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	WORKUP	Section 5 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Lab 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.

• 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 Leyden, anticardiolipin antibodies, and homocysteine.

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

• 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:

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

• 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.

• Echocardiography: Two-dimensional echocardiography usually demonstrates signs of chronic right ventricular pressure overload. As this overload progresses, increased thickness of the right ventricular wall with paradoxical motion of the interventricular septum during systole occurs. At an advanced stage, right ventricular 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.
  Doppler echocardiography is used now 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.

• 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.

• Ultrafast, ECG-gated CT scanning has been recently evaluated to study RV function. In addition to estimating right ventricular ejection fraction (RVEF), it can estimate RV wall mass. Its use is still experimental, but with further improvement, it may be used to evaluate the progression of cor pulmonale in the near future.

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

• Radionuclide ventriculography can determine RVEF noninvasively.

Other Tests:

• Electrocardiography (ECG): ECG abnormalities in cor pulmonale reflect the presence of RVH, RV strain, or underlying pulmonary disease. These electrocardiographic changes may include right axis deviation, R/S amplitude ratio in V1 greater than 1 (increase in anteriorly directed forces may be a sign of posterior infarct), R/S amplitude ratio in V6 less than 1, P-pulmonale pattern (an increase in P wave amplitude in leads 2, 3, and aVF), S₁Q₃T₃ pattern and incomplete (or complete) right bundle branch block, especially if pulmonary embolism is the underlying etiology, low-voltage QRS because of underlying COPD with hyperinflation and increased AP diameter of the chest. Severe RVH may reflect as Q waves in the precordial leads that may be interpreted as anterior myocardial infarction by mistake (on the other hand, since electrical activity of the RV is significantly less than the LV, small changes in RV forces may be lost in ECG).

• Additionally, many rhythm disturbances may be present in chronic cor pulmonale; these range from isolated premature atrial depolarizations to various supraventricular tachycardia, including paroxysmal atrial tachycardia, multifocal atrial tachycardia, atrial fibrillation, atrial flutter, and junctional tachycardia. These dysrhythmias may be triggered by processes secondary to the underlying disease, (eg, anxiety, hypoxemia, acid-base imbalance, electrolyte disturbances, excessive use of bronchodilators, heightened sympathetic activity). Life-threatening ventricular tachyarrhythmias are less common.

• In selected cases, pulmonary function testing may be indicated to determine underlying obstructive or interstitial lung disease.

Procedures:

• Cardiac catheterization: Right-heart catheterization is considered the most precise method for diagnosis and quantification of pulmonary hypertension. It is indicated when echocardiography cannot assess the severity of a tricuspid regurgitant jet, thus excluding an assessment of pulmonary hypertension. Right-heart catheterization is occasionally important for differentiating cor pulmonale from occult left ventricular dysfunction, especially when the presentation is confusing. Another indication may be for evaluation of the potential reversibility of pulmonary arterial hypertension with vasodilator therapy or when a left-side catheterization is indicated.

• Lung biopsy occasionally may be indicated to determine underlying etiology.

	TREATMENT	Section 6 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Medical Care: Medical therapy 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, epinephrin) 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 is of great importance in patients with underlying COPD, 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 significant reduction in the mortality rate. 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 Hgor O₂ saturation is greater than 88%.

  Although it is not clear whether oxygen therapy has a mortality rate benefit in patients with cor pulmonale due to pulmonary disorders other than COPD, 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 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 volume depletion 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 have been advocated in the long-term management of chronic cor pulmonale with modest results. Calcium channel blockers, particularly oral sustained-release nifedipine and diltiazem, can lower pulmonary pressures, although they appear more effective in primary rather than secondary pulmonary hypertension. 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 with COPD with disproportionately high pulmonary blood pressure.

  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 DrugAdministration (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. 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. PDE5 inhibitor sildenafil has also been intensively studied and recently approved by the FDA for treatment of pulmonary hypertension based on a large randomized study. Sildenafil promotes selective smooth muscle relaxation in lung vasculature. Not enough data are available regarding the efficacy of these drugs in patients with secondary pulmonary hypertension such as in patients with COPD.

• 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. 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.

• 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. Theophylline has a weak inotropic effect and thus may improve right and left ventricular ejection. 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.

• 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 clearly was demonstrated in a variety of clinical trials. 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, and an improvement in exercise performance in such patients. There is, however, no evidence of 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 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. Apparently, lung transplantation will lead to a reversal of right ventricular dysfunction from the chronic stress of pulmonary hypertension. Strict selection criteria for lung transplant recipients must be met, however, because of the limited availability of organ donors.

