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E-Fig. 18.4 Computed tomography angiography shows a saddle

embolus entering both right and left (arrow) pulmonary arteries. (Courtesy Dr. Charles Kuhn.)

CHAPTER 18 Pulmonary Vascular Diseases

219.e1

220 SECTION III Pulmonary and Critical Care Medicine

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clinical appearance, vital signs, validated PE risk scores, and RV function assessed by imaging modalities and cardiac biomarkers. Acute PE that causes hemodynamic instability is referred to as massive PE or high-risk PE and warrants immediate consideration of reperfusion therapies. In acute PE patients who present without shock or hemodynamic instability, multimodal risk stratiﬁcation is used to identify patients at low and intermediate risk, the latter typically deﬁned by signs of RV dysfunction on CT or echocardiography, or elevated levels of troponin or B-type natriuretic peptide (BNP).

Treatment of acute PE centers on supportive care, systemic anticoagulation, and consideration of reperfusion therapy. Unless there are contraindications, systemic anticoagulation should be started after the diagnosis of acute PE is established. Intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin (LMWH) are typically the preferred agents. For patients with a contraindication to anticoagulation, an inferior vena cava ﬁlter should be placed. Reperfusion therapies include systemic thrombolysis and surgical thrombectomy and are indicated in massive PE. The use of systemic thrombolytics in intermediate risk PE remains controversial and is not practiced routinely. Catheter-directed thrombolysis and catheter embolectomy are other available reperfusion therapies that are less well studied and not recommended for routine use.

After stabilization and clinical improvement, patients are transitioned to their long-term anticoagulation therapy. Options for anticoagulation include vitamin K antagonists such as warfarin, non–vitamin K oral anticoagulants (NOACs), such as apixaban or rivaroxaban, or LMWH. NOACs have increasingly become the preferred oral anticoagulant due to their safety proﬁle and ease of use, but risks and beneﬁts of each agent should be discussed with patients to allow for individualized decision making. Duration of anticoagulation for an acute pulmonary embolism is at least 3 months, after which extended therapy can be considered based on clinical risk factors (e.g. provoked vs. unprovoked event) and bleeding risk.

Chronic Thromboembolic Pulmonary Hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is a distinct type of pulmonary hypertension, classiﬁed as WHO group 4 PH. CTEPH is characterized by incomplete or abnormal resolution of acute pulmonary thromboembolism such that residual emboli become organized and ﬁbrotic. This develops in approximately 4% of patients after acute pulmonary embolism. However, nearly half of CTEPH cases occur in patients without a prior history of venous thromboembolism. The diagnosis of CTEPH requires precapillary pulmonary hypertension on RHC in the presence of chronic/organized ﬂow limiting thrombi/emboli in the elastic pulmonary arteries after at least 3 months of effective anticoagulation (E-Fig 18.5). Unlike other forms of pulmonary hypertension, the mainstay of treatment is surgical. Pulmonary endarterectomy (PEA) is performed via median sternotomy with cardiopulmonary bypass, after which deep hypothermic circulatory arrest allows for visualization, identiﬁcation of the dissection plane, and complete endarterectomy. PEA is often curative, and is associated with improved symptoms, hemodynamics, and survival.

In patients for whom PEA is not feasible, medical therapy with pulmonary vasodilators, namely riociguat, has been shown to be effective in improving hemodynamics and functional capacity. Balloon pulmonary angioplasty is an emerging therapeutic option for CTEPH patients with inoperable disease or in whom the risk-to-beneﬁt ratio of PEA is not favorable.

PROSPECTUS FOR THE FUTURE

Numerous advances in our understanding of pulmonary vascular biology over the last 35 years have markedly enhanced understanding of the pathogenesis of pulmonary hypertensive disorders and have led to the development of therapies that slow disease progression, increase functional capacity, and increase quality of life. However, most pulmonary vascular diseases are not curable and result in decreased survival. New therapies designed to prevent the loss of healthy vessels and reverse vascular remodeling are needed before substantial gains in disease reversal and cure can be achieved. Cellular mechanisms that regulate endothelial apoptosis, angiogenesis, and perivascular inﬂammation appear to have potential as future therapeutic targets. Modulation of sex hormones, cellular bioenergetics, and epigenetic factors may be other promising approaches. Little is understood about the adaptive changes of the right ventricle to chronically increased afterload. Furthermore, studies are needed in the area of genetic predisposition to thromboembolic disease and vascular dysfunction leading to thrombus formation as well as the determination of appropriate follow-up evaluation for patients after acute PE and who might beneﬁt from screening for chronic thromboembolic disease. Finally, national studies currently underway that seek to provide deep phenotyping of pulmonary vascular disease and establish national biobanks and patient registries should provide important tools to help investigators ﬁnd more effective therapies for these devastating diseases.

