incomplete AV block may progress to complete block when treated with digoxin; exercise caution in hypothyroidism,

hypoxia, and acute myocarditis

Anticoagulants

These agents may reduce incidence of embolisms when used fast, effectively, and early.

Warfarin (Coumadin)

Most commonly used oral anticoagulant. Interferes with hepatic synthesis of vitamin K-dependent coagulation factors. Used for

prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders.

Dosing

Adult

2-10 mg/d PO qd; adjust dose to an INR of 1.5:2 or higher depending on the condition requiring anticoagulation




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Pediatric

Administer weight-based dose of 0.05-0.34 mg/kg/d PO/IV; adjust dose according to desired INR

Interactions

Griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin

K, spironolactone, oral contraceptives, and sucralfate may decrease anticoagulant effects; oral antibiotics, phenylbutazone,

salicylates, sulfonamides, chloral hydrate, clofibrate, diazoxide, anabolic steroids, ketoconazole, ethacrynic acid, miconazole, nalidixic

acid, sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram, metronidazole, phenylbutazone, phenytoin, propoxyphene,sulfonamides, gemfibrozil, acetaminophen, and sulindac may increase anticoagulant effects

Contraindications

Documented hypersensitivity; severe liver or kidney disease; open wounds; GI ulcers

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Dose needs to be adjusted to INR; caution in bleeding tendency and hazardous active hemorrhagic conditions, malignant

hypertension, patients at high risk of recurrent trauma, (eg, people with alcoholism or psychosis, unsupervised patients who are

senile); warfarin anaphylaxis, hepatic, renal, thyroid, allergic, and hematologic hypocoagulable conditions and disorders; do not switch

brands after achieving therapeutic response; caution in active tuberculosis or diabetes; patients with protein C or S deficiency are at

risk of developing skin necrosis

Methylxanthines

Potentiate exogenous catecholamines and stimulate endogenous catecholamine release and diaphragmatic muscular relaxation,

which, in turn, stimulates bronchodilation.

Theophylline (Aminophyllin, Theo-24, Theolair, Theo-Dur)

Mechanism of action is not well defined yet. Was formerly thought that this drug increases intracellular cyclic AMP by causing

inhibition of phosphodiesterase; however, current data do not support that.

Dosing

Adult

Loading dose: 5.6 mg/kg IV over 20 min (based on aminophylline)

Maintenance dose: IV infusion at 0.5-0.7 mg/kg/h; also available in oral preparation

Pediatric

1 year: Administer as in adults

Interactions

Effects may decrease with aminoglutethimide, barbiturates, carbamazepine, ketoconazole, loop diuretics, charcoal, hydantoins,

phenobarbital, phenytoin, rifampin, isoniazid, and sympathomimetics; effects may increase with allopurinol, beta-blockers,

ciprofloxacin, corticosteroids, disulfiram, quinolones, thyroid hormones, ephedrine, carbamazepine, cimetidine, erythromycin,

macrolides, propranolol, and interferon

Contraindications

Documented hypersensitivity; uncontrolled arrhythmias; peptic ulcers; hyperthyroidism; uncontrolled seizure disorders

Precautions

Pregnancy





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Precautions

Has low serum therapeutic-to-toxicity ratio, and, therefore, serum level monitoring is important; peptic ulcer; hypertension;

tachyarrhythmias; hyperthyroidism; compromised cardiac function; do not inject IV solution faster than 25 mg/min; patients diagnosed

with pulmonary edema or liver dysfunction are at greater risk of toxicity because of reduced drug clearance

Endothelin receptor antagonists

Competitively bind to endothelin-1 (ET-1) receptors ETA and ETB causing reduction in pulmonary artery pressure (PAP), pulmonary

vascular resistance (PVR), and mean right atrial pressure (RAP).

Bosentan (Tracleer)

Endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension in patients with WHO Class II-IV

symptoms, to improve exercise ability and decrease rate of clinical worsening. Inhibits vessel constriction and elevation of blood

pressure by competitively binding to endothelin-1 (ET-1) receptors ETA and ETB in endothelium and vascular smooth muscle. This

leads to significant increase in cardiac index (CI) associated with significant reduction in pulmonary artery pressure (PAP), mean right

atrial pressure (RAP), pulmonary vascular resistance (PVR), and, to a lesser extent, systemic vascular resistance (SVR). Due to

teratogenic potential, can only be prescribed through the Tracleer Access Program (1-866-228-3546).