	MEDICATION	Section 7 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

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 mild pulmonary vasodilatory effect, and enhances the diaphragmatic contractility.

Drug Category: Diuretics -- Are used to decrease the elevated right ventricular filling volume in patients with chronic cor pulmonale.

Drug Name	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.
Adult Dose	20-80 mg/d PO/IV/IM; may titrate to maximum dose of 600 mg/d
Pediatric Dose	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
Contraindications	Documented hypersensitivity; hepatic coma; anuria; concurrent severe electrolyte depletion
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
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Perform frequent serum electrolyte, carbon dioxide, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter

Drug Category: Calcium channel blockers -- These agents inhibit movement of calcium ions across the cell membrane, depressing both impulse formation (automaticity) and conduction velocity.

Drug Name	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.
Adult Dose	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 Dose	Not recommended
Contraindications	Documented hypersensitivity
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
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Aortic stenosis; angina; congestive heart failure; pregnancy; nursing mothers; may cause lower extremity edema; allergic hepatitis has occurred but is rare

Drug Category: Cardiac glycosides -- These agents decrease AV nodal conduction primarily by increasing vagal tone.

Drug Name	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.
Adult Dose	0.125-0.375 mg PO qd; may be administered qod; available in PO/IV/IM preparations
Pediatric Dose	8-10 mcg/kg/d PO/IV/IM; maximum dose 100-150 mcg/kg/d
Contraindications	Documented hypersensitivity; beriberi heart disease; idiopathic hypertrophic subaortic stenosis; constrictive pericarditis; carotid sinus syndrome
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
Pregnancy	C - Safety for use during pregnancy has not been established.
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

Drug Category: Anticoagulants -- These agents may reduce incidence of embolisms when used fast, effectively, and early.

Drug Name	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.
Adult Dose	2-10 mg/d PO/IV qd; adjust dose to an INR of 1.5:2 or higher depending on the condition requiring anticoagulation
Pediatric Dose	Administer weight-based dose of 0.05-0.34 mg/kg/d PO/IV; adjust dose according to desired INR
Contraindications	Documented hypersensitivity; severe liver or kidney disease; open wounds; GI ulcers
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
Pregnancy	D - Unsafe in pregnancy
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

Drug Category: Methylxanthines -- Potentiate exogenous catecholamines and stimulate endogenous catecholamine release and diaphragmatic muscular relaxation, which, in turn, stimulates bronchodilation.

Drug Name	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.
Adult Dose	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 Dose	6 weeks to 6 months: 0.5 mg/kg/h loading dose IV in first 12 h (based on aminophylline), followed by maintenance infusion of 12 mg/kg/d thereafter; may administer continuous infusion by dividing total daily dose by 24 h 6 months to 1 year: 0.6-0.7 mg/kg/h loading dose IV in first 12 h, followed by maintenance infusion of 15 mg/kg/d; may administer as continuous infusion as above >1 year: Administer as in adults
Contraindications	Documented hypersensitivity; uncontrolled arrhythmias; peptic ulcers; hyperthyroidism; uncontrolled seizure disorders
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
Pregnancy	C - Safety for use during pregnancy has not been established.
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

Drug Category: Endothelin receptor antagonists -- Competitively bind to endothelin-1 (ET-1) receptors ET_A and ET_B causing reduction in pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), and mean right atrial pressure (RAP).

Drug Name	Bosentan (Tracleer) -- Endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension in patients with WHO Class III or 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), pulmonary vascular resistance (PVR), and mean right atrial pressure (RAP). Due to teratogenic potential, can only be prescribed through the Tracleer Access Program (1-866-228-3546).
Adult Dose	<40 kg: 62.5 mg PO bid; not to exceed 125 mg/d >40 kg: 62.5 mg PO bid for 4 wk initially, then increase to 125 mg PO bid
Pediatric Dose	Not established; 62.5 mg PO bid recommended if <40 kg, or >12 years; not to exceed 125 mg/d
Contraindications	Documented hypersensitivity; coadministration with cyclosporine A or glyburide
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
Pregnancy	X - Contraindicated in pregnancy
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

	FOLLOW-UP	Section 8 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Further Inpatient Care:

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

Further Outpatient Care:

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

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

• 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:

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

• 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	Section 9 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Medical/Legal Pitfalls:

• 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.

• When diagnosing cor pulmonale, considering the possibility of thromboembolic disease and primary pulmonary hypertension as possible etiologies is important.

• 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.