SUGGESTED READINGS

Girerd B, Weatherald J, Montani D, Humbert M: Heritable pulmonary hyper-

tension: from bench to bedside, Eur Respir Rev 26(145), 2017.

Humbert M, Guignabert C, Bonnet S, et al: Pathology and pathobiology of

pulmonary hypertension: state of the art and research perspectives, Eur Respir J 53(1), 2019.

Klinger JR, Elliott CG, Levine DJ, et al: Therapy for Pulmonary Arterial

Hypertension in Adults: Update of the CHEST Guideline and Expert Panel Report, Chest 155(3):565-586, 2019.

Konstantinides SV, Meyer G, Becattini C, et al, ESC Scientiﬁc Document

Group: 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS), Eur Heart J 41:543-603, 2020.

Mullin CJ, Klinger JR: Chronic thromboembolic pulmonary hypertension,

Heart Fail Clin 14(3):339-351, 2018.

Simonneau G, Montani D, Celermajer DS, et al: Haemodynamic deﬁnitions

and updated clinical classiﬁcation of pulmonary hypertension, Eur Respir J 53(1), 2019.

Stacher E, Graham BB, Hunt JM, et al: Modern age pathology of pulmonary

arterial hypertension, Am J Respir Crit Care Med 186:261-272, 2012.

CHAPTER 18 Pulmonary Vascular Diseases

LUNG PERFUSION

220.e1

Posterior

LAO

RAO RPO

Right Lateral

LPOLeft Lateral

E-Fig. 18.5 (A) VQ lung scan showing multiple segmental and subsegmental perfusion defects throughout both lungs. (B) Pulmonary angiogram

on the same patient showing cutoff sign (arrows) and aneurysm formation (arrowheads) in same area as perfusion defects seen on VQ scan. (C) Organized vascular lesions removed from same patient at time of pulmonary endarterectomy. LAO, Left anterior oblique; LPO, left posterior oblique; RAO, right anterior oblique; RPO, right posterior oblique. (From Mullin CJ, Klinger JR. Chronic Thromboembolic Pulmonary Hypertension. Heart Failure Clin 14 [2018] 339-351)

Left

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Disorders of the Pleura,

Mediastinum, and Chest Wall

Eric J. Gartman, F. Dennis McCool

PLEURAL DISEASE

The pleura is a thin membrane that covers the entire surface of the lung, inner surface of the rib cage, diaphragm, and mediastinum. There are two pleural membranes: the visceral pleura, which covers the lung; and the parietal pleura, which lines the rib cage, diaphragm, and mediastinum. A layer of mesothelial cells lines both pleural surfaces. The closed space in between the surface of the lung and the chest cavity is called the pleural space. A small amount of ﬂuid normally resides in this space and forms a thin layer between the pleural surfaces. Pleural ﬂuid serves as a lubricant for the visceral and parietal pleurae as they move against each other during inspiration and expiration.

The blood vessels in the visceral pleura are supplied from the pulmonary circulation and have less hydrostatic pressure than the blood vessels in the parietal pleura, which are supplied by the systemic circulation. The pressure in the pleural space is subatmospheric during quiet breathing. Fluid is ﬁltered from the higher-pressure vascular structures into the pleural space. The normal ﬂuid turnover is about 10 to 20 mL per day, with 0.2 to 1 mL remaining in the pleural space. Pleural ﬂuid usually contains a small amount of protein and a small number of cells that are mostly mononuclear cells. Although both parietal and visceral pleurae contribute to pleural ﬂuid formation, most of the ﬂuid results from ﬁltration of the higher-pressure vessels supplying the parietal pleura.

After the ﬂuid enters the pleural space, it is drained from the pleural space by a network of pleural lymphatics located beneath the mesothelial monolayer. The lymphatics originate in stomas on the parietal pleural surface. In abnormal circumstances of increased ﬂuid production or impaired removal, ﬂuid can accumulate in the pleural space. Factors that promote the entry of ﬂuid into the pleural space include an increase in systemic venous pressure, an increase in pulmonary venous pressure, an increase in permeability of pleural vessels, and a reduction in pleural pressure. Conditions that increase hydrostatic pressure can be seen in congestive heart failure; changes in pleural membrane permeability can be seen in various inﬂammatory states or malignancy; and a reduction in pleural pressure can be seen with atelectasis. Occasionally, microvascular oncotic pressure may be sufﬁciently reduced to promote ﬂuid entry into the pleural space in patients with hypoalbuminemia. Factors that block lymphatic drainage and interfere with the egress of ﬂuid from the pleural space include central lymphatic obstruction and obstruction of lymphatic channels at the pleural surface by tumor.

