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InternalMed_Harrison. PULMONARY ALVEOLAR PROTEINOSIS (PAP) Clinical Manifestations Although not strictly an ILD, PAP resembles and is therefore considered with these conditions. It has been proposed that a defect in macrophage function, more specifically an impaired ability to process surfactant, may play a role in the pathogenesis of PAP. PAP is an autoimmune disease with a neutralizing antibody of immunoglobulin G isotype against granulocyte-macrophage colony-stimulating factor (GM-CSF). These findings suggest that neutralization of GM-CSF bioactivity by the antibody causes dysfunction of alveolar macrophages, which results in reduced surfactant clearance. There are three distinct classes of PAP: acquired (>90% of all cases), congenital, and secondary. Congenital PAP is transmitted in an autosomal recessive manner and is caused by homozygosity for a frame-shift mutation (121ins2) in the SP-B gene, which leads to an unstable SP-B mRNA, reduced protein levels, and secondary disturbances of SP-C processing.


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InternalMed_Harrison. and is caused by homozygosity for a frame-shift mutation (121ins2) in the SP-B gene, which leads to an unstable SP-B mRNA, reduced protein levels, and secondary disturbances of SP-C processing. Secondary PAP is rare among adults and is caused by lysinuric protein intolerance, acute silicosis and other inhalational syndromes, immunodeficiency disorders, and malignancies (almost exclusively of hematopoietic origin) and hematopoietic disorders.


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InternalMed_Harrison. The typical age of presentation is 30–50 years, and males predominate. The clinical presentation is usually insidious and is manifested by progressive exertional dyspnea, fatigue, weight loss, and low-grade fever. A nonproductive cough is common, but occasionally expectoration of “chunky” gelatinous material may occur. Polycythemia, hypergammaglobulinemia, and increased LDH levels are common. Markedly elevated serum levels of lung surfactant proteins A and D have been found in PAP. In the absence of any known secondary cause of PAP, an elevated serum anti-GM-CSF titer is highly sensitive and specific for the diagnosis of acquired PAP. BAL fluid levels of anti-GM-CSF antibodies correlate better with the severity of PAP than do serum titers. Radiographically, bilateral symmetric alveolar opacities located centrally in middle and lower lung zones result in a “bat-wing” distribution. HRCT shows a ground-glass opacification and thickened intralobular structures and interlobular septa.


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InternalMed_Harrison. Histologic Findings This diffuse disease is characterized by the accumulation of an amorphous, periodic acid–Schiff–positive lipoproteinaceous material in the distal air spaces. There is little or no lung inflammation, and the underlying lung architecture is preserved. Treatment Whole-lung lavage(s) through a double-lumen endotracheal tube provides relief to many patients with dyspnea or progressive hypoxemia and also may provide long-term benefit.


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InternalMed_Harrison. PULMONARY LYMPHANGIOLEIOMYOMATOSIS Clinical Manifestations Pulmonary LAM is a rare condition that afflicts premenopausal women and should be suspected in young women with “emphysema,” recurrent pneumothorax, or chylous pleural effusion. It is often misdiagnosed as asthma or chronic obstructive pulmonary disease. Whites are affected much more commonly than are members of other racial groups. The disease accelerates during pregnancy and abates after oophorectomy. Common complaints at presentation are dyspnea, cough, and chest pain. Hemoptysis may be life threatening. Spontaneous pneumothorax occurs in 50% of patients; it may be bilateral and necessitate pleurodesis. Meningioma and renal angiomyolipomas (hamartomas), characteristic findings in the genetic disorder tuberous sclerosis, are also common in patients with LAM. Chylothorax, chyloperitoneum (chylous ascites), chyluria, and chylopericardium are other complications. Pulmonary function testing usually reveals an obstructive or


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InternalMed_Harrison. also common in patients with LAM. Chylothorax, chyloperitoneum (chylous ascites), chyluria, and chylopericardium are other complications. Pulmonary function testing usually reveals an obstructive or mixed obstructive-restrictive pattern, and gas exchange is often abnormal. HRCT shows thin-walled cysts surrounded by normal lung without zonal predominance.


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InternalMed_Harrison. Histologic Findings Pathologically, LAM is characterized by the proliferation of atypical pulmonary interstitial smooth muscle and cyst formation. The immature-appearing smooth-muscle cells react with monoclonal antibody HMB45, which recognizes a 100-kDa glycoprotein (gp100) originally found in human melanoma cells.


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InternalMed_Harrison. Treatment Progression is common, with a median survival of 8–10 years from diagnosis. No therapy is of proven benefit in LAM. Sirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), appears to be an active agent for LAM. After 12 months, it stabilized lung function (FVC, FEV1, and functional residual capacity) and was associated with a reduction in symptoms and improvement in quality of life. Adverse effects (e.g., mucositis, diarrhea, nausea, hypercholesterolemia, acneiform rash, peripheral edema) were more common in the sirolimus group, but serious adverse effects were not increased. Subjects were followed off sirolimus for an additional 12 months, during which time pulmonary function declined at the same rate as in the placebo group. Progesterone and luteinizing hormone–releasing hormone analogues have been used. Oophorectomy is no longer recommended, and estrogen-containing drugs should be discontinued. Lung transplantation offers the only hope for cure despite


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InternalMed_Harrison. hormone analogues have been used. Oophorectomy is no longer recommended, and estrogen-containing drugs should be discontinued. Lung transplantation offers the only hope for cure despite reports of recurrent disease in the transplanted lung.


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InternalMed_Harrison. SYNDROMES OF ILD WITH DIFFUSE ALVEOLAR HEMORRHAGE Clinical Manifestations The clinical onset is often abrupt, with cough, fever, and dyspnea. Severe respiratory distress requiring ventilatory support may be evident at initial presentation. Although hemoptysis is expected, it can be absent at the time of presentation in one-third of the cases. For patients without hemoptysis, new alveolar opacities, a falling hemoglobin level, and hemorrhagic BAL fluid point to the diagnosis. The chest radiograph is nonspecific and most commonly shows new patchy or diffuse alveolar opacities. Recurrent episodes of DAH may lead to pulmonary fibrosis, resulting in interstitial opacities on the chest radiograph. An elevated white blood cell count and falling hematocrit are common. Evidence for impaired renal function caused by focal segmental necrotizing glomerulonephritis, usually with crescent formation, also may be present. Varying degrees of hypoxemia may occur and are often severe enough to require


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InternalMed_Harrison. function caused by focal segmental necrotizing glomerulonephritis, usually with crescent formation, also may be present. Varying degrees of hypoxemia may occur and are often severe enough to require ventilatory support. DlCO may be increased, resulting from the increased hemoglobin within the alveoli compartment.


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InternalMed_Harrison. Histologic Findings Injury to arterioles, venules, and the alveolar septal (alveolar wall or interstitial) capillaries can result in hemoptysis secondary to disruption of the alveolar-capillary basement membrane. This results in bleeding into the alveolar spaces, which characterizes DAH. Pulmonary capillaritis, characterized by a neutrophilic infiltration of the alveolar septae, may lead to necrosis of these structures, loss of capillary structural integrity, and the pouring of red blood cells into the alveolar space. Fibrinoid necrosis of the interstitium and red blood cells within the interstitial space are sometimes seen. Bland pulmonary hemorrhage (i.e., DAH without inflammation of the alveolar structures) also may occur.


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InternalMed_Harrison. Evaluation of either lung or renal tissue by immunofluorescent techniques indicates an absence of immune complexes (pauci-immune) in granulomatosis with polyangiitis (Wegener), microscopic polyangiitis, pauci-immune glomerulonephritis, and isolated pulmonary capillaritis. A granular pattern is found in the CTDs, particularly SLE, and a characteristic linear deposition is found in Goodpasture syndrome. Granular deposition of IgA-containing immune complexes is present in Henoch-Schönlein purpura.


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InternalMed_Harrison. Treatment The mainstay of therapy for the DAH associated with sys-1715 temic vasculitis, CTD, Goodpasture syndrome, and isolated pulmonary capillaritis is IV methylprednisolone, 0.5–2 g daily in divided doses for up to 5 days, followed by a gradual tapering, and then maintenance on an oral preparation. Prompt initiation of therapy is important, particularly in the face of renal insufficiency, because early initiation of therapy has the best chance of preserving renal function. The decision to start other immunosuppressive therapy (cyclophosphamide or azathioprine) acutely depends on the severity of illness.


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InternalMed_Harrison. Goodpasture Syndrome • CLINICAL MANIFESTATIONS Pulmonary hemorrhage and glomerulonephritis are features in most patients with this disease. Autoantibodies to renal glomerular and lung alveolar basement membranes are present. This syndrome can present and recur as DAH without an associated glomerulonephritis. In such cases, circulating anti-basement membrane antibody is often absent, and the only way to establish the diagnosis is by demonstrating linear immunofluorescence in lung tissue. HISTOLOGIC FINDINGS The underlying histology may be bland hemorrhage or DAH associated with capillaritis. TREATMENT Plasmapheresis has been recommended as adjunctive treatment.


