- Diseases, Disorders & Conditions
Clinical details and basic medical information about Pleurisy and Pyogenic lung diseases
Pleurisy – inflammation of pleura, usually producing an exudative pleural effusion and stabbing chest pain worsened by respiration and cough.
Pleurisy may result from an underlying lung process (eg, pneumonia, infarction, irritating substance into the pleural space (eg, with a ruptured esophagus, amebic empyema, or pancreatic pleurisy); transport of an infectious or noxious agent or neoplastic cells to the pleura via the bloodstream or lymphatics; parietal pleural injury (eg, trauma, especially rib fracture, or epidemic pleurodynia /due to coxsackievirus B/); asbestos-related pleural disease in which asbestos particles reach the pleura by traversing the conducting airways and respiratory tissues; or, rarely, pleural effusion related to drug ingestion.
The pleura usually first becomes edematous and congested. Cellular infiltration follows, and fibrinous exudate develops on the pleural surface. The exudate may be reabsorbed or organized into fibrous tissue resulting in pleural adhesions. In sme diseases (eg, epidemic pleurodynia), the pleurisy remains dry or fibrinous, with no significant exudaiton of fluid from the inflamed pleura. More often, pleural exudate develops from an outpouring of fluid rich in plasma proteins from damaged capillaries. Occasionally, marked fibrous or even calcific thickening of pleura (eg, asbestos pleural plaques, idiopathic pleural calcification) develops without an antecedent acute pleurisy.
Symptoms and Signs
Sudden pain is the dominant symptom of pleurisy. Typically, pleuritic pain is a stubbing sensation aggravated by breathing and coughing, but it can vary. It may only a vague discomfort, or it may occur only when the patient breathes deeply or coughs. The visceral pleura is insensitive; pain results from inflammation of parietal pleura, which is mainly innervated by intercostal nerves. Pain is usually felt over the pleuritic site but may be referred to distant regions. Irritation of posterior and peripheral portioms of the diaphragmatic pleura, which are supplied by the lower six intercostal nerves, may cause pain referred to the lower chest wall or abdomen and may simulate intra-abdominal disease. Irritation of the central portion of the diaphragmatic pleura, innervated by the phrenic nerves, causes pain referred to the neck and shoulder.
Respiration is usually rapid and shallow. Motion of the affected side may be limited. Breath sounds may be diminished. A pleural friction rub, although infrequent, is the characteristic physical sign.It may not be accompanied by pleuritic pain, but it usually is. The friction rub varies from a few intermittent sounds that may simulate crackles to a fully developed harsh grating, creaking, or leathery sound synchronous with respiration, heard on inspiration and expiration. Friction sounds due to pleuritis adjacent to the heart (pleuropericardial rub) may vary with the heart beat as well.
When pleural effusion develops, pleuritic pain usually subsides. Percussion dullness, absent tactile fremitus, decreased or absent breath sounds, and egophony at the upper border of the fluid are then noticeable. The larger the effusion, the more obvious the above signs. A large effusion may produce or contribute to dyspnea through diminished lung volume, especially if there is underlying pulmonary disease, mediastinal shift to the contralateral side, and diminished function and recruitment of inspiratory muscles due to an expanded thoracic cage.
Pleurisy is readily diagnosed when characteristic pleuritic pain occurs. A pleural friction rub is pathognomonic. Pleurisy that produces referred abdominal pain is usually differentiated from acute inflammatory abdominal disease by x-ray and clinical evidence of a respiratory process; absence of nausea, vomiting, and disturbed bowel function; marked aggravation of pain by deep breathing or coughing; shallow rapid breathing; and a tendency toward relief of pain by pressure on the chest wall or abdomen. Intercostal neuritis may be confused with pleurisy, but the pain is rarely related to respiration and there is no friction rub. With herpetic neuritis, development of the characteristic skin eruption is diagnostic. Miocardial infarction, spontaneous pneumothorax, pericarditis, and chest wall lesions may simulate pleurisy. A plueral friction rub may be confused with a friction rub of pericarditis (pericardial rub), which is heard best over the left border of the sternum in the third and forth interspaces, is characteristically a to-and-fro sound synchronous with the heartbeat, and is not influenced significantly by respiration.