Pleural Effusion

Pleural effusion is the accumulation of ﬂuid in the pleural space. Pleural effusions usually are detected by chest radiography; however, the volume of ﬂuid in the pleural space must exceed 250 mL to be visualized

on a chest radiograph. When an effusion exists, there is blunting of the costophrenic angle on a posteroanterior chest ﬁlm, which represents a ﬂuid meniscus that can be detected posteriorly on the lateral chest radiograph, and ﬂuid occasionally can be demonstrated in the minor or major ﬁssures (E-Figs. 19.1 and 19.2). Apparent elevation or changes in the contour of the diaphragm on a posteroanterior chest ﬁlm may signify a subpulmonic effusion, so called because it retains the general shape of the diaphragm without blunting the costophrenic angle; however, it is evident on the lateral ﬁlm.

A decubitus chest radiograph can be obtained to determine whether the ﬂuid is free ﬂowing or loculated. Computed tomography (CT) of the chest provides better deﬁnition of the pleural space than plain radiography. Chest CT is particularly useful in deﬁning loculated effusions and in differentiating pulmonary parenchymal abnormalities from pleural abnormalities, atelectasis from effusion, and loculated effusion from lung abscess or other parenchymal processes (E-Fig. 19.3). The edge of a parenchymal process usually touches the chest wall and forms an acute angle (0-90 degrees), whereas that of an empyema is usually an obtuse angle (90-180 degrees).

Thoracentesis is a procedure in which ﬂuid is aspirated from the pleural space. To help minimize procedural complications and assist in needle placement, ultrasound or CT guidance should be used to direct the thoracentesis catheter into the pleural space.

Classifying pleural effusions as transudates or exudates greatly assists with the differential diagnosis. The approach to pleural effusions is outlined in E-Fig. 19.4. Further analysis of pleural ﬂuid may provide a deﬁnitive diagnosis (e.g., malignancy); however, even without a deﬁnitive diagnosis, pleural ﬂuid analysis can be useful in excluding possible causes of disease such as infection.

Transudates

Effusions that accumulate due to changes in oncotic and hydrostatic forces usually have a low protein content and are called transudates (Table 19.1). Congestive heart failure is the most common cause of a transudate, and the effusions are typically bilateral. If the effusion is unilateral, it involves the right hemithorax in most instances. Effusions due to heart failure almost universally are related to dysfunction of the left side of the heart, although they rarely can result from right heart failure (e.g., advanced pulmonary arterial hypertension).

Transudative effusions may be seen in cirrhosis, nephrotic syndrome, myxedema, pulmonary embolism, superior vena cava obstruction, and peritoneal dialysis. In patients with cirrhosis, the effusions are often right-sided, and the mechanism may be related to ﬂow from the peritoneal space across diaphragmatic defects into the pleural space (i.e., hepatic hydrothorax). Transudative effusions are typically small to moderate sized and rarely require drainage to improve symptoms.

221

CHAPTER 19 Disorders of the Pleura, Mediastinum, and Chest Wall

E-Fig. 19.1 Posteroanterior and lateral chest radiographs show a large, right pleural effusion (arrow) and left upper lobe mass (double arrows).

Pleural fluid

221.e1

E-Fig. 19.2 Computed tomography of the patient in E-Fig. 19.1 shows

a large, right pleural effusion (arrow) and left upper lobe mass (double arrows).

F/S LDH 0.6 Fluid LDH 0.66 normal serum and F/S protein 0.5

Transudate

CHF

Cirrhosis

complicated

E-Fig. 19.4 Work-up for pleural effusion. CHF, Congestive heart failure;

F/S, ﬂuid/serum; LDH, lactate dehydrogenase.

F/S LDH 0.6 Fluid LDH 0.66 normal serum or F/S protein 0.5

Exudate

pH 7.2 pH 7.2

Not

Complicated

Drainage

Bacteria

pus

Malignant

cells

Mesothelioma

Metastatic

cancer

E-Fig. 19.3 Computed tomography demonstrates a pleural effusion

(arrow) and atelectasis (double arrows).