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InternalMed_Harrison. HISTOLOGIC FINDINGS The underlying histology may be bland hemorrhage or DAH associated with capillaritis. TREATMENT Plasmapheresis has been recommended as adjunctive treatment. Pulmonary opacities and respiratory symptoms typical of ILD can develop in related family members and in several inherited diseases. These diseases include the phakomatoses, tuberous sclerosis and neurofibromatosis (Chap. 118), and the lysosomal storage diseases, Niemann-Pick disease and Gaucher disease (Chap. 432e). The Hermansky-Pudlak syndrome is an autosomal recessive disorder in which granulomatous colitis and ILD may occur. It is characterized by oculocutaneous albinism, bleeding diathesis secondary to platelet dysfunction, and the accumulation of a chromolipid, lipofuscin material in cells of the reticuloendothelial system. A fibrotic pattern is found on lung biopsy, but the alveolar macrophages may contain cytoplasmic ceroid-like inclusions.


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InternalMed_Harrison. Inhalation of organic dusts, which cause hypersensitivity pneumonitis, or of inorganic dust, such as silica, which elicits a granulomatous inflammatory reaction leading to ILD, produces diseases of known etiology (Table 315-1) that are discussed in Chaps. 310 and 311. Sarcoidosis (Chap. 390) is prominent among granulomatous diseases of unknown cause in which ILD is an important feature.


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InternalMed_Harrison. Granulomatous Vasculitides (See also Chap. 385) The granulomatous vasculitides are characterized by pulmonary angiitis (i.e., inflammation and necrosis of blood vessels) with associated granuloma formation (i.e., infiltrates of lymphocytes, plasma cells, epithelioid cells, or histiocytes, with or without the presence of multinucleated giant cells, sometimes with tissue necrosis). The lungs are almost always involved, although any organ system may be affected. Granulomatosis with polyangiitis (Wegener) and Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) primarily affect the lung but are associated with a systemic vasculitis as well. The granulomatous vasculitides generally limited to the lung include necrotizing sarcoid granulomatosis and benign lymphocytic angiitis and granulomatosis. Granulomatous infection and pulmonary angiitis due to irritating embolic material (e.g., talc) are important known causes of pulmonary vasculitis.


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InternalMed_Harrison. This group of disorders features lymphocyte and plasma cell infiltration of the lung parenchyma. The disorders either are benign or can behave as low-grade lymphomas. Included is angioimmunoblastic lymphadenopathy with dysproteinemia, a rare lymphoproliferative disorder characterized by diffuse lymphadenopathy, fever, hepatosplenomegaly, and hemolytic anemia, with ILD in some cases. 1716 Lymphocytic Interstitial Pneumonitis This rare form of ILD occurs in adults, some of whom have an autoimmune disease or dysproteinemia. It has been reported in patients with Sjögren syndrome and HIV infection.


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InternalMed_Harrison. Lymphomatoid Granulomatosis • CLINICAL MANIFESTATIONS Pulmonary lymphomatoid granulomatosis generally presents predominantly in men between the ages of 30 and 50, although patients can be affected at any age. The effects of race and geography on disease incidence are not known, although a higher diagnosis rate is reported in Western countries. Although it may affect virtually any organ, it is most frequently characterized by pulmonary (>90%), skin, and central nervous system involvement. The most common presenting symptoms and signs include cough, fever, rash/nodules, malaise, weight loss, neurologic abnormalities, dyspnea, and chest pain. HISTOLOGIC FINDINGS This multisystem disorder of unknown etiology is an angiocentric malignant (T cell) lymphoma characterized by a polymorphic lymphoid infiltrate, an angiitis, and granulomatosis.


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InternalMed_Harrison. HISTOLOGIC FINDINGS This multisystem disorder of unknown etiology is an angiocentric malignant (T cell) lymphoma characterized by a polymorphic lymphoid infiltrate, an angiitis, and granulomatosis. TREATMENT The clinical course of lymphomatoid granulomatosis ranges from remission without treatment to death from malignant lymphoma within 2 years. The choice of a treatment strategy should be based upon the presence of symptoms, history of using an inciting medication, extent of extrapulmonary involvement, and careful assessment of the histopathologic grade of the lesion. Referral to a hematology oncology specialist for consultation is recommended.


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InternalMed_Harrison. BRONCHOCENTRIC GRANULOMATOSIS Clinical Manifestations Rather than a specific clinical entity, bronchocentric granulomatosis (BG) is a descriptive histologic term that is applied to an uncommon and nonspecific pathologic response to a variety of airway injuries. There is evidence that BG is caused by a hypersensitivity reaction to Aspergillus or other fungi in patients with asthma. About one-half of the patients described have had chronic asthma with severe wheezing and peripheral blood eosinophilia. In patients with asthma, BG probably represents one pathologic manifestation of allergic bronchopulmonary aspergillosis or another allergic mycosis. In patients without asthma, BG has been associated with RA and a variety of infections, including tuberculosis, echinococcosis, histoplasmosis, coccidioidomycosis, and nocardiosis. The chest roentgenogram reveals irregularly shaped nodular or mass lesions with ill-defined margins, which are usually unilateral and solitary, with upper lobe


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InternalMed_Harrison. coccidioidomycosis, and nocardiosis. The chest roentgenogram reveals irregularly shaped nodular or mass lesions with ill-defined margins, which are usually unilateral and solitary, with upper lobe predominance.


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InternalMed_Harrison. Histologic Findings Bronchocentric granulomatosis is characterized by peribronchial and peribronchiolar necrotizing granulomatous inflammation. Destruction of airway walls and adjacent parenchyma leads to granulomatous replacement of mucosa and submucosa by palisading, epithelioid, and multinucleated histiocytes. Bronchocentric granulomatosis does not typically involve the pulmonary arteries. Treatment Glucocorticoids are the treatment of choice, often with an excellent outcome, although recurrences may occur as therapy is tapered or stopped. Limited epidemiologic data exist describing the prevalence or incidence of ILD in the general population. With a few exceptions, e.g., sarcoidosis and certain occupational and environmental exposures, there appear to be no significant differences in the prevalence or incidence of ILD among various populations. For sarcoidosis, there are important environmental, racial, and genetic differences (Chap. 390). Disorders of the pleura


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InternalMed_Harrison. Disorders of the pleura Richard W. Light The pleural space lies between the lung and the chest wall and normally contains a very thin layer of fluid, which serves as a coupling system. A pleural effusion is present when there is an excess quantity of fluid in the pleural space.


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InternalMed_Harrison. Etiology Pleural fluid accumulates when pleural fluid formation exceeds pleural fluid absorption. Normally, fluid enters the pleural space from the capillaries in the parietal pleura and is removed via the lymphatics in the parietal pleura. Fluid also can enter the pleural space from the interstitial spaces of the lung via the visceral pleura or from the peritoneal cavity via small holes in the diaphragm. The lymphatics have the capacity to absorb 20 times more fluid than is formed normally. Accordingly, a pleural effusion may develop when there is excess pleural fluid formation (from the interstitial spaces of the lung, the parietal pleura, or the peritoneal cavity) or when there is decreased fluid removal by the lymphatics.


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InternalMed_Harrison. Diagnostic Approach Patients suspected of having a pleural effusion should undergo chest imaging to diagnose its extent. Chest ultrasound has replaced the lateral decubitus x-ray in the evaluation of suspected pleural effusions and as a guide to thoracentesis. When a patient is found to have a pleural effusion, an effort should be made to determine the cause (Fig. 316-1). The first step is to determine whether the effusion is a transudate or an exudate. A transudative pleural effusion occurs when systemic factors that influence the formation and absorption of pleural fluid are altered. The leading causes of transudative pleural effusions in the United States are left ventricular failure and cirrhosis. An exudative pleural effusion occurs when local factors that influence the formation and absorption of pleural fluid are altered. The leading causes of exudative pleural effusions are bacterial pneumonia, malignancy, viral infection, and pulmonary embolism. The primary reason for making


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InternalMed_Harrison. absorption of pleural fluid are altered. The leading causes of exudative pleural effusions are bacterial pneumonia, malignancy, viral infection, and pulmonary embolism. The primary reason for making this differentiation is that additional diagnostic procedures are indicated with exudative effusions to define the cause of the local disease.