Chest x-rays are of limited value in diagnosing fibrinous pleurisy. The pleural lesion causes no shadow, but an associated pulmonary or chest wall lesion may. The presence of a pleural effusion, generally small, confirms the presence of acute pleurisy
Treatment of the underlying disease is essential.
Chest pain may be relieved by wrapping the entire chest with two or three 6-in-wide nonadhesive elastic bandages, which must be reapplied once or twice daily. Acetaminophen 0.65 g qid or an NSAID is often effective. Oral narcotics may be necessary, but cough suppression may be not desired.
Adequate bronchial drainage must be provided to prevent pneumonia. A patient receiving narcotics should be urged to breathe deeply and cough when pain relief from the drug is maximal. Antibiotics and bronchodilators should be considered for treatment of associated bronchitis.
x-ray and CT Scan findings
Essentials of Diagnosis
• Development of pulmonary symptoms about 1-2 weeks after possible aspiration, bronchial obstruction, or previous pneumonia.
• Septic fever and sweats, and periodic sudden ex pectoration of large amounts of purulent, foul-smelling, or "musty" sputum. Hemoptysis may occur.
• X-ray density with central radiolucency and fluid level.
Lung abscess develops when necrosis and liquefaction occur in an area where necrotizing pneumonia is present (picture 1-3). Symptoms and signs occur 1-2 weeks after the following events: (1) massive-aspira tion of upper respiratory tract secretions and microbial flora, especially during profound suppression of cough reflex (eg, with alcohol, drugs, unconsciousness, anesthesia, brain trauma); (2) bronchial obstruction (eg, by atelectasis, foreign body, neoplasm); (3) pres ence of pneumonias, especially those caused by gram-negative bacteria or staphylococci; or (4) forma tion of septic emboli from other foci of infection, or, during bacteremia, with pulmonary infarcts. Abscess is more commonly in the lower dependent portions of the lung. The main etiologic organisms are related to the underlying condition, but a dense mixed anaerobic flora is often prominent, particularly when aspiration has occurred.
A. Symptoms and Signs: Onset may be abrupt or gradual. Symptoms include septic fever, sweats, cough, and chest pain. Cough is often nonproductive at onset. Expectoration of foul-smelling brown or gray sputum (anaerobic flora) or of purulent sputum without odor (pyogenic organism) may occur abruptly and in large quantity. Blood-streaked sputum is also common.
Pleural pain, especially with coughing, is common because the abscess is often subpleural. Weight loss, anemia, and pulmonary osteoarthropathy may appear when the abscess becomes chronic (8-12 weeks after onset).
Physical findings may be minimal. Consolidation due to pneumonitis surrounding the abscess is the most frequent finding. Rupture into the pleural space produces signs of fluid or pneumothorax.
B. Laboratory Findings: Sputum cultures are usually inadequate in determining the bacterial cause of a lung abscess. Transtracheal aspirates should be obtained with the proper technique employed to cul ture anaerobic organisms in addition to the usual aerobic cultures. Special methods of transporting specimens are required for anaerobic organisms, and appropriate culture media and methods must be employed.
Smear and cultures for the tubercle bacilli are required, especially in lesions of the upper lobe and in chronic abscess.
C. X-Ray Findings: A dense shadow is the initial finding. A central radiolucency, often with a visible fluid level, appears as surrounding densities subside. Computerized tomography can supply the detailed lo calization of the abscess and may also reveal primary lesions (eg, bronchogenic carcinoma) and provide guidance for contemplated surgery. Various x-ray pro cedures also permit localization of pleural involvement to facilitate drainage.
D. Instrumental Examination: Fiberoptic bronchoscopy may help to 'diagnose location and nature of obstructions (foreign body, tumor), obtain specimens for microbiologic and pathologic examina tion, and, occasionally, aid drainage.
Differentiate from other causes of pulmonary cavitation: tuberculosis, bronchogenic carcinoma, mycotic infections, and staphylococcal or gram-nega tive bacterial pneumonia.
Postural drainage and bronchoscopy are impor tant to promote drainage of secretions.