222 SECTION III Pulmonary and Critical Care Medicine

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TABLE 19.1 Causes of Pleural Effusions

Conditions Associated With Transudates

Ascites Cirrhosis Congestive heart failure Hypoalbuminemia Intra-abdominal ﬂuid Malnutrition Nephrotic syndrome Peritoneal dialysis

Conditions Associated With Exudates

Asbestosis Chylothorax Collagen vascular disease Complications of abdominal surgery Dressler’s syndrome (myocardial infarction, cardiotomy) Drug-induced lupus Empyema Hemothorax Infection Intra-abdominal pathologic abnormalities (abscess) Lymphedema Malignancy (primary lung cancer, lymphoma, metastatic cancer) Meigs’ syndrome (benign ovarian tumor) Myxedema Pancreatitis Parapneumonic causes (pneumonia, lung abscess, bronchiectasis) Pulmonary embolism and infarction Rheumatoid arthritis (pleurisy) Ruptured esophagus Subphrenic abscess Systemic lupus erythematosus Trauma Uremia Urinothorax Miscellaneous sources

Modiﬁed from Light RW, Macgregor MI, Luchsinger PC, et al: Pleural effusions: the diagnostic separation of transudates and exudates, Ann Intern Med 77:507-513, 1972.

Exudates

Exudative effusions occur when there is an alteration in vascular permeability or pleural ﬂuid resorption. They can be observed in inﬂammatory, infectious, or neoplastic conditions.

To distinguish an exudate from a transudate, one of three criteria must be fulﬁlled: (1) An exudate must have a pleural ﬂuid–to-serum protein ratio greater than 0.5; (2) a pleural ﬂuid–to-serum lactate dehydrogenase (LDH) ratio must be greater than 0.6; or (3) a pleural ﬂuid LDH level must be greater than two thirds of the upper limit of normal (Table 19.2). When all three criteria are met, the sensitivity, speciﬁcity, and positive predictive value exceed 98% for deﬁning an exudative effusion.

Measuring pleural ﬂuid cholesterol may also help to distinguish an exudate from a transudate. Pleural ﬂuid cholesterol is derived from degenerating cells within the pleural space and from vascular leakage due to increased permeability. A cholesterol level greater than 45 mg/ dL is consistent with an exudative effusion.

Exudative effusions are commonly caused by infection. Parapneumonic effusion typically occurs in patients with bacterial pneumonia and can be further classiﬁed as an uncomplicated or complicated effusion.

TABLE 19.2 Differentiation of Exudative and

Transudative Pleural Effusions

Characteristic Exudate Transudate

Pleural ﬂuid–to-se-

rum protein ratio

Pleural ﬂuid LDH

level

Pleural ﬂuid–to-se-

rum LDH ratio

LDH, Lactate dehydrogenase. Modiﬁed from Light RW, Macgregor MI, Luchsinger PC, et al: Pleural effusions: the diagnostic separation of transudates and exudates, Ann Intern Med 77:507-513, 1972.

Uncomplicated parapneumonic effusions do not require drainage and respond to antibiotic therapy alone used for treatment of the underlying pneumonia. In contrast, complicated parapneumonic effusions do not respond to antibiotic therapy alone and require drainage to prevent the formation of an empyema. The transition from uncomplicated to complicated can occur extremely rapidly, within a 24-hour period in some cases.

Typically, an uncomplicated parapneumonic effusion has a pH level greater than 7.3, a glucose level greater than 60 mg/dL, and an LDH level less than 1000 IU/L. A pH level of less than 7.2 usually identiﬁes a complicated effusion. However, this ﬁnding is not speciﬁc for infection, and the cause may be malignancy, rheumatoid arthritis, or trauma with esophageal disruption causing an associated reduction in pH level.

Complicated exudative effusions require drainage to avoid development of loculation, cutaneous ﬁstulas, bronchopleural ﬁstulas, or ﬁbrothorax. The ﬁndings of pus or bacteria by Gram stain or culture conﬁrms the diagnosis of empyema and requires immediate drainage. The injection of ﬁbrolytic agents and DNase into the pleural space can augment full drainage of infected pleural effusions; however, treatment of complicated pleural effusions occasionally requires surgical intervention and lung decortication.

Primary tuberculosis in endemic areas may be associated with pleural effusion in up to 30% of patients. The effusion is caused by increased vascular permeability of the pleural membrane because of a hypersensitivity reaction, not direct infection. Typically, the pleural ﬂuid is lymphocyte predominant and acid-fast stain and culture negative. Adenosine deaminase levels greater than 50 U/L may be helpful in identifying tuberculous pleural effusions. Tuberculous empyema is distinct from a tuberculous pleural effusion and can occur when there is an extension of infection from the thoracic lymph nodes into the pleural space or hematogenous spread of tuberculosis to the pleural space.

Malignant effusions are the second most common cause of exudative pleural effusions and confer a poor prognosis. Seeding of the parietal or visceral pleura with malignant cells can change vascular permeability and impede resorption, resulting in effusion formation. However, the ﬁnding of a pleural effusion in an individual with malignancy does not necessarily imply that there is a malignant process in the pleural space. Effusions in these individuals may be caused by atelectasis, postobstructive pneumonia, hypoalbuminemia, pulmonary emboli, or complications from irradiation or chemotherapy.