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InternalMed_Harrison. Transudative and exudative pleural effusions are distinguished by measuring the lactate dehydrogenase (LDH) and protein levels in the pleural fluid. Exudative pleural effusions meet at least one of the following criteria, whereas transudative pleural effusions meet none: 1. Pleural fluid protein/serum protein >0.5 2. Pleural fluid LDH/serum LDH >0.6 3. Pleural fluid LDH more than two-thirds the normal upper limit for serum These criteria misidentify ~25% of transudates as exudates. If one or more of the exudative criteria are met and the patient is clinically thought to have a condition producing a transudative effusion, the difference between the protein levels in the serum and the pleural fluid should be measured. If this gradient is >31 g/L (3.1 g/dL), the exudative categorization by these criteria can be ignored because almost all such patients have a transudative pleural effusion.


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InternalMed_Harrison. If a patient has an exudative pleural effusion, the following tests on the pleural fluid should be obtained: description of the appearance of the fluid, glucose level, differential cell count, microbiologic studies, and cytology. Effusion Due to Heart Failure The most common cause of pleural effusion is left ventricular failure. The effusion occurs because the increased amounts of fluid in the lung interstitial spaces exit in part across the visceral pleura; this overwhelms the capacity of the lymphatics in the parietal pleura to remove fluid. In patients with heart failure,


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InternalMed_Harrison. Perform diagnostic thoracentesis Measure pleural fluid protein and LDH Exudate Further diagnostic procedures Transudate Treat CHF, cirrhosis, nephrosis Measure PF glucose Obtain PF cytology Obtain differential cell count Culture, stain PF PF marker for TB Consider:Malignancy Bacterial infections Rheumatoid pleuritis Glucose < 60 mg/dL No diagnosis Consider pulmonary embolus (spiral CT or lung scan) Treat for PE Treat for TB PF marker for TB Observe Consider thoracoscopy or image-guided pleural biopsy Any of following met? PF/serum protein > 0.5 PF/serum LDH > 0.6 PF LDH > 2/3 upper normal serum limit Pleural effusion Yes No Yes Yes Yes No No No SYMPTOMS IMPROVING FIGURE 316-1 Approach to the diagnosis of pleural effusions. CHF, congestive heart failure; CT, computed tomography; LDH, lactate dehydrogenase; PE, pulmonary embolism; PF, pleural fluid; TB, tuberculosis.


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InternalMed_Harrison. CHF, congestive heart failure; CT, computed tomography; LDH, lactate dehydrogenase; PE, pulmonary embolism; PF, pleural fluid; TB, tuberculosis. a diagnostic thoracentesis should be performed if the effusions are not bilateral and comparable in size, if the patient is febrile, or if the patient has pleuritic chest pain to verify that the patient has a transudative effusion. Otherwise the patient’s heart failure is treated. If the effusion persists despite therapy, a diagnostic thoracentesis should be performed. A pleural fluid N-terminal pro-brain natriuretic peptide (NT-proBNP) >1500 pg/mL is virtually diagnostic that the effusion is secondary to congestive heart failure.


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InternalMed_Harrison. Hepatic Hydrothorax Pleural effusions occur in ~5% of patients with cirrhosis and ascites. The predominant mechanism is the direct movement of peritoneal fluid through small openings in the diaphragm into the pleural space. The effusion is usually right-sided and frequently is large enough to produce severe dyspnea. Parapneumonic Effusion Parapneumonic effusions are associated with bacterial pneumonia, lung abscess, or bronchiectasis and are probably the most common cause of exudative pleural effusion in the United States. Empyema refers to a grossly purulent effusion. Patients with aerobic bacterial pneumonia and pleural effusion 1717 present with an acute febrile illness consisting of chest pain, sputum production, and leukocytosis. Patients with anaerobic infections present with a subacute illness with weight loss, a brisk leukocytosis, mild anemia, and a history of some factor that predisposes them to aspiration.


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InternalMed_Harrison. The possibility of a parapneumonic effusion should be considered whenever a patient with bacterial pneumonia is initially evaluated. The presence of free pleural fluid can be demonstrated with a lateral decubitus radiograph, computed tomography (CT) of the chest, or ultrasound. If the free fluid separates the lung from the chest wall by >10 mm, a therapeutic thoracentesis should be performed. Factors indicating the likely need for a procedure more invasive than a thoracentesis (in increasing order of importance) include the following: 1. 2. Pleural fluid pH <7.20 3. Pleural fluid glucose <3.3 mmol/L (<60 mg/dL) 4. Positive Gram stain or culture of the pleural fluid 5. Presence of gross pus in the pleural space


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InternalMed_Harrison. 2. Pleural fluid pH <7.20 3. Pleural fluid glucose <3.3 mmol/L (<60 mg/dL) 4. Positive Gram stain or culture of the pleural fluid 5. Presence of gross pus in the pleural space If the fluid recurs after the initial therapeutic thoracentesis and if any of these characteristics are present, a repeat thoracentesis should be performed. If the fluid cannot be completely removed with the therapeutic thoracentesis, consideration should be given to inserting a chest tube and instilling the combination of a fibrinolytic agent (e.g., tissue plasminogen activator, 10 mg) and deoxyribonuclease (5 mg) or performing a thoracoscopy with the breakdown of adhesions. Decortication should be considered when these measures are ineffective.


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InternalMed_Harrison. Effusion Secondary to Malignancy Malignant pleural effusions secondary to metastatic disease are the second most common type of exudative pleural effusion. The three tumors that cause ~75% of all malignant pleural effusions are lung carcinoma, breast carcinoma, and lymphoma. Most patients complain of dyspnea, which is frequently out of proportion to the size of the effusion. The pleural fluid is an exudate, and its glucose level may be reduced if the tumor burden in the pleural space is high.


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InternalMed_Harrison. The diagnosis usually is made via cytology of the pleural fluid. If the initial cytologic examination is negative, thoracoscopy is the best next procedure if malignancy is strongly suspected. At the time of thoracoscopy, a procedure such as pleural abrasion should be performed to effect a pleurodesis. An alternative to thoracoscopy is CTor ultrasound-guided needle biopsy of pleural thickening or nodules. Patients with a malignant pleural effusion are treated symptomatically for the most part, since the presence of the effusion indicates disseminated disease and most malignancies associated with pleural effusion are not curable with chemotherapy. The only symptom that can be attributed to the effusion itself is dyspnea. If the patient’s lifestyle is compromised by dyspnea and if the dyspnea is relieved with a therapeutic thoracentesis, one of the following procedures should be considered: (1) insertion of a small indwelling catheter or (2) tube thoracostomy with the instillation of a


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InternalMed_Harrison. is relieved with a therapeutic thoracentesis, one of the following procedures should be considered: (1) insertion of a small indwelling catheter or (2) tube thoracostomy with the instillation of a sclerosing agent such as doxycycline (500 mg).


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InternalMed_Harrison. Mesothelioma Malignant mesotheliomas are primary tumors that arise from the mesothelial cells that line the pleural cavities; most are related to asbestos exposure. Patients with mesothelioma present with chest pain and shortness of breath. The chest radiograph reveals a pleural effusion, generalized pleural thickening, and a shrunken hemithorax. The diagnosis is usually established with image-guided needle biopsy or thoracoscopy.


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InternalMed_Harrison. Effusion Secondary to Pulmonary Embolization The diagnosis most commonly overlooked in the differential diagnosis of a patient with an undiagnosed pleural effusion is pulmonary embolism. Dyspnea is the most common symptom. The pleural fluid is almost always an exudate. The diagnosis is established by spiral CT scan or pulmonary arteriography (Chap. 300). Treatment of a patient with a pleural effusion secondary to pulmonary embolism is the same as it is for any patient with pulmonary emboli. If the pleural effusion increases in size after anticoagulation, the patient probably has recurrent emboli or another complication, such as a hemothorax or a pleural infection.


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InternalMed_Harrison. Disorders of the Pleura 1718 Tuberculous Pleuritis (See also Chap. 202) In many parts of the world, the most common cause of an exudative pleural effusion is tuberculosis (TB), but tuberculous effusions are relatively uncommon in the United States. Tuberculous pleural effusions usually are associated with primary TB and are thought to be due primarily to a hypersensitivity reaction to tuberculous protein in the pleural space. Patients with tuberculous pleuritis present with fever, weight loss, dyspnea, and/or pleuritic chest pain. The pleural fluid is an exudate with predominantly small lymphocytes. The diagnosis is established by demonstrating high levels of TB markers in the pleural fluid (adenosine deaminase >40 IU/L or interferon γ >140 pg/mL). Alternatively, the diagnosis can be established by culture of the pleural fluid, needle biopsy of the pleura, or thoracoscopy. The recommended treatments of pleural and pulmonary TB are identical (Chap. 202).