A. Acute Abscess: Intensive antibacterial ther apy is necessary to prevent further destruction of lung tissue. While cultures and sensitivity tests are pending, treatment should be started with penicillin G, 2-6 million units daily. In penicillin hypersensitivity clindamycin and chloramphenicol are alternatives. If the patient improves on antimicrobial drugs (and postural drainage),
the drugs should be continued for 4—8 weeks. If the patient fails to respond significantly to the initial treatment, laboratory results may suggest other antimicrobials, eg, nafcillin for staphylococci, cefotaxime for Klebsiella, cefoxitin or metronidazole for mixed anaerobes. Postural drainage is important adjunctive treatment. Percutaneous catheter drainage has been used successfully in selected cases. Surgical therapy is indicated mainly for severe hemoptysis and for me infrequent abscesses that fail to respond to antimicrobial management. Failure of fever to subside after 2 weeks of therapy, abscess diameter of more than 6 cm, and very thick cavity waits are all factors that lessen the likelihood of success with nonsurgical treatment alone.
B. Chronic Abscess: After acute systemic man ifestations have subsided, the abscess may persist. Although many patients with chronic lung abscess can be cured with long-term treatment with antibacterial agents, surgery may occasionally be required.
Rupture of pus into the pleural space (empyema) causes severe symptoms: increase in fever, marked pleural pain, and sweating; the patient becomes “tox ic" in appearance. Adequate drainage of empyema is mandatory. In chronic abscess, severe and even fatal hemorrhage may occur. Metastatic brain abscess is a well-recognized complication, and the infection may seed other organ sites. Bronchiectasis may occur as a sequela to lung abscess even when the abscess itself is cured.
The prognosis in acute abscess is excellent with prompt and intensive antibiotic therapy. About 80% of patients are healed within 7-8 weeks. The incidenee of chronic abscess is consequently low; Inchronic cases, surgery is curative.
Essentials of Diagnosis:
• Chronic cough with expectoration of large amounts of purulent sputum; hemoptysis.
• Rales and rhonchi over lower lobes.
• X-ray of chest reveals little; bronchograms show characteristic dilatations.
Bronchiectasis is a dilatation of small and medium-sized bronchi resulting from destruction of bronchial elastic and muscular elements. It may be, caused by pulmonary infections (eg, pneumonia, per tussis, tuberculosis) or by a bronchial obstruction (eg, foreign bodies or extrinsic pressure). In many patients, a history of onset following one or more episodes of pulmonary infection, usually in early childhood, is obtained. However,since infection does not regularly produce significant bronchiectasis, unknown intrinsic host factors presumably are present. The incidence of
the disease has been reduced by treating pulmonary infections with antibiotics.
A. Symptoms and Signs: Most patients with bronchiectasis have a history of chronic cough with expectoration of large volumes of sputum, especially upon awakening. The sputum has a characteristic qual ity of "layering out" into 3 layers upon standing, a frothy top layer, a middle clear layer, and a dense particulate bottom layer. It is usually purulent in ap pearance and foul-smelling.
Intermittent hemoptysis, occasionally in dangerous proportions, is often combined with intercurrent respiratory infections. Symptoms occur most often in patients with idiopathic bronchiectasis (ie, childhood respiratory infections). However, patients who have bronchiectasis secondary either to tuberculosis or chronic obstruction may not exhibit characteristic symptoms. Idiopathic bronchiectasis occurs most fre quently in the middle and lower lobes and posttuberculous bronchiectasis in the upper lobes. Hemoptysis is thought to result from erosion of bronchiolar mucosa with resultant destruction of un derlying blood vessels. Pulmonary insufficiency may result from progressive destruction of pulmonary tis sue.
Physical findings consist primarily of rales and rhonchi over the affected segments. If the condition is far-advanced, emaciation, cyanosis, and digital club bing may appear.
B. Laboratory Findings: There are no charac teristic laboratory findings. If hypoxemia is chronic and severe, secondary polycythemia may develop. There may be either restrictive or obstructive pulmo nary function defects associated with bronchiectasis. Hypoxemia and hypocapnia or hypercapnia may also be associated with the disease, depending on the se verity of the underlying condition. .
C.X-Ray Findings (figure 1-6): Plain films of the chest often show increased bronchopulmonary markings in af fected segments; in severe cases there may be areas of radiodensities surrounding portions of radiolucency. Early in the course of bronchiectasis, however, the chest x-ray may be normal.