The most common cause of malignant effusion is lung cancer, followed by breast cancer and lymphoma. An effusion that is bloody suggests a malignant process; however, other causes of bloody pleural effusions include trauma, asbestos exposure, tuberculosis, collagen vascular disease, and thromboembolic disease. To conﬁrm the diagnosis of malignancy, cytologic examination of the ﬂuid is needed. Malignant cells can be seen in 60% of malignant effusions on the ﬁrst thoracentesis. Sensitivity rises to 80% if three separate samples are obtained. If needed, a biopsy

>0.5 <0.5

>2⁄3 of the upper

limit of normal

>0.6 <0.6

<2⁄3 of the upper limit of normal

CHAPTER 19 Disorders of the Pleura, Mediastinum, and Chest Wall

223

of the pleura may be useful in identifying a malignancy. Biopsies may be obtained via medical thoracoscopy, surgical video-assisted thoracoscopy or, less optimally, in a blinded fashion through a Cope or Abrams needle.

A low pleural ﬂuid pH has prognostic and therapeutic implications for patients with malignant effusions. Patients with a low pleural ﬂuid pH due to malignancy tend to have shorter survival times and poorer responses to chemical pleurodesis. Recurrent malignant pleural effusions may improve with chemical pleurodesis with talc or tetracycline derivatives, but effectiveness varies and a complete response is achieved in little more than 50% of patients. Alternatively, many patients with recurrent malignant effusions have tunneled indwelling pleural catheters placed, allowing intermittent drainage, relief of symptoms, and possibly mechanical pleurodesis over time.

Systemic inﬂammatory disorders such as rheumatoid arthritis and lupus erythematosus can be associated with exudative effusions. Rheumatoid pleural effusions are a common intrathoracic manifestation of rheumatoid disease and may be seen in as many as 5% of patients. Rheumatoid factor titers in pleural ﬂuid are often greater than 1:320, and the pleural ﬂuid glucose level is less than 60 mg/dL (or the pleural ﬂuid–to-serum glucose ratio is less than 0.5). However, a low glucose level also may be found in complicated parapneumonic effusions or empyema, malignant effusion, tuberculosis pleurisy, lupus pleuritis, and esophageal rupture. In systemic lupus erythematosus, 15% to 50% of patients have pleural effusions, and the pleural ﬂuid antinuclear antibody titer is greater than 1:160.

Measuring pleural ﬂuid amylase concentrations may further reﬁne the differential diagnosis for an exudative effusion. Finding a pleural amylase level greater than the upper limit of normal for serum amylase is consistent with acute pancreatitis, chronic pancreatic pleural effusion, esophageal rupture, or malignancy. Pancreatic disease is associated with pancreatic amylase isoenzymes, whereas malignancy and esophageal rupture are characterized by a predominance of salivary isoenzymes.

Pneumothorax

Pneumothorax is the accumulation of air in the pleural space. In this instance, pleural pressure becomes positive and there is compression of underlying lung. Patients with pneumothorax typically have acute onset of dyspnea. Findings include tachycardia, decreased breath sounds, decreased tactile fremitus, a pleural friction rub, subcutaneous emphysema, hyperresonance, and a tracheal shift to the opposite side.

The diagnosis can be made by obtaining an upright chest radiograph, and rapid assessment can be achieved with point-of-care ultrasound. Typically, the visceral pleura separates from the parietal pleura, and air can be seen between the visceral pleural lining and the rib cage. An end-expiratory radiograph increases the density of lung while reducing its volume, highlighting the difference between the lung parenchyma and the pleural gas.

Management of a signiﬁcant pneumothorax usually requires insertion of a thoracostomy tube and suction followed by water-seal drainage. However, if the pneumothorax is small and the patient is not in distress, observation alone may be indicated. If there is not a continuing air leak, as from a bronchopleural ﬁstula, the pleural air is reabsorbed into the blood with resolution of the pneumothorax.

A tension pneumothorax is a medical emergency that requires immediate decompression by placement of a chest catheter. A tension pneumothorax occurs when pleural pressure reaches levels sufﬁcient to cause mediastinal shift, compression of the vena cava and heart, and hemodynamic compromise. This physiology implies an ongoing leak of air into the pleural space.

Pneumothorax is often associated with blunt or penetrating trauma. With penetrating trauma, air may leak into the pleural space through the chest wall or the lung. Mechanical ventilation has also

been associated with pneumothorax. Patients with underlying lung disease receiving mechanical ventilation may acutely develop a pneumothorax. A sudden rise in peak airway pressures with a reduction in breath sounds can alert the clinician to this complication.