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InternalMed_Harrison. Effusion Secondary to Viral Infection Viral infections are probably responsible for a sizable percentage of undiagnosed exudative pleural effusions. In many series, no diagnosis is established for ~20% of exudative effusions, and these effusions resolve spontaneously with no long-term residua. The importance of these effusions is that one should not be too aggressive in trying to establish a diagnosis for the undiagnosed effusion, particularly if the patient is improving clinically.


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InternalMed_Harrison. Chylothorax A chylothorax occurs when the thoracic duct is disrupted and chyle accumulates in the pleural space. The most common cause of chylothorax is trauma (most frequently thoracic surgery), but it also may result from tumors in the mediastinum. Patients with chylothorax present with dyspnea, and a large pleural effusion is present on the chest radiograph. Thoracentesis reveals milky fluid, and biochemical analysis reveals a triglyceride level that exceeds 1.2 mmol/L (110 mg/ dL). Patients with chylothorax and no obvious trauma should have a lymphangiogram and a mediastinal CT scan to assess the mediastinum for lymph nodes. The treatment of choice for most chylothoraxes is insertion of a chest tube plus the administration of octreotide. If these modalities fail, a pleuroperitoneal shunt should be placed unless the patient has chylous ascites. Alternative treatments are ligation of the thoracic duct and percutaneous transabdominal thoracic duct blockage. Patients with


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InternalMed_Harrison. shunt should be placed unless the patient has chylous ascites. Alternative treatments are ligation of the thoracic duct and percutaneous transabdominal thoracic duct blockage. Patients with chylothoraxes should not undergo prolonged tube thoracostomy with chest tube drainage because this will lead to malnutrition and immunologic incompetence.


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InternalMed_Harrison. Hemothorax When a diagnostic thoracentesis reveals bloody pleural fluid, a hematocrit should be obtained on the pleural fluid. If the hematocrit is more than one-half of that in the peripheral blood, the patient is considered to have a hemothorax. Most hemothoraxes are the result of trauma; other causes include rupture of a blood vessel or tumor. Most patients with hemothorax should be treated with tube thoracostomy, which allows continuous quantification of bleeding. If the bleeding emanates from a laceration of the pleura, apposition of the two pleural surfaces is likely to stop the bleeding. If the pleural hemorrhage exceeds 200 mL/h, consideration should be given to thoracoscopy or thoracotomy.


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InternalMed_Harrison. Miscellaneous Causes of Pleural Effusion There are many other causes of pleural effusion (Table 316-1). Key features of some of these conditions are as follows: If the pleural fluid amylase level is elevated, the diagnosis of esophageal rupture or pancreatic disease is likely. If the patient is febrile, has predominantly polymorphonuclear cells in the pleural fluid, and has no pulmonary parenchymal abnormalities, an intraabdominal abscess should be considered.


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InternalMed_Harrison. The diagnosis of an asbestos pleural effusion is one of exclusion. Benign ovarian tumors can produce ascites and a pleural effusion (Meigs’ syndrome), as can the ovarian hyperstimulation syndrome. Several drugs can cause pleural effusion; the associated fluid is usually eosinophilic. Pleural effusions commonly occur after coronary artery bypass surgery. Effusions occurring within the first weeks are typically left-sided and bloody, with large numbers of eosinophils, and respond to one or two therapeutic thoracenteses. Effusions occurring after the first few weeks are typically left-sided and clear yellow, with predominantly small lymphocytes, and tend to recur. Other medical manipulations that induce pleural effusions include abdominal 1. 2. 3. Nephrotic syndrome 4. 5. 6. 7. 1. Neoplastic diseases a. b. 2. Infectious diseases a. b. c. d. e. 3. 4. a. b. c. d. e. f. g. 5. Collagen vascular diseases a. b. c. d. e. f.


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InternalMed_Harrison. 5. 6. 7. 1. Neoplastic diseases a. b. 2. Infectious diseases a. b. c. d. e. 3. 4. a. b. c. d. e. f. g. 5. Collagen vascular diseases a. b. c. d. e. f. Granulomatosis with polyangiitis (Wegener) g. 6. 7. 8. 9. 10. 11. 12. a. b. c. d. e. f. g. 13. 14. 15. 16. 17. 18. 19. 20. surgery; radiation therapy; liver, lung, or heart transplantation; and the 1719 intravascular insertion of central lines. Disorders of the Mediastinum PNEUMOTHORAX Richard W. Light


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InternalMed_Harrison. 18. 19. 20. surgery; radiation therapy; liver, lung, or heart transplantation; and the 1719 intravascular insertion of central lines. Disorders of the Mediastinum PNEUMOTHORAX Richard W. Light Pneumothorax is the presence of gas in the pleural space. A spontaneous pneumothorax is one that occurs without antecedent trauma to the thorax. A primary spontaneous pneumothorax occurs in the absence of underlying lung disease, whereas a secondary pneumothorax occurs in its presence. A traumatic pneumothorax results from penetrating or nonpenetrating chest injuries. A tension pneumothorax is a pneumothorax in which the pressure in the pleural space is positive throughout the respiratory cycle.


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InternalMed_Harrison. Primary Spontaneous Pneumothorax Primary spontaneous pneumothoraxes are usually due to rupture of apical pleural blebs, small cystic spaces that lie within or immediately under the visceral pleura. Primary spontaneous pneumothoraxes occur almost exclusively in smokers; this suggests that these patients have subclinical lung disease. Approximately one-half of patients with an initial primary spontaneous pneumothorax will have a recurrence. The initial recommended treatment for primary spontaneous pneumothorax is simple aspiration. If the lung does not expand with aspiration or if the patient has a recurrent pneumothorax, thoracoscopy with stapling of blebs and pleural abrasion is indicated. Thoracoscopy or thoracotomy with pleural abrasion is almost 100% successful in preventing recurrences.


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InternalMed_Harrison. Secondary Pneumothorax Most secondary pneumothoraxes are due to chronic obstructive pulmonary disease, but pneumothoraxes have been reported with virtually every lung disease. Pneumothorax in patients with lung disease is more life-threatening than it is in normal individuals because of the lack of pulmonary reserve in these patients. Nearly all patients with secondary pneumothorax should be treated with tube thoracostomy. Most should also be treated with thoracoscopy or thoracotomy with the stapling of blebs and pleural abrasion. If the patient is not a good operative candidate or refuses surgery, pleurodesis should be attempted by the intrapleural injection of a sclerosing agent such as doxycycline.


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InternalMed_Harrison. Traumatic Pneumothorax Traumatic pneumothoraxes can result from both penetrating and nonpenetrating chest trauma. Traumatic pneumothoraxes should be treated with tube thoracostomy unless they are very small. If a hemopneumothorax is present, one chest tube should be placed in the superior part of the hemithorax to evacuate the air and another should be placed in the inferior part of the hemithorax to remove the blood. Iatrogenic pneumothorax is a type of traumatic pneumothorax that is becoming more common. The leading causes are transthoracic needle aspiration, thoracentesis, and the insertion of central intravenous catheters. Most can be managed with supplemental oxygen or aspiration, but if these measures are unsuccessful, a tube thoracostomy should be performed.


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InternalMed_Harrison. Tension Pneumothorax This condition usually occurs during mechanical ventilation or resuscitative efforts. The positive pleural pressure is life-threatening both because ventilation is severely compromised and because the positive pressure is transmitted to the mediastinum, resulting in decreased venous return to the heart and reduced cardiac output.


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InternalMed_Harrison. Difficulty in ventilation during resuscitation or high peak inspiratory pressures during mechanical ventilation strongly suggest the diagnosis. The diagnosis is made by physical examination showing an enlarged hemithorax with no breath sounds, hyperresonance to percussion, and shift of the mediastinum to the contralateral side. Tension pneumothorax must be treated as a medical emergency. If the tension in the pleural space is not relieved, the patient is likely to die from inadequate cardiac output or marked hypoxemia. A large-bore needle should be inserted into the pleural space through the second anterior intercostal space. If large amounts of gas escape from the needle after insertion, the diagnosis is confirmed. The needle should be left in place until a thoracostomy tube can be inserted.


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InternalMed_Harrison. The mediastinum is the region between the pleural sacs. It is separated into three compartments (Table 317-1). The anterior mediastinum extends from the sternum anteriorly to the pericardium and brachiocephalic vessels posteriorly. It contains the thymus gland, the anterior mediastinal lymph nodes, and the internal mammary arteries and veins. The middle mediastinum lies between the anterior and posterior mediastina and contains the heart; the ascending and transverse arches of the aorta; the venae cavae; the brachiocephalic arteries and veins; the phrenic nerves; the trachea, the main bronchi, and their contiguous lymph nodes; and the pulmonary arteries and veins. The posterior mediastinum is bounded by the pericardium and trachea anteriorly and the vertebral column posteriorly. It contains the descending thoracic aorta, the esophagus, the thoracic duct, the azygos and hemiazygos veins, and the posterior group of mediastinal lymph nodes.