The differential diagnosis includes other disorders that lead to chronic cough, sputum produc tion, and hemoptysis, ie, chronic bronchitis, tuber culosis, and bronchogenic carcinoma. The diagnosis of bronchiectasis is suggested by the patient's history and can be confirmed only by bronchographic examination or histopathologic examination of surgically removed tissue.
Recurrent infection in poorly drained pulmonary segments leads to chronic suppuration and may cause pulmonary insufficiency. Complications include hemoptysis, respiratory failure, chronic cor pulmonale, and amyloidosis. There is also an increased incidence of brain abscess, which is thought to be secondary to abnormal anastomoses between bron chial (systemic) and pulmonary venous circulation. These anastomoses produce right-to-left shunts and allow for the dissemination of septic emboli.Treatment
. A. General Measures and Medical Treatment:
1. Environmental changes- The patient should avoid exposure to all common pulmonary irritants such as smoke, fumes, and dust and should stop smoking cigarettes.
2. Control of bronchial secretions (improved drainage)-
a. Postural drainage often gives effective relief of symptoms and should be utilized in every case. The patient should assume the position that gives maximum drainage, usually lying on a bed in the prone, supine, or right or left lateral decubitus position with the hips elevated on several pillows and no pillow under the head. Any effective position should be main tained for 10 minutes, 2-4 times a day. The first drainage should be done upon awakening and tee last drainage at bedtime. Family members can be trained in the art of chest percussion to facilitate drainage of secretions.
b. Liquefaction of thick sputum may be pro moted by inhaling warm mists and, in some cases, mucolytic agents such as acetylcysteine or 5% sodium bicarbonate given by aerosol may also be helpful.
3. Control of respiratory infection-Exposure to respiratory infections should be minimized and the patient should be vaccinated against influenza and pneumococcal pneumonia. Antibiotic therapy is indicated for acute exacerbations (ie, increased production of purulent sputum, hemoptysis, etc). Long-term or prophylactic antibiotic therapy is controversial, since it has not been conclusively shown to be of lasting benefit. Therefore, it seems rational to treat acute exacerbations in order to control infection but mini mize the emergence of resistant strains. Because the bacteria most commonly involved are H inftuenzae and S pneumoniae, the drug most commonly employed is ampicillin, 250-500 mg orally every 6 hours for 5 days. Alternative therapies for the penicillin-allergic patient are erythromycin, given in the same dosage schedule as ampicillin, or trimethoprim-sulfamethoxazole, 2 double-strength tablets twice a day for 5 days.
B. Surgical Treatment: Surgical treatment is most often employed when hemoptysis with bron-chiectasis is recurrent and severe. Despite antibiotic therapy, localized bronchiectasis (eg, in a lower lobe or segment) with progressive uncontrolled infection and sputum production may be an indication for surgical removal of the affected segments.
Bronchiectasis is also associated with mucoviscidosis. It is thought to be secondary to the thick viscid secretions that cannot be cleared by normal cough mechanisms and that lead to stasis of.sputum and chronic infection. This disorder, usually associated with sinusitis, may be accompanied by other manifes tations of mucoviscidosis. Its most common organisms are S aureus or Pseudomonas aeruginosa.
Bronchiectasis is also associated with certain ab normalities of cellular ciliary function, the mostcommon of which is Kartagener's syndrome, a combina tion of sinusitis, situs in versus, andbronchiectasis. Patients with this disorder show immotile cilia second ary to ultrastructural abnormalities, stasis of sputum, failure to clear secretions, and chronic pulmonary infection that results in bronchiectasis.
Antibiotic treatment of mucoviscidosis and Kartagener's syndrome must be guided by sensitivity studies of organisms cultured from sputum.
Iodized contrast media instilled into the bronchial tree (a bronchogram) demonstrates saccular, cylindric, or fusiform dilatation of small and medium bronchi with consequent loss of the normal branching pattern. Cylindric changes of bronchiectasis that may result from acute pneumonia will revert to normal after 6-8 weeks, but saccular dilatations represent long-standing damage and permanent disease.
Patients with Cor Pulmonale
CHRONIC COR PULMONALE
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.
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; (3) increased blood viscosity secondary to blood disorders, eg, polycythemia vera, sickle cell disease, macroglobulinemia; and (4) 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, further increase in the degree of pulmonary arterial pressure brings significant RV dilation, an increase in RV end-diastolic pressure, and 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. This is a vicious cycle between decreases in LV and RV output.