Dosing

Adult

40 kg: 62.5 mg PO bid for 4 wk initially, then increase to 125 mg PO bid

Pediatric

Not established; 62.5 mg PO bid recommended if 12 years; not to exceed 125 mg/d

Interactions

Toxicity may increase when administered concomitantly with inhibitors of isoenzymes CYP450 2C9 and CYP450 3A4 (eg,

ketoconazole, erythromycin, fluoxetine, sertraline, amiodarone, and cyclosporine A); induces isoenzymes CYP450 2C9 and CYP450

3A4 causing decrease in plasma concentrations of drugs metabolized by these enzymes including glyburide as well as other

hypoglycemics, cyclosporine A, hormonal contraceptives, simvastatin, and possibly other statins; hepatotoxicity increases with

concomitant administration of glyburide

Contraindications

Documented hypersensitivity; coadministration with cyclosporine A or glyburide

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Causes at least 3-fold elevation of liver aminotransferases (ie, ALT, AST) in about 11% of patients; may elevate bilirubin (serum

aminotransferase levels must be measured prior to initiation of treatment and then monthly); caution in patients with mildly impaired

liver function (avoid in patients with moderate or severe liver impairment); not recommended while breastfeeding; monitor hemoglobin

levels after 1 and 3 mo of treatment and every 3 mo thereafter; exclude pregnancy before initiating treatment and prevent thereafter

by use of reliable contraception; headache and nasopharyngitis may occur

Ambrisentan (Letairis)

Endothelin receptor antagonist indicated for pulmonary arterial hypertension in patients with WHO class II or III symptoms. Improves

exercise ability and decreases progression of clinical symptoms. Inhibits vessel constriction and elevation of blood pressure by

competitively binding to endothelin-1 receptors ETA and ETB in endothelium and vascular smooth muscle. This leads to significant

increase in cardiac index associated with significant reduction in pulmonary artery pressure, mean right atrial pressure, pulmonary

vascular resistance, and, to a lesser extent, systemic vascular resistance (SVR). Because of the risks of hepatic injury and

teratogenic potential, only available through the Letairis Education and Access Program (LEAP). Prescribers and pharmacies must

register with LEAP in order to prescribe and dispense. For more information, see http://www.letairis.com or call (866) 664-LEAP(5327).

Dosing




12/16

Adult

5 mg PO qd initially; may increase to 10 mg PO qd if 5 mg/d tolerated; do not chew, crush, or split tab

Pediatric

Not established

Interactions

Glycoprotein-P, OATP, UGTs (ie, 1A9S, 2B7S, 1A3S), CYP2C19, and CYP3A substrate; coadministration with CYP3A (eg,cyclosporine, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir,

telithromycin) or 2C19 inhibitors (eg, omeprazole) may decrease elimination and therefore increase serum levels; CYP3A and 2C19

inducers (eg, rifampin) may increase metabolism and therefore decrease serum levels

Contraindications

Pregnancy

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Common adverse effects include peripheral edema, nasal congestion, sinusitis, and facial flushing; caution with mild hepatic

impairment or history of moderate-to-severe hepatic impairment; hepatic injury may occur (monitor bilirubin, ALT, and AST values at

baseline and then monthly); may use in women of childbearing potential only after negative pregnancy test result and must use 2

reliable methods of contraception (unless tubal sterilization or Copper T 380A or LNg 20 IUD inserted); may decrease hemoglobin

and hematocrit values (monitor at baseline, 1 mo, and then periodically)

Follow-up

Further Inpatient Care

Appropriate treatment is directed both at the underlying etiology and at correction of hypoxia when present.

Further Outpatient Care

z Patients with cor pulmonale generally require close attention in the outpatient setting.

z Regular assessment of oxygen needs and pulmonary function are appropriate.

z Many patients benefit from a formal program of pulmonary rehabilitation.

Complications

Complications of cor pulmonale include syncope, hypoxia, pedal edema, passive hepatic congestion, and death.

Prognosis

z The prognosis of cor pulmonale is variable depending upon underlying pathology.

z Patients with cor pulmonale due to COPD have a high 2-year mortality.

Patient Education

Patient education regarding the importance of adherence to medical therapy is vital because appropriate treatment of both hypoxia

and underlying medical illness can improve mortality and morbidity.