Pneumothorax may occur spontaneously or result secondarily from underlying lung disease. Typically, spontaneous pneumothorax occurs in tall, young, thin men, presumably a result of rupture of apical blebs. Underlying lung diseases that can be complicated by pneumothorax include emphysema, cystic ﬁbrosis, granulomatous inﬂammation, necrotizing pneumonia, pulmonary ﬁbrosis, and lung abscess. Catamenial pneumothorax occurs in women who have subpleural and diaphragmatic endometriosis, with rupture of the endometrial nodules at the time of menstruation causing pneumothorax.

Mesothelioma

Malignant mesotheliomas are neoplasms arising from the serosal membranes of the body cavities. Eighty percent of mesotheliomas originate in the pleura. Individuals usually are older than 55 years, and there is an association with asbestos exposure in the distant past. Symptoms include shortness of breath, chest pain, and weight loss.

The most common radiologic ﬁnding is a large, unilateral pleural effusion that may completely opacify the hemithorax. There may be circumferential pleural thickening, usually associated with various amounts of calciﬁed pleural plaque and effusions. CT of the chest is the most accurate noninvasive method for assessing stage and progression of mesothelioma. Pleural ﬂuid cytology frequently is insufﬁcient for diagnosis, and the most efﬁcient way of obtaining tissue is by CT-guided core biopsy or thoracoscopy.

The overall prognosis for patients with malignant mesothelioma is poor. No particular therapy has emerged as superior to supportive therapy alone in terms of survival.

MEDIASTINAL DISEASE

Lesion Location

The mediastinum is the central part of the thoracic cavity between the lungs that contains the heart and aorta, esophagus, trachea, lymph nodes, and thymus. The mediastinum is bordered by the two pleural cavities laterally, the diaphragm inferiorly, and the thoracic inlet superiorly. The mediastinal space can be divided into three compartments: anterior, middle, and posterior. The localization of mediastinal masses in one of these compartments assists in the differential diagnosis (Fig. 19.1).

The anterior mediastinal compartment is anterior to the pericardium and includes lymphatic tissue, the thymus, and the great veins. Lesions most commonly found in the anterior mediastinum are thymomas, germ cell tumors, lymphomas, intrathoracic thyroid tissue, and parathyroid lesions. Thymomas comprise 20% of mediastinal neoplasms in adults, and they are the most common anterior mediastinal primary neoplasm in adults. Symptoms due to myasthenia gravis may affect one third of patients with thymomas. Middle mediastinal lesions include tracheal masses, bronchogenic and pericardial cysts, enlarged lymph nodes, and proximal aortic disease (i.e., aneurysm or dissection). Posterior mediastinal masses include neurogenic tumors and cysts, meningocele, lymphoma, aneurysm of the descending aorta, and esophageal disorders such as diverticula and neoplasms.

Patients with systemic lymphoma often have mediastinal involvement, and 5% to 10% of patients with lymphoma have primary mediastinal lesions at clinical presentation. Mediastinal cysts can arise in the pericardium, bronchi, esophagus or stomach, thymus, and thoracic duct, and although benign, they can produce compressive symptoms. Lung cancer often presents with metastatic mediastinal adenopathy and is a sign of advanced stage.

224 SECTION III Pulmonary and Critical Care Medicine

A Posteroanterior B Lateral

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Mediastinal

Compartment

Neurogenic tumors and cysts

Meningocele

Lymphoma

Esophageal disease

Megaesophagus Diverticula Neoplasm Bochdalek

hernia

Aneurysm

Middle Mediastinal

Compartment

Bronchogenic cysts Pleuropericardial cysts Lymphadenopathy

Sarcoidosis Malignancy—carcinoma and lymphoma Granulomatous disease

Aneurysms

Fig. 19.1 Masses of the mediastinum and their anatomic locations.

Thymomas

Substernal thyroid

Parathyroid lesions

Germinal cell neoplasms

Lymphomas

Treatment of a mediastinal mass depends on the underlying pathology. Many require surgical resection, irradiation, chemotherapy, or careful monitoring over time.

Mediastinitis

Inﬂammation of the mediastinal structures can be acute or chronic. Acute mediastinitis is a rapidly progressive condition due to infection, and it most commonly complicates cardiothoracic surgical procedures or occurs as a result of trauma. Chest imaging studies may show a widening of the mediastinum, pneumothorax, or hydrothorax. Treatment requires microbiological identiﬁcation, antibiotics, pleural drainage, and mediastinal evacuation.

Chronic mediastinitis (i.e., ﬁbrosing mediastinitis) is a progressive illness that results from fungal or granulomatous infections, neoplasms, radiotherapy, occasionally drugs (such as methysergide), or it may be idiopathic. Patients usually remain asymptomatic until vascular, respiratory, or neurologic structures are affected; tracheobronchial narrowing is the most common manifestation. Diagnosis and treatment often require surgical intervention, although no treatment is highly successful.