Right ventricular overload is associated with septal displacement toward the left ventricle. Septal displacement, which is seen in 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 embolism causing 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 tidal 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
right ventricular dilatation
- In the US: 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. 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 insensitive for the detection of pulmonary hypertension. In contrast, acute cor pulmonale usually is secondary to massive pulmonary embolism. Acute massive pulmonary thromboembolism is the most common cause of acute life-threatening cor pulmonale in adults. 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.
- Internationally: 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 it 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 been shown to be dependent on presence or absence of cor pulmonale.
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.
- The patient may complain of fatigue, tachypnea, exertional dyspnea, and cough.
- 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.
- 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.
- Variety of neurologic symptoms may be seen due to decreased cardiac output and hypoxemia.
- In advanced stages, passive hepatic congestion secondary to severe right ventricular failure may lead to anorexia, right upper quadrant abdominal discomfort, and jaundice.
- 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.
- Elevated pulmonary artery pressure can lead to elevated right atrial pressure, peripheral venous pressure, and then capillary pressure and by increasing the hydrostatic gradient, it leads to transudation of fluid, which appears as 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 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.
Physical: Physical findings may reflect the underlying lung disease or pulmonary hypertension, RVH, and RV failure.
- On inspection, an increase in chest diameter, labored respiratory efforts with retractions of chest wall, distended neck veins with prominent a or v waves, and cyanosis may be seen.
- 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 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.
- RVH is characterized by a left parasternal or subxiphoid heave. Hepatojugular reflex and pulsatile liver are signs of RV failure with systemic venous congestion.
- On percussion, hyperresonance of the lungs may be a sign of underlying COPD; ascites can be seen in severe disease.
- Disorders with primary involvement of pulmonary vasculature and circulation
- Repeated pulmonary emboli
- Pulmonary vasculitis
- Pulmonary veno-occlusive disease
- Congenital heart disease with left-to-right shunting
- Sickle cell disease
- High altitude disease with pulmonary vasoconstriction
- Primary pulmonary hypertension
- Disorders with secondary involvement of pulmonary vasculature and circulation
- Parenchymal lung diseases (interstitial lung diseases, chronic obstructive lung diseases)
- Neuromuscular disorders (eg, myasthenia gravis, poliomyelitis, amyotrophic lateral sclerosis)
- Obstructive and central sleep apnea
- Thoracic deformities (eg, kyphoscoliosis)
Other Problems to be Considered:
Congestive (biventricular) heart failure
Primary pulmonic stenosis
Primary pulmonary hypertension
Right-sided heart failure due to congenital heart diseases
Right heart failure due to right ventricular infarction
- 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 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 (picture 12): 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 LVand 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.
(A) Parasternal long axis view obtained from a patient admitted for septic shock secondary to a severe aortic endocarditis (arrows indicate vegetations) associated with a massive regurgitation and dilated left ventricle. (B) Parasternal short axis view obtained from a patient with an acute respiratory distress syndrome and associated cor pulmonale. The right ventricle was markedly enlarged and the ventricular septum bulged towards the left ventricular cavity at end systole, due to severe pulmonary hypertension (arrow). (C) Apical four-chamber view obtained from a ventilated patient with refractory hypoxemia. The contrast study (intravenous injection of saline microbubbles) revealed a large interatrial right-to-left shunt through a patent foramen ovale, which participated to persistent hypoxemia: left cardiac cavities were filled up by the microbubbles within two cardiac cycles. (D) Subcostal view obtained from a patient presenting with shock and pulsus paradoxus. A mild pericardial effusion responsible for prolonged right atrial collapse during the cardiac cycle (arrow) was consistent with a tamponade, and the patient underwent successful pericardotomy. LV, left ventricle; RV, right ventricle; LA, left atrium; RA, right atrium; Ao, ascending aorta.
- 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.
- 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).
Criteria of Cor Pumonale
I. QRS morphology
- Limb leads
1. Right axis deviation
2. S > R in lead I
- Precordial leads
1. S > R in V5 - V6
2. S > R in V2
3. Lead V1 rs, Rs, or rS
- Orthogonal leads
1. S > R in lead X
2. Tall R wave in lead II
II. T wave variable
III. P wave
- Limb leads
1. Vertical axis
2. P > 3 mm in lead II or III
- Precordial leads
1. Negative P in lead V1
- 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.