Miscellaneous

Medicolegal Pitfalls

z Making a diagnosis of cor pulmonale should be followed by further investigation to determine the underlying lung pathology.

Sometimes a common lung disease such as COPD is not the only lung pathology as the cause of cor pulmonale; other lung

diseases may coexist.




13/16

z When diagnosing cor pulmonale, considering the possibility of thromboembolic disease and primary pulmonary hypertension

as possible etiologies is important.

z Note the importance of continuous supplemental oxygen therapy in appropriate patients, as well as the dangers of cigarette

smoking while using supplemental oxygen. Elevation of carboxyhemoglobin in the blood due to smoking can significantly

decrease the effect of O2 on arterial O2 content.

Multimedia

Media file 1: This ECG shows some typical abnormalities that may be seen in cor pulmonale and other chronic

pulmonary diseases: (1) R/S ratio >1 in V1 and


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Keywords

cor pulmonale, pulmonary hypertension, cardiopulmonary disease, COPD, chronic obstructive pulmonary disease, ARDS, acute

respiratory distress syndrome, right heart failure, right ventricular failure, right ventricular hypertrophy, RVH, pulmonary

thromboembolism, interstitial lung disease, polycythemia vera, macroglobulinemia, pulmonary embolism, pulmonary emboli, diastolic

pulmonary regurgitation murmur

Contributor Information and Disclosures

Author

Al i A Sovari , MD, Clinical and Research Fellow in Cardiovascular Medicine, Section of Cardiology, University of Illinois at ChicagoAli A Sovari, MD is a member of the following medical societies: American College of Cardiology, American College of Physicians,

American Heart Association, American Medical Association, and Heart Rhythm Society

Disclosure: Nothing to disclose.

Coauthor(s)

Ravi H Dave, MD, Associate Professor of Medicine, University of California at Los Angeles David Geffen School of Medicine


Abr aham G Kocheril , MD, FACC, FACP, FHRS, Professor of Medicine, Director of Clinical Electrophysiology, University of Illinois at

Chicago

Abraham G Kocheril, MD, FACC, FACP, FHRS is a member of the following medical societies: American College of Cardiology,

American College of Physicians, American Heart Association, American Medical Association, Cardiac Electrophysiology Society,

Central Society for Clinical Research, Heart Failure Society of America, and Illinois State Medical Society


Medical Editor

Gregory J Dehmer, MD, Director, Division of Cardiology, Scott & White Healthcare; Professor of Medicine, Texas A&M Health

Science Center College of Medicine

Gregory J Dehmer, MD is a member of the following medical societies: American College of Cardiology, American Heart Association,

Society for Cardiac Angiography and Interventions, and Society of Cardiac Angiography and Interventions


Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine

Disclosure: eMedicine Salary Employment

Managing Editor




16/16

Steven J Compton, MD, FACC, FACP, Director of Cardiac Electrophysiology, Alaska Heart Institute, Providence and Alaska

Regional Hospitals

Steven J Compton, MD, FACC, FACP is a member of the following medical societies: Alaska State Medical Association, American

College of Cardiology, American College of Physicians, American Heart Association, American Medical Association, and Heart

Rhythm Society


CME Editor

Amer Sul eman, MD, Consultant in Electrophysiology and Cardiovascular Medicine, Department of Internal Medicine, Division of

Cardiology, Medical City Dallas Hospital

Amer Suleman, MD is a member of the following medical societies: American College of Physicians, American Heart Association,

American Institute of Stress, American Society of Hypertension, Federation of American Societies for Experimental Biology, Royal

Society of Medicine, and Society of Cardiac Angiography and Interventions


Chief Editor

Henry H Ooi, MBBCh, BAO, MRCPI, Director, Advanced Heart Failure and Cardiac Transplant Program, Nashville Veterans Affairs

Medical Center; Cardiologist, Heart Failure and Cardiac Transplant Program, Vanderbilt University Medical Center

Henry H Ooi, MBBCh, BAO, MRCPI is a member of the following medical societies: American College of Cardiology, American Heart

Association, Heart Failure Society of America, and International Society for Heart and Lung Transplantation


Ack now ledgments

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors Robert S Crausman, MD, MMS and Nidal A Yunis, MD tothe development and writing of this article.

Further Reading

Clinical trials

Educational and Supportive Interventions to Prevent Cardiopulmonary Rehospitalization

Identification of Genetic Markers for Cardiopulmonary Diseases (Genotype)

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