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InternalMed_Harrison. The first step in evaluating a mediastinal mass is to place it in one of the three mediastinal compartments, since each has different characteristic lesions (Table 317-1). The most common lesions in the anterior mediastinum are thymomas, lymphomas, teratomatous neoplasms, and thyroid masses. The most common masses in the middle mediastinum are vascular masses, lymph node enlargement from metastases or granulomatous disease, and pleuropericardial and bronchogenic cysts. In the posterior mediastinum, neurogenic tumors, meningoceles, meningomyeloceles, gastroenteric cysts, and esophageal diverticula are commonly found.


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InternalMed_Harrison. Computed tomography (CT) scanning is the most valuable imaging technique for evaluating mediastinal masses and is the only imaging technique that should be done in most instances. Barium studies of the gastrointestinal tract are indicated in many patients with posterior mediastinal lesions, because hernias, diverticula, and achalasia are readily diagnosed in this manner. An iodine-131 scan can efficiently establish the diagnosis of intrathoracic goiter.


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InternalMed_Harrison. A definite diagnosis can be obtained with mediastinoscopy or anterior mediastinotomy in many patients with masses in the anterior or middle mediastinal compartments. A diagnosis can be established without thoracotomy via percutaneous fine-needle aspiration biopsy or endoscopic transesophageal or endobronchial ultrasound-guided biopsy of mediastinal masses in most cases. An alternative way to establish the diagnosis is video-assisted thoracoscopy. In many cases, the diagnosis can be established and the mediastinal mass removed with video-assisted thoracoscopy.


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InternalMed_Harrison. Most cases of acute mediastinitis either are due to esophageal perforation or occur after median sternotomy for cardiac surgery. Patients with esophageal rupture are acutely ill with chest pain and dyspnea due to the mediastinal infection. The esophageal rupture can occur spontaneously or as a complication of esophagoscopy or the insertion of a Blakemore tube. Appropriate treatment consists of exploration of the mediastinum with primary repair of the esophageal tear and drainage of the pleural space and the mediastinum. The incidence of mediastinitis after median sternotomy is 0.4–5.0%. Patients most commonly present with wound drainage. Other presentations include sepsis and a widened mediastinum. The diagnosis usually is established with mediastinal needle aspiration. Treatment includes immediate drainage, debridement, and parenteral antibiotic therapy, but the mortality rate still exceeds 20%.


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InternalMed_Harrison. The spectrum of chronic mediastinitis ranges from granulomatous inflammation of the lymph nodes in the mediastinum to fibrosing Disorders of the Mediastinum Common abnormalities Manubrium and sternum anteriorly, Anterior mediastinum anteriorly, posterior Pericardium and trachea anteriorly; pericardium, aorta, and brachiocephalic mediastinum posteriorly vertebral column posteriorly vessels posteriorly Thymus gland, anterior mediastinal lymph Pericardium, heart, ascending and transverse arch Descending thoracic aorta, esophagus, nodes, internal mammary arteries and of aorta, superior and inferior vena cavae, brachio-thoracic duct, azygos and hemiazygos veins cephalic arteries and veins, phrenic nerves, trachea, veins, sympathetic chains, and the posterior and main bronchi and their contiguous lymph group of mediastinal lymph nodes nodes, pulmonary arteries, and veins


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InternalMed_Harrison. Thymoma, lymphomas, teratomatous Metastatic lymph node enlargement, granuloma-Neurogenic tumors, meningocele, meninneoplasms, thyroid masses, parathyroid tous lymph node enlargement, pleuropericardial gomyelocele, gastroenteric cysts, esophamasses, mesenchymal tumors, giant cysts, bronchogenic cysts, masses of vascular origin geal diverticula, hernia through foramen of lymph node hyperplasia, hernia through foramen of Morgagni mediastinitis. Most cases are due to histoplasmosis or tuberculosis, but sarcoidosis, silicosis, and other fungal diseases are at times causative. Patients with granulomatous mediastinitis are usually asymptomatic. Those with fibrosing mediastinitis usually have signs of compression of a mediastinal structure such as the superior vena cava or large airways, phrenic or recurrent laryngeal nerve paralysis, or obstruction of the pulmonary artery or proximal pulmonary veins. Other than antituberculous therapy for tuberculous mediastinitis, no medical or surgical


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InternalMed_Harrison. or recurrent laryngeal nerve paralysis, or obstruction of the pulmonary artery or proximal pulmonary veins. Other than antituberculous therapy for tuberculous mediastinitis, no medical or surgical therapy has been demonstrated to be effective for mediastinal fibrosis.


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InternalMed_Harrison. In this condition, there is gas in the interstices of the mediastinum. The three main causes are (1) alveolar rupture with dissection of air into the mediastinum; (2) perforation or rupture of the esophagus, trachea, or main bronchi; and (3) dissection of air from the neck or the abdomen into the mediastinum. Typically, there is severe substernal chest pain with or without radiation into the neck and arms. The physical examination usually reveals subcutaneous emphysema in the suprasternal notch and Hamman’s sign, which is a crunching or clicking noise synchronous with the heartbeat and is best heard in the left lateral decubitus position. The diagnosis is confirmed with the chest radiograph. Usually no treatment is required, but the mediastinal air will be absorbed faster if the patient inspires high concentrations of oxygen. If mediastinal structures are compressed, the compression can be relieved with needle aspiration.


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InternalMed_Harrison. Disorders of Ventilation John F. McConville, Babak Mokhlesi, Julian Solway DEFINITION AND PHYSIOLOGY In health the arterial level of carbon dioxide (PaCO2) is maintained between 37 and 43 mmHg at sea level. All disorders of ventilation result in abnormal measurements of PaCO2. This chapter reviews 318 chronic ventilatory disorders. The continuous production of CO2 by cellular metabolism necessitates its efficient elimination by the respiratory system. The relationship between CO2 production and PaCO2 is described by the equation:


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InternalMed_Harrison. PaCO2 = (k) (V CO2)/V A, where V CO2 represents the carbon dioxide production, k is a constant, and VA is fresh gas alveolar ventilation (Chap. 306e). VA can be calculated as minute ventilation × (1 – Vd/ Vt), where the dead space fraction Vd/Vt represents the portion of a tidal breath that remains within the conducting airways at the conclusion of inspiration and so does not contribute to alveolar ventilation. As such, all disturbances of PaCO2 must reflect altered CO2 production, minute ventilation, or dead space fraction. Bochdalek, extramedullary hematopoiesis Diseases that alter VCO2 are often acute (e.g., sepsis, burns, or pyrexia), and their contribution to ventilatory abnormalities and/or respiratory failure is reviewed elsewhere. Chronic ventilatory disorders typically involve inappropriate levels of minute ventilation or increased dead space fraction. Characterization of these disorders requires a review of the normal respiratory cycle.


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InternalMed_Harrison. The spontaneous cycle of inspiration and expiration is automatically generated in the brainstem. Two groups of neurons located within the medulla are particularly important: the dorsal respiratory group (DRG) and the ventral respiratory column (VRC). These neurons have widespread projections including the descending projections into the contralateral spinal cord where they perform many functions. They initiate activity in the phrenic nerve/diaphragm, project to the upper airway muscle groups and spinal respiratory neurons, and innervate the intercostal and abdominal muscles that participate in normal respiration. The DRG acts as the initial integration site for many of the afferent nerves relaying information about PaO2, PaCO2, pH, and blood pressure from the carotid and aortic chemoreceptors and baroreceptors to the central nervous system (CNS). In addition, the vagus nerve relays information from stretch receptors and juxtapulmonary-capillary receptors in the lung parenchyma and


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InternalMed_Harrison. and baroreceptors to the central nervous system (CNS). In addition, the vagus nerve relays information from stretch receptors and juxtapulmonary-capillary receptors in the lung parenchyma and chest wall to the DRG. The respiratory rhythm is generated within the VRC as well as the more rostrally located parafacial respiratory group (pFRG), which is particularly important for the generation of active expiration. One particularly important area within the VRC is the so-called pre-Bötzinger complex. This area is responsible for the generation of various forms of inspiratory activity, and lesioning of the pre-Bötzinger complex leads to the complete cessation of breathing. The neural output of these medullary respiratory networks can be voluntarily suppressed or augmented by input from higher brain centers and the autonomic nervous system. During normal sleep, there is an attenuated response to hypercapnia and hypoxemia, resulting in mild nocturnal hypoventilation that corrects upon


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InternalMed_Harrison. brain centers and the autonomic nervous system. During normal sleep, there is an attenuated response to hypercapnia and hypoxemia, resulting in mild nocturnal hypoventilation that corrects upon awakening.