- 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.
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 Hg or 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 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. 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.
- 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.
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.
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 ETA and ETB 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
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Contributors and acknowledgement
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 of cor pulmonale include syncope, hypoxia, pedal edema, passive hepatic congestion, and death.
- 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 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.
- 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.
Cor pulmonale is not a disease, per se, but a manifestation common to many disease states. Accordingly, a variety of medical and surgical treatments are available, but therapy must be based on the etiologic and pathophysiologic factors responsible. In addition, therapy must be individualized, taking into account the severity of symptoms and prognosis. Treatment of the underlying disorder, if one can be identified, is the first approach to the treatment of cor pulmonale. Improving airflow, alveolar ventilation, and gas exchange through the use of bronchodilators, corticosteroids, mucolytics, and, occasionally, assisted ventilation often ameliorates the pulmonary hypertensive state in patients with parenchymal disease. Supple-mental oxygen therapy reduces the degree of pulmonary hypertension in hypoxemic cor pulmonale by abolishing hypoxic vasoconstriction; indeed, low-flow continuous On therapy is the only modality that has been proven to prolong life in cor pulmonale due to chronic obstructive lung disease.
Because of the ominous prognosis associated with pulmonary hypertension from any cause, an aggressive approach to treatment is warranted as soon as a clinical diagnosis is made. It should be emphasized that physical findings and noninvasive studies alone are insufficient to confirm the presence and severity of pulmonary hypertension; right-heart catheterization is necessary both to establish the diagnosis and to monitor therapeutic responses.
As stated previously, therapy directed at improving gas exchange and alleviating hypoxic vasoconstriction is the initial step in the treatment for cor pulmonale secondary to parenchymal lung disease, and it should be initiated at the earliest sign of cor pulmonale. Although this approach is often successful, the maximal effects may not be clinically apparent for several months.
Patients with PPH should also be considered candidates for aggressive therapy immediately upon the establishment of a diagnosis. However, patients with severe, overt right-heart failure pose the greatest risk for adverse effects and are less likely to derive benefit from medical therapy.
Mechanisms of Action of Drugs Used
Oxygen. Low-flow supplemental oxygen therapy alleviates hypoxic pulmonary vasoconstriction and may halt the progressive vascular remodeling that is seen inpatients with cor pulmonale due to severe parenchymal lung disease. Whereas it may relieve the subjective sensation of dyspnea in patients with non hypoxemic cor pulmonale, supplemental oxygen does not usually pro-duce hemodynamic improvement in these patients
Methylxanthines. Theophylline, the most widely used methytxanthine derivative, has several potentially beneficial effects in cor pulmonale: Theophylline improves airflow by its bronchodilator effects and by a direct enhancement of mucociliary clearance. In addition, theophylime enhances diaphragmatic contractility, decreasing the work of breathing. It has also been suggested that theophylline improves right ventricular function in patients with chronic obstructive pulmonary disease with cor pulmonale, possibly by a direct vasodilator effect on the pulmonary circulation. Finally, the modest diuretic effects of theophylline may limit fluid retention in patients with right ventricular dysfunction.
Vasodilators. The rationale for the use of vasodilators in pulmonary hypertension is based on the suggestion that pulmonary vasoconstriction is present, to varying degrees, and that systemic vasodilators exert comparable effects on pulmonary vascular smooth muscle. Reduction in vascular smooth muscle tone would reduce right ventricular afterload, thereby improving right ventricular function and oxygen transport to the peripheral tissues. A variety of vasodilators have been shown to reduce pulmonary vasoconstriction in experimental and clinical conditions, including the calcium channel blockers, prostaglandins I and E, nitrates. Other agents, such as the angiotensin converting enzyme inhibitors, appear far less active on the pulmonary vascular bed. It should also be emphasized that the presence or degree of reversible vasoconstriction is variable in cor pulmonale. It may be a predominant factor in some patients, especially those with hypoxemic lung disease and primary pulmonary hypertension, but it is unlikely to contribute substantially to the hypertensive state in patients with chronic thrombotic pulmonary hypertension or cor pulmonale due to connective tissue disease.