CHEST WALL DISEASE

The chest wall is composed of the bony structures of the rib cage, the articulations between the ribs and the vertebrae, the diaphragm, and other respiratory muscles. Normal function of this ventilatory pump is needed to bring oxygen from the atmosphere into the body. A wide variety of chest wall and neuromuscular disorders can result in dysfunction of the ventilatory pump. These disorders typically result in a restrictive dysfunction characterized by a reduction in total lung capacity and vital capacity with a normal residual volume. Hypoventilation may ensue, resulting in hypercapnia, atelectasis, and hypoxemia.

60°

70°

Fig. 19.2 Schematic depiction of the lines constructed to measure the

Cobb angle of scoliosis (A) and kyphosis (B).

Skeletal Disease

Kyphoscoliosis and ankylosing spondylitis are disorders that involve the spine and its articulations. Pectus excavatum involves the sternum, ﬂail chest affects the ribs, and obesity adds to the soft tissue mass of the chest wall. These disorders primarily affect the respiratory system by stiffening its tissues. Of these disorders, kyphoscoliosis produces the most severe restrictive impairment, and ankylosing spondylitis and pectus excavatum cause little respiratory compromise.

Kyphoscoliosis refers to a group of disorders characterized by excessive spinal curvature in the lateral plane (i.e., scoliosis) and sagittal plane (i.e., kyphosis). The degree of curvature can be assessed by measuring the Cobb angle (Fig. 19.2). Greater degrees of spinal curvature are associated with greater restriction and an increased risk of respiratory failure (E-Fig. 19.5).

Kyphoscoliosis may be idiopathic, caused by neuromuscular disease, or associated with congenital vertebral malformations. Idiopathic kyphoscoliosis is the most common form, usually manifesting in late childhood or early adolescence and affecting females more than males (ratio of 4:1). It is thought to be a multigene condition with an autosomal or sex-linked inheritance pattern and variable phenotypic expression. A defect in the chromatin-remodeling gene (CHD7) has been associated with idiopathic kyphoscoliosis.

For a given degree of spinal deformity, individuals with kyphoscoliosis due to a neuromuscular disease have more respiratory impairment than those with idiopathic kyphoscoliosis. Factors that contribute to respiratory failure in patients with kyphoscoliosis include inspiratory muscle weakness, underlying neuromuscular disease, sleep-disordered breathing, and airway compression due to distortion of lung parenchyma and twisting of airways.

Treatment consists of general supportive measures such as immunizations against inﬂuenza and pneumococci, smoking cessation, maintenance of a normal body weight, supplemental oxygen, and treatment of respiratory infections. It is important to recognize nocturnal hypoventilation because it can be treated with noninvasive positive-pressure ventilation. This is typically delivered through a nasal or full face mask. Indications for instituting noninvasive ventilation include symptoms suggesting nocturnal hypoventilation, signs of cor pulmonale, nocturnal oxyhemoglobin desaturation, or an elevated daytime Paco2.

Obesity

Obesity is a major health problem that affects children and adults throughout the world. Body fat usually constitutes 15% to 20% of body mass in healthy men and 25% to 30% of body mass in healthy women. In cases of obesity, the body fat content may increase by as much as 500% in women and 800% in men. The degree of obesity can be assessed by the body mass index, which is the ratio of body weight (BW) in kilograms to the square of the height (Ht) in meters (BW/Ht2). Individuals with a BMI between 18.5 and 24.9 kg/m2 are normal, and those with a BMI greater than 40 kg/m2 are considered severely or morbidly obese.

CHAPTER 19 Disorders of the Pleura, Mediastinum, and Chest Wall

E-Fig. 19.5 A patient with post-polio syndrome had severe kyphosco-

liosis, and Harrington rods were placed to correct the spinal curvature.

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CHAPTER 19 Disorders of the Pleura, Mediastinum, and Chest Wall

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Reductions in functional residual capacity and expiratory reserve volume are the most common pulmonary function abnormalities in obesity, whereas vital capacity and total lung capacity may be only minimally reduced. Obesity promotes breathing at low lung volumes, which reduces lung compliance and increases the work of breathing. A subgroup of individuals with obesity hypoventilate and become hypercapnic. When obesity is associated with hypoventilation, it is called the obesity-hypoventilation syndrome (i.e., Pickwickian syndrome). The mechanism underlying hypoventilation is unknown but may result from factors that reduce respiratory center chemosensitivity, such as hypoxia, sleep apnea, or adipokines such as leptin. The most important consequences of chronic hypoventilation are hypoxemia and pulmonary hypertension.