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InternalMed_Harrison. Once neural input has been delivered to the respiratory pump muscles, normal gas exchange requires an adequate amount of respiratory muscle strength to overcome the elastic and resistive loads of the respiratory system (Fig. 318-1A) (Chap. 306e). In health, the strength of the respiratory muscles readily accomplishes this, and normal respiration continues indefinitely. Reduction in respiratory drive or neuromuscular competence or substantial increase in respiratory load can diminish minute ventilation, resulting in hypercapnia (Fig. 318-1B). Alternatively, if normal respiratory muscle strength is coupled with excessive respiratory drive, then alveolar hyperventilation ensues and leads to hypocapnia (Fig. 318-1C).


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InternalMed_Harrison. Diseases that reduce minute ventilation or increase dead space fall into four major categories: parenchymal lung and chest wall disease, sleep-disordered breathing, neuromuscular disease, and respiratory drive disorders (Fig. 318-1B). The clinical manifestations of hypoventilation Increased drive with acceptable strength strength and load. A. Excess respiratory muscle strength in health. B. Load greater than strength. C. Increased drive with acceptable strength.


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InternalMed_Harrison. Increased drive with acceptable strength strength and load. A. Excess respiratory muscle strength in health. B. Load greater than strength. C. Increased drive with acceptable strength. syndromes are nonspecific (Table 318-1) and vary depending on the severity of hypoventilation, the rate at which hypercapnia develops, the degree of compensation for respiratory acidosis, and the underlying disorder. Patients with parenchymal lung or chest wall disease typically present with shortness of breath and diminished exercise tolerance. Episodes of increased dyspnea and sputum production are hallmarks of obstructive lung diseases such as chronic obstructive pulmonary disease, whereas progressive dyspnea and cough are common in interstitial lung diseases. Excessive daytime somnolence, poor-quality sleep, and snoring are common among patients with sleep-disordered breathing. Sleep disturbance and orthopnea are also described in SignS anD SyMptoMS of hypoVentiLation


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InternalMed_Harrison. SignS anD SyMptoMS of hypoVentiLation Dyspnea during activities of daily living neuromuscular disorders. As neuromuscular weakness progresses, the respiratory muscles, including the diaphragm, are placed at a mechanical disadvantage in the supine position due to the upward movement of the abdominal contents. New-onset orthopnea is frequently a sign of reduced respiratory muscle force generation. More commonly, however, extremity weakness or bulbar symptoms develop prior to sleep disturbance in neuromuscular diseases such as amyotrophic lateral sclerosis (ALS) or muscular dystrophy. Patients with respiratory drive disorders do not have symptoms distinguishable from other causes of chronic hypoventilation.


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InternalMed_Harrison. The clinical course of patients with chronic hypoventilation from neuromuscular or chest wall disease follows a characteristic sequence: an asymptomatic stage where daytime PaO2 and PaCO2 are normal followed by nocturnal hypoventilation, initially during rapid eye movement (REM) sleep and later in non-REM sleep. Finally, if vital capacity drops further, daytime hypercapnia develops. Symptoms can develop at any point along this time course and often depend on the pace of respiratory muscle functional decline. Regardless of cause, the hallmark of all alveolar hypoventilation syndromes is an increase in alveolar PCO2 (PACO2) and therefore in PaCO2. The resulting respiratory acidosis eventually leads to a compensatory increase in plasma bicarbonate concentration. The increase in PACO2 results in an obligatory decrease in PAO2, often resulting in hypoxemia. If severe, the hypoxemia manifests clinically as cyanosis and can stimulate erythropoiesis and thus induce secondary erythrocytosis.


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InternalMed_Harrison. in an obligatory decrease in PAO2, often resulting in hypoxemia. If severe, the hypoxemia manifests clinically as cyanosis and can stimulate erythropoiesis and thus induce secondary erythrocytosis. The combination of chronic hypoxemia and hypercapnia may also induce pulmonary vasoconstriction, leading eventually to pulmonary hypertension, right ventricular hypertrophy, and right heart failure.


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InternalMed_Harrison. Elevated plasma bicarbonate in the absence of volume depletion is suggestive of hypoventilation. An arterial blood gas demonstrating elevated PaCO2 with a normal pH confirms chronic alveolar hypoventilation. The subsequent evaluation to identify an etiology should initially focus on whether the patient has lung disease or chest wall abnormalities. Physical examination, imaging studies (chest x-ray and/or computed tomography [CT] scan), and pulmonary function tests are sufficient to identify most lung/chest wall disorders leading to hypercapnia. If these evaluations are unrevealing, then the clinician should screen for obesity hypoventilation syndrome (OHS), the most frequent sleep disorder leading to chronic hypoventilation, which is typically accompanied by obstructive sleep apnea (OSA). Several screening tools have been developed to identify patients at risk for OSA. The Berlin Questionnaire has been validated in a primary care setting and identifies patients likely to have OSA. The


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InternalMed_Harrison. Several screening tools have been developed to identify patients at risk for OSA. The Berlin Questionnaire has been validated in a primary care setting and identifies patients likely to have OSA. The Epworth Sleepiness Scale (ESS) and the STOP-Bang questionnaires have not been validated in outpatient primary care settings but are quick and easy to use. The ESS measures daytime sleepiness, with a score of ≥10 indentifying individuals who warrant additional investigation. The STOP-Bang survey has been used in preoperative clinics to identify patients at risk of having OSA. In this population, it has 93% sensitivity and 90% negative predictive value.


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InternalMed_Harrison. If the ventilatory apparatus (lungs, airways, chest wall) is not responsible for chronic hypercapnia, then the focus should shift to respiratory drive and neuromuscular disorders. There is an attenuated increase in minute ventilation in response to elevated CO2 and/ or low O2 in respiratory drive disorders. These diseases are difficult to diagnose and should be suspected when patients with hypercapnia are


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InternalMed_Harrison. Disorders of Ventilation 1722 found to have normal respiratory muscle strength, normal pulmonary function, and normal alveolar-arterial PO2 difference. Hypoventilation is more marked during sleep in patients with respiratory drive defects, and polysomnography often reveals central apneas, hypopneas, or hypoventilation. Brain imaging (CT scan or magnetic resonance imaging [MRI]) can sometimes identify structural abnormalities in the pons or medulla that result in hypoventilation. Chronic narcotic use or significant hypothyroidism can depress the central respiratory drive and lead to chronic hypercapnia as well. Respiratory muscle weakness has to be profound before lung volumes are compromised and hypercapnia develops. Typically physical examination reveals decreased strength in major muscle groups prior to the development of hypercapnia. Measurement of maximum inspiratory and expiratory pressures or forced vital capacity (FVC) can be used to monitor for respiratory muscle involvement


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InternalMed_Harrison. groups prior to the development of hypercapnia. Measurement of maximum inspiratory and expiratory pressures or forced vital capacity (FVC) can be used to monitor for respiratory muscle involvement in diseases with progressive muscle weakness. These patients also have increased risk for sleep-disordered breathing, including hypopneas, central and obstructive apneas, and hypoxemia. Nighttime oximetry and capnometry during polysomnography are helpful in better characterizing sleep disturbances in this patient population.


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InternalMed_Harrison. Nocturnal noninvasive positive-pressure ventilation (NIPPV) has been used successfully in the treatment of hypoventilation and apneas, both central and obstructive, in patients with neuromuscular and chest wall disorders. Nocturnal NIPPV has been shown to improve daytime hypercapnia, prolong survival, and improve health-related quality of life when daytime hypercapnia is documented. ALS guidelines recommend consideration of nocturnal NIPPV if symptoms of hypoventilation exist and one of the following criteria is present: PaCO2 ≥45 mmHg; nocturnal oximetry demonstrates oxygen saturation ≤88% for 5 consecutive min; maximal inspiratory pressure <60 cmH2O; FVC <50% predicted; or sniff nasal pressure <40 cmH2O. However, at present, there is inconclusive evidence to support preemptive nocturnal NIPPV use in all patients with neuromuscular and chest wall disorders who demonstrate nocturnal but not daytime hypercapnia. Nevertheless, at some point, the institution of full-time ventilatory


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InternalMed_Harrison. NIPPV use in all patients with neuromuscular and chest wall disorders who demonstrate nocturnal but not daytime hypercapnia. Nevertheless, at some point, the institution of full-time ventilatory support with either pressure or volume-preset modes is required in progressive neuromuscular disorders. There is less evidence to direct the timing of this decision, but ventilatory failure requiring mechanical ventilation and chest infections related to ineffective cough are frequent triggers for the institution of full-time ventilatory support.