Dosage, Routes of, and Practical Considerations in Drug Administration
Oxygen. Patients with hypoxemic cor pulmonale should be treated with low-flow oxygen delivered via nasal cannula and to achieve an arterial Po greater than 60 to 65 torr. Oxygen therapy should be used for at least 18 hours per day, and preferably for 24 hours per day; even intermittent alveolar hypoxia is sufficient to promote ongoing pulmonary vasoconstriction. Some authors have suggested empirically increasing the flow rate by 1 liter per minute during sleep because hypoventilation with resultant hypoxemia is common in patients with cor pulmonale due to obstructive lung disease Although oxygen concentrators are efficient and cost effective devices for the delivery of continuous supplemental oxygen, they are of limited benefit in ambulatory patients because of their size and electrical requirements. Liquid oxygen systems, which are portable albeit more expensive, allow patients to ambulate while still receiving supplemental oxygen.
In some patients with pulmonary hypertension, arterial hypoxemia may be due to right-to-left shunting through a patent foramen ovale. Such patients may not substantially increase arterial Po in response to sup-plemental oxygen, but dyspnea and activity tolerance may nevertheless be improved.
Methylxanthines. I prefer to use theophylline inpatients with cor pulmonale due to chronic obstructive pulmonary disease in doses that achieve low therapeutic levels. Higher serum levels (15 to 20 u,g per milliliter) may be associated with adverse effects, such as tachycardia, arrhythmias, nausea, and tremors. Oral sustained-release preparations, titrated to achieve the desired serum concentration, can be administered twice daily and provide reliable bioavailabity.
Vasodilators. The use of vasodilators in pulmonary hypertension should be considered experimental, and their role in management is unclear. My approach is to withhold their use in patients with cor pulmonale due to lung disease until conventional therapy has proven in adequate. In contrast, patients with primary pulmonary hypertension are viewed as potential candidates for vasodilator therapy as soon as the diagnosis is established because no other modality of treatment has proven any more successful. Prostacyclin (PGI) is well suited for this purpose in that it is a potent, titratabic, short-acting agent. Individuals who manifest reductions in pulmonary artery pressure and pulmonary vascular resistance in response to the acute intravenous infusion of prostacyclin are more likely to respond in a similar fashion to oral or transdermal vasodilators. As of this writing, prostacyclin is an experimental agent that has not been approved by the Food and Drug Administration for general use; commercially available intravenous agents, may be suitable alternatives, although they may be less potent than prostacyclin.
Individuals who manifest beneficial responses to intravenous prostacyclin are treated with oral or topical vasodilators. The calcium channel blockers appear to be the most potent agents, although side effects are common and may preclude their use Nifedipine and diltiazem hydrochloride appear equally effective; verapamil is generally not used because it is less potent in the pulmonary vascular bed and it possesses negative effects. I usually begin therapy with sustained-release nifedipine in doses of 30 mg once daily, increasing the dose as tolerated; sustained-release diltiazem hydrochloride therapy is instituted in doses of 120 mg once daily, increasing as tolerated. Studies have suggested that large doses of these agents may be necessary to produce sustained responses in pulmonary hypertension, although side effects may limit the doses that can be achieved. Survival is improved in patients who are responsive to calcium channel blocking therapy.
If calcium channel blockers cannot be used because of adverse effects, I consider nitrates as a second line of therapy in patients with demonstrated pulmonary vasoreactivity. I prefer to use topical nitroglycerin ointment, every 6 hours,increasing as tolerated.
Patients who are refractory to these approaches may be considered candidates for continuous intravenous infusion of prostacyclin. This approach, which is still experimental, may be particularly useful as a bridge to transplantation in severely impaired individuals. Prostacyclin is delivered intravenously from a portable syringe pump connected to a chronic indwelling central venous catheter.
Anticoagulation. Recent experience suggests that PPH patients who arc treated with anticoagulants tend to live longer. I treat patients with PPH or chronic thrombotic pulmonary vascular disease with warfarin, adjusting the dose to achieve a prothrombin time of approximately 1 5 times control I generally do not treat patients with other causes of cor pulmonale with anticoagulants unless a specific indication exists.