Nocturnal noninvasive positive-pressure ventilation can help to reverse these abnormalities. Weight loss is the optimal therapy, but it is not always attainable, and long-term weight loss maintenance is even more difﬁcult. Pharmacotherapy or bariatric surgery should be considered for obese individuals who do not achieve weight control with conventional methods (i.e., diet, enhanced physical activity, and behavioral therapy).

Diaphragm Paralysis

The diaphragm separates the thorax from the abdomen and is the major muscle of inspiration. Diaphragm weakness or paralysis can involve one or both hemidiaphragms. Unilateral diaphragm paralysis is more common than bilateral diaphragm paralysis. The most frequent causes of unilateral paralysis include traumatic phrenic nerve injury, herpes zoster infection, cervical spinal disease, and compressive tumors. Patients may be asymptomatic, or the abnormality may be discovered as an incidental ﬁnding of an elevated hemidiaphragm on a chest radiograph (Fig. 19.3). The diagnosis is conﬁrmed by seeing on ﬂuoroscopy a paradoxical upward motion of the affected diaphragm during a vigorous sniff maneuver. There is no speciﬁc treatment for this disorder, but recovery after the initial injury occasionally occurs. When the patient has disabling symptoms and signiﬁcant elevation of the diaphragm is seen on the chest radiograph, surgical plication of the diaphragm may provide some relief of symptoms.

Bilateral diaphragm paralysis is most often seen in the setting of a disease producing generalized muscle weakness or motor neuron disease such as amyotrophic lateral sclerosis. Pulmonary function test results are associated with severe restrictive impairments. When the patient assumes the supine position, there may be a further reduction (≤50%) in vital capacity. It is not surprising that orthopnea is an especially prominent symptom, and patients often have difﬁculty sleeping

in the supine position. Patients also complain of dyspnea when bending or lifting objects.

Bilateral diaphragm paralysis can be difﬁcult to diagnose. Restriction evidenced by pulmonary function test results is nonspeciﬁc, as is the ﬁnding of low lung volumes on chest radiographs. Fluoroscopic sniff testing (i.e., diaphragm ﬂuoroscopy) can yield false-negative and false-positive results. Measurement of transdiaphragmatic pressure is the gold standard, but it is somewhat invasive, requiring placement of catheters in the esophagus and stomach. Alternatively, B-mode ultrasound of the diaphragm in the zone of apposition is a very useful noninvasive means of diagnosing diaphragm paralysis, as it can directly assess the thickening of the diaphragm muscle (or lack thereof).

Treatment should address the underlying disease, which may or may not be reversible. If paralysis is idiopathic or caused by neuralgic amyotrophy (i.e., brachial plexus neuritis), more than 50% of individuals may recover. Phrenic nerve pacing may be used in patients with spinal cord injuries above C3, and noninvasive positive-pressure ventilation can be used to treat patients with nocturnal hypoventilation. Diaphragm plication is not indicated in patients with bilateral diaphragm paralysis.

PROSPECTUS FOR THE FUTURE

Numerous advances can be expected in treating individuals with pleural, mediastinal, and chest wall diseases. Progress in pleural ﬂuid analysis using novel biomarkers and nucleic acid ampliﬁcation tests may lead to more rapid and accurate diagnosis of tuberculous pleural effusions. Assays of pleural ﬂuid tumor markers and chromosome analysis are promising developments for the differentiation of malignant from nonmalignant effusions. Mesothelioma remains resistant to traditional therapeutic approaches, but evolving technology centered on gene therapy may produce a new treatment modality.

Better visualization of mediastinal structures can be achieved as magnetic resonance imaging (MRI) evolves and becomes more routinely applied to examination of the chest. Molecular tracers targeting tumor receptors or proteins may be used with MRI and positron emission tomography imaging techniques to better differentiate malignant from benign mediastinal masses.

Noninvasive nocturnal ventilation remains a cornerstone of therapy for patents with chest wall and neuromuscular diseases, but compliance can be problematic. Continued evolution of techniques to deliver nocturnal noninvasive ventilation may improve compliance with treatment, and application of this technique to patients with obesity-hypoventilation syndrome may reduce morbidity and mortality for them.

Patients with diaphragm paralysis due to high cervical spinal cord lesions may beneﬁt from advances in intramuscular diaphragm pacing. This technique may provide an alternative means of treating respiratory failure in these individuals and others with diaphragm paralysis.

For a deeper discussion on this topic, please see Chapter 92, “Diseases of the Diaphragm, Chest Wall, Pleura, and Mediastinum,” in Goldman-Cecil Medicine, 26th Edition.