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InternalMed_Harrison. Treatment of chronic hypoventilation from lung or neuromuscular diseases should be directed at the underlying disorder. Pharmacologic agents that stimulate respiration, such as medroxyprogesterone and acetazolamide, have been poorly studied in chronic hypoventilation and should not replace treatment of the underlying disease process. Regardless of the cause, excessive metabolic alkalosis should be corrected, because plasma bicarbonate levels elevated out of proportion for the degree of chronic respiratory acidosis can result in additional hypoventilation. When indicated, administration of supplemental oxygen is effective in attenuating hypoxemia, polycythemia, and pulmonary hypertension. However, in some patients, supplemental oxygen can worsen hypercapnia.


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InternalMed_Harrison. Phrenic nerve or diaphragm pacing is a potential therapy for patients with hypoventilation from high cervical spinal cord lesions or respiratory drive disorders. Prior to surgical implantation, patients should have nerve conduction studies to ensure normal bilateral phrenic nerve function. Small case series suggest that effective diaphragmatic pacing can improve quality of life in these patients.


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InternalMed_Harrison. The diagnosis of OHS requires body mass index (BMI) ≥30 kg/m2 and chronic daytime alveolar hypoventilation, defined as PaCO2 ≥45 mmHg at sea level in the absence of other known causes of hypercapnia. In almost 90% of cases, the sleep-disordered breathing is in the form of OSA. Several international studies in different populations confirm that the overall prevalence of OSA syndrome, defined by an apnea-hypopnea index (AHI) ≥5 and daytime sleepiness, is approximately 3–4% in middle-aged men and 2% in middle-aged women. Thus, the population at risk for the development of OHS continues to rise as the worldwide obesity epidemic persists. Although no population-based prevalence studies of OHS have been performed, some estimates suggest there may be as many as 500,000 individuals with OHS in the United States.


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InternalMed_Harrison. Some, but not all, studies suggest that severe obesity (BMI >40 kg/ m2) and severe OSA (AHI >30 events per hour) are risk factors for the development of OHS. The pathogenesis of hypoventilation in these patients is the result of multiple physiologic variables and conditions including OSA, increased work of breathing, respiratory muscle impairment, ventilation-perfusion mismatching, and depressed central ventilatory responsiveness to hypoxemia and hypercapnia. These defects in central respiratory drive often improve with treatment, which suggests that decreased ventilatory responsiveness is a consequence rather than a primary cause of OHS. The treatment of OHS is similar to that for OSA: weight reduction and nocturnal NIPPV. There is evidence that weight loss alone lowers PaCO2 in patients with OHS. However, treatment with NIPPV should never be delayed while the patient attempts to lose weight. Continuous positive airway pressure (CPAP) improves daytime hypercapnia and hypoxemia in


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InternalMed_Harrison. with OHS. However, treatment with NIPPV should never be delayed while the patient attempts to lose weight. Continuous positive airway pressure (CPAP) improves daytime hypercapnia and hypoxemia in more than half of patients with OHS and concomitant OSA. Bilevel positive airway pressure should be reserved for patients not able to tolerate high levels of CPAP support or patients who remain hypoxemic despite resolution of obstructive respiratory events. NIPPV with bilevel positive airway pressure should be strongly considered if hypercapnia persists after several weeks of CPAP therapy with objectively proven adherence. Patients with OHS and no evidence of OSA are typically started on bilevel positive airway pressure, as are patients presenting with acute decompensated OHS. Finally, comorbid conditions that impair ventilation, such as chronic obstructive pulmonary disease, should be aggressively treated in conjunction with coexisting OHS.


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InternalMed_Harrison. This syndrome can present later in life or in the neonatal period where it is often called Ondine’s curse or congenital central hypoventilation syndrome. Abnormalities in the gene encoding PHOX2b, a transcription factor with a role in neuronal development, have been implicated in the pathogenesis of congenital central hypoventilation syndrome. Regardless of the age of onset, these patients have absent respiratory response to hypoxia or hypercapnia, mildly elevated PaCO2 while awake, and markedly elevated PaCO2 during non-REM sleep. Interestingly these patients are able to augment their ventilation and “normalize” PaCO2 during exercise and during REM sleep. These patients typically require NIPPV or mechanical ventilation as therapy and should be considered for phrenic nerve or diaphragmatic pacing at centers with experience performing these procedures.


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InternalMed_Harrison. Hyperventilation is defined as ventilation in excess of metabolic requirements (CO2 production) leading to a reduction in PaCO2. The physiology of patients with chronic hyperventilation is poorly understood, and there is no typical clinical presentation. Symptoms can include dyspnea, paresthesias, tetany, headache, dizziness, visual disturbances, and atypical chest pain. Because symptoms can be so diverse, patients with chronic hyperventilation present to a variety of health care providers, including internists, neurologists, psychologists, psychiatrists, and pulmonologists.


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InternalMed_Harrison. It is helpful to think of hyperventilation as having initiating and sustaining factors. Some investigators believe that an initial event leads to increased alveolar ventilation and a drop in PaCO2 to ~20 mmHg. The ensuing onset of chest pain, breathlessness, paresthesia, or altered consciousness can be alarming. The resultant increase in minute volume to relieve these acute symptoms only serves to exacerbate symptoms that are often misattributed by the patient and health care workers to cardiopulmonary disorders. An unrevealing evaluation for causes of these symptoms often results in patients being anxious and fearful of additional attacks. It is important to note that anxiety disorders and panic attacks are not synonymous with hyperventilation. Anxiety disorders can be both an initiating and sustaining factor in the pathogenesis of chronic hyperventilation, but these are not necessary for the development of chronic hypocapnia.


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InternalMed_Harrison. Respiratory symptoms associated with acute hyperventilation can be the initial manifestation of systemic illnesses such as diabetic ketoacidosis. Causes of acute hyperventilation need to be excluded before a diagnosis of chronic hyperventilation is considered. Arterial blood gas sampling that demonstrates a compensated respiratory alkalosis with a near normal pH, low PaCO2, and low calculated bicarbonate is necessary to confirm chronic hyperventilation. Other causes of respiratory alkalosis, such as mild asthma, need to be diagnosed and treated before chronic hyperventilation can be considered. A high index of suspicion is required because increased minute ventilation can be difficult to detect on physical examination. Once chronic hyperventilation is established, a sustained 10% increase in alveolar ventilation is enough to perpetuate hypocapnia. This increase can be accomplished with subtle changes in the respiratory pattern, such as occasional sigh breaths or yawning two to three


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InternalMed_Harrison. in alveolar ventilation is enough to perpetuate hypocapnia. This increase can be accomplished with subtle changes in the respiratory pattern, such as occasional sigh breaths or yawning two to three times per minute.


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InternalMed_Harrison. There are few well-controlled treatment studies of chronic hyperventilation due to its diverse features and the lack of a universally accepted diagnostic process. Clinicians often spend considerable time identifying initiating factors, excluding alternative diagnoses, and discussing the patient’s concerns and fears. In some patients, reassurance and frank discussion about hyperventilation can be liberating. Identifying and eliminating habits that perpetuate hypocapnia, such as frequent yawning or sigh breathing, can be helpful. Some evidence suggests that breathing exercises and diaphragmatic retraining may be beneficial for some patients. The evidence for using medications to treat hyperventilation is scant. Beta blockers may be helpful in patients with sympathetically mediated symptoms such as palpitations and tremors. We would like to acknowledge Eliot A. Phillipson for earlier versions of this chapter and Jan-Marino Ramirez for his careful critique and helpful suggestions.


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InternalMed_Harrison. We would like to acknowledge Eliot A. Phillipson for earlier versions of this chapter and Jan-Marino Ramirez for his careful critique and helpful suggestions. Andrew Wellman, Susan Redline


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InternalMed_Harrison. Andrew Wellman, Susan Redline Obstructive sleep apnea/hypopnea syndrome (OSAHS) and central sleep apnea (CSA) are both classified as sleep-related breathing disorders. OSAHS and CSA share some risk factors and physiological bases but also have unique features. Each disorder is associated with impaired ventilation during sleep and disruption of sleep, and each diagnosis requires careful elicitation of the patient’s history, physical examination, and physiological testing. OSAHS, the more common disorder, causes daytime sleepiness, impairs daily function, and is a major contributor to cardiovascular disease in adults and to behavioral 1723 problems in children. CSA is less common and may occur in combination with obstructive sleep apnea, as a primary condition, or secondary to a medical condition or medication. CSA impairs overnight gas exchange and may result in symptoms of either insomnia or excessive sleepiness.


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InternalMed_Harrison. OBSTRUCTIVE SLEEP APNEA/HYPOPNEA SYNDROME (OSAHS) Definition OSAHS is defined on the basis of nocturnal and daytime symptoms as well as sleep study findings. Diagnosis requires the patient to have (1) either symptoms of nocturnal breathing disturbances (snoring, snorting, gasping, or breathing pauses during sleep) or daytime sleepiness or fatigue that occurs despite sufficient opportunities to sleep and is unexplained by other medical problems; and (2) five or more episodes of obstructive apnea or hypopnea per hour of sleep (the apnea-hypopnea index [AHI], calculated as the number of episodes divided by the number of hours of sleep) documented during a sleep study. OSAHS also may be diagnosed in the absence of symptoms if the AHI is above 15. Each episode of apnea or hypopnea represents a reduction in breathing for at least 10 sec. OSAHS is often identified when associated with a ≥3% drop in oxygen saturation and/ or a brain cortical arousal. OSAHS severity is based on the frequency


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InternalMed_Harrison. a reduction in breathing for at least 10 sec. OSAHS is often identified when associated with a ≥3% drop in oxygen saturation and/ or a brain cortical arousal. OSAHS severity is based on the frequency of breathing disturbances (AHI), the amount of oxygen desaturation with respiratory events, the duration of apneas and hypopneas, the degree of sleep fragmentation, and the level of daytime sleepiness.


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InternalMed_Harrison. Pathophysiology During inspiration, intraluminal pharyngeal pressure becomes increasingly negative, creating a “suctioning” force. Because the pharyngeal airway has no bone or cartilage, airway patency is dependent on the stabilizing influence of the pharyngeal dilator muscles. Although these muscles are continuously activated during wakefulness, neuromuscular output declines with sleep onset. In patients with a collapsible airway, the reduction in neuromuscular output results in transient episodes of pharyngeal collapse (manifesting as an “apnea”) or near collapse (manifesting as a “hypopnea”). The episodes of collapse are terminated when ventilatory reflexes are activated and cause arousal, thus stimulating an increase in neuromuscular activity and opening of the airway. The airway may collapse at various levels: the soft palate (most common), tongue base, lateral pharyngeal walls, and/or epiglottis (Fig. 319-1). OSAHS may be most


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InternalMed_Harrison. TongueFIGURE 319-1 Common sites of airway collapse. For example, the palate, tongue, and/or epiglottis (Ep) can be posteriorly displaced, and the lateral pharyngeal walls (LW) can collapse.


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InternalMed_Harrison. 1724 severe during REM (rapid eye movement) sleep, when neuromuscular output to the skeletal muscles is particularly low, and in the supine position due to gravitational forces. Individuals with a small pharyngeal lumen require relatively high levels of neuromuscular innervation to maintain patency during wakefulness and thus are predisposed to excessive airway collapsibility during sleep. The airway lumen may be narrowed with enlargement of soft tissue structures (tongue, palate, and uvula) due to fat deposition, increased lymphoid tissue, or genetic variation. Craniofacial factors such as mandibular retroposition or micrognathia, reflecting genetic variation or developmental influences, also can reduce lumen dimensions. In addition, lung volumes influence the caudal traction on the pharynx and consequently the stiffness of the pharyngeal wall. Accordingly, low lung volume in the recumbent position, which is particularly pronounced in the obese, contributes to collapse. A high degree


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InternalMed_Harrison. and consequently the stiffness of the pharyngeal wall. Accordingly, low lung volume in the recumbent position, which is particularly pronounced in the obese, contributes to collapse. A high degree of nasal resistance (e.g., due to nasal septal deviation or polyps) can contribute to airway collapse by increasing the negative intraluminal suction pressure. High-level nasal resistance also may trigger mouth opening during sleep, which breaks the seal between the tongue and the teeth and allows the tongue to fall posteriorly and occlude the airway. Pharyngeal muscle activation is integrally linked to ventilatory drive. Thus, factors related to ventilatory control, particularly ventilatory sensitivity, arousal threshold, and neuromuscular responses to CO2, contribute to the pathogenesis of OSAHS. A buildup in CO2 during sleep activates both the diaphragm and the pharyngeal muscles, which stiffen the upper airway and can counteract inspiratory suction pressures and maintain airway patency


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InternalMed_Harrison. A buildup in CO2 during sleep activates both the diaphragm and the pharyngeal muscles, which stiffen the upper airway and can counteract inspiratory suction pressures and maintain airway patency to an extent that depends on the anatomic predisposition to collapse. However, pharyngeal collapse can occur when the ventilatory control system is overly sensitive to CO2, with resultant wide fluctuations in ventilation and ventilatory drive and in upper airway instability. Moreover, increasing levels of CO2 during sleep result in central nervous system arousal, causing the individual to move from a deeper to a lighter level of sleep or to awaken. A low arousal threshold (i.e., awaken to a low level of CO2 or ventilatory drive) can preempt the CO2-mediated process of pharyngeal muscle compensation and prevent airway stabilization. A high arousal threshold, conversely, may prevent appropriate termination of apneas, prolonging apnea duration and oxyhemoglobin desaturation severity. Finally, any


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InternalMed_Harrison. and prevent airway stabilization. A high arousal threshold, conversely, may prevent appropriate termination of apneas, prolonging apnea duration and oxyhemoglobin desaturation severity. Finally, any impairment in the ability of the muscles to compensate during sleep can contribute to collapse of the pharynx. The relative contributions of risk factors vary among individuals. Approaches to the measurement of these factors in clinical settings, with consequent enhancement of “personalized” therapeutic interventions, are being actively investigated.


InternalMed_Harrison

InternalMed_Harrison. Risk Factors and Prevalence The major risk factors for OSAHS are obesity and male sex. Additional risk factors include mandibular retrognathia and micrognathia, a positive family history of OSAHS, genetic syndromes that reduce upper airway patency (e.g., Down syndrome, Treacher-Collins syndrome), adenotonsillar hypertrophy (especially in children), menopause (in women), and various endocrine syndromes (e.g., acromegaly, hypothyroidism).


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InternalMed_Harrison. Approximately 40–60% of cases of OSAHS are attributable to excess weight. Obesity predisposes to OSAHS through the narrowing effects of upper airway fat on the pharyngeal lumen. Obesity also reduces chest wall compliance and decreases lung volumes, resulting in a loss of caudal traction on upper airway structures. Obese individuals are at a fourfold or greater risk for OSAHS than their normal-weight counterparts. A 10% weight gain is associated with a >30% increase in AHI. Even modest weight loss or weight gain can influence the risk and severity of OSAHS. However, the absence of obesity does not exclude this diagnosis.


InternalMed_Harrison

InternalMed_Harrison. The prevalence of OSAHS is twoto fourfold higher among men than among women. Factors that predispose men to OSAHS include android patterns of obesity (resulting in upper-airway fat deposition) and relatively great pharyngeal length, which exacerbates collapsibility. Premenopausal women are relatively protected from OSAHS by the influence of sex hormones on ventilatory drive. The decline in sex differences in older age is associated with an increased OSAHS prevalence in women after menopause. Variations in craniofacial morphology that reduce the size of the posterior airway space increase OSAHS risk. The contribution of hard-tissue structural features to OSAHS is most evident in nonobese patients. Identification of features such as retrognathia can influence therapeutic decision-making.


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InternalMed_Harrison. OSAHS has a strong genetic basis, as evidenced by its significant familial aggregation and heritability. For a first-degree relative of a patient with OSAHS, the odds ratio of having OSAHS is approximately twofold higher than that for someone without an affected relative. OSAHS prevalence varies with age, from 2–15% among middle-aged adults to >20% among elderly individuals. There is a peak due to lymphoid hypertrophy among children between the ages of 3 and 8 years; with airway growth and lymphoid tissue regression during later childhood, prevalence declines. Then, as obesity prevalence increases in middle life and women enter menopause, OSAHS again increases.


InternalMed_Harrison

InternalMed_Harrison. The prevalence of OSAHS may be especially high among patients with diabetes or hypertension. Individuals of Asian ancestry appear to be at increased risk of OSAHS at relatively low levels of body mass index, possibly because of the influence of craniofacial risk factors that narrow the nasopharynx. In the United States, African Americans, especially children and young adults, are at higher risk for OSAHS than their Caucasian counterparts. In a majority of adults with OSAHS, the disorder is undiagnosed. Course of the Disorder The precise onset of OSAHS is usually hard to identify. A person may snore for many years, often beginning in childhood, before OSAHS is identified. Weight gain may precipitate an increase in symptoms, which in turn may lead the patient to pursue an evaluation. OSAHS may become less severe with weight loss, particularly after bariatric surgery. Marked increases and decreases in the AHI are uncommon unless accompanied by weight change. APPROACH TO THE PATIENT:


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InternalMed_Harrison. APPROACH TO THE PATIENT: An evaluation for OSAHS should be considered in patients with symptoms of OSAHS and one or more risk factors. Screening also should be considered in patients who report symptoms consistent with OSAHS and who are at high risk for OSAHS-related morbidities, such as hypertension, diabetes mellitus, and cardiac and cerebrovascular diseases.


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InternalMed_Harrison. When possible, a sleep history should be obtained in the presence of a bed partner. Snoring is