Cardiac Glycosides and Diuretics. Cardiac glycosides appear to be of limited usefulness in cor pulmonale due to parenchymal lung disease unless left vcntricular dysfunction is present. Furthermore, the risk of digitalis toxicity is increased in the setting of chronic lung disease, in part because of the presence of hypoxemia, and diuretic-induced hypokalemia. Accordingly, I use cardiac glycosides in this setting only when supraventricular tachyarrhythmias requiring atrioventricular node blockade are present; verapamil may bean alternative, although its other hemodynamic effects may limit its usefulness
Some authors have advocated combining cardiac glycosides with calcium channel blocker therapy inpatients with primary pulmonary hypertension to counteract the negative inotropic effects of nifedipine or diltiazem hydrochloride.
Diuretics should be used cautiously in patients with cor pulmonale because excessive reduction in right-heart preload may actually compromise right ventricular function. In addition, the hypokalemia and metabolic alkalosis that may result from diuretic use are poorly tolerated by patients with severe chronic lung disease. Finally, many patients with hypoxemic cor pulmonale experience a gradual hemodynamic response to supple-mental oxygen therapy, precluding the need for diuretics.
Despite these caveats, patients with persistent or severe volume overload attributable to right-heart failure should be treated with diuretics. Furoscmide, doses of 40 to 120 mg per day, are usually sufficient. In refractory situations, potent diuretics, such as metolazone in doses of 2.5 to 5 mg, may be added. Monitoring of serum electrolytes is mandatory when these agents are used, and aggressive potassium or magnesium replacement may be necessary.
Side Effects of the Drugs Used
Low-flow supplemental oxygen therapy is generally safe and is well tolerated by most patients with hypoxemic lung disease. Modest increases in PCo can accompany its use in hypercapnic individuals with chronic obstructive pulmonary disease, but overt suppression of respiratory drive is unlikely unless very high flow rates are used or other factors precipitating acute respiratory failure are present. The use of nasal cannulas can produce nasal mucosal drying and irritation, which can be minimized by keeping flow rates lower than 4 to5 liters per minute and applying topical lubricants to the mucosa.
Side effects from bronchodilators are generally minor and include tachycardia, tremor, and nervousness. Selective beta-agonists and cholinergic agonists administered by inhalation are better tolerated than oral beta-agonists. Oral theophylline preparations should be given in doses that achieve scrum levels and that arc not accompanied by side effects.
The major adverse effects of vasodilators are systemic hypotension, deterioration in gas exchange, and depression of cardiac contractility. Because there is noselective pulmonary vasodilator, most patients with cor pulmonale experience some degree of systemic vasodilation in response to the administration of a vasodilator. Patients with "fixed" pulmonary vascular disease are more likely to experience hypotension with vasodilators because cardiac output is unlikely to increase.
Some vasodilators, particularly calcium channel blockers and nitrates, can worsen gas exchange by increasing perfusion to poorly ventilated lung units. The hypoxemia may be poorly tolerated by individuals with underlying parenchymal lung disease and pre-existent impaired gas exchange. Careful monitoring of arterial blood gases or saturation is important in this setting.
The calcium channel blocking agents may also precipitate a deterioration in right-heart function as a result of their negative inotropic properties. The phenomenon is more common with verapamil than with either nifedipine or diltiazem hydrochloride, but it can occur with any of these compounds and at any dose. Differentiating drug-induced heart failure from disease progression or drug-induced fluid retention (which occurs in up to 30 percent of patients taking calcium channel blockers) is often difficult and may require empirically reducing the dose or repeated right-heart catheterization.
Assessment of Therapeutic Responses
Although improvement in symptoms, such as decreased exertional dyspnea, is suggestive of a beneficial therapeutic response, evaluation by invasive or noninvasive techniques is usually required. Echocardiography and radionuclide ventriculography are useful in providing a qualitative assessment of right ventricular function. Right ventncular catheterization, is the preferred approach in monitoring therapy.
The debate regarding the definition of a beneficial response to vasodilator therapy remains unsettled. I treat patients with vasodilators if they experience a sustained reduction in pulmonary vascular resistance greater than 25 to 30 percent, which is produced by a reduction in pulmonary artery pressure, increase in cardiac output, or both. An increased pulmonary artery pressure, decreased cardiac output, symptomatic systemic hypotension, or substantial deterioration in gas exchange (usually due to either right-to-left shunting through a patent foramen ovale or increased V/Q mismatching) constitute contraindications to vasodilator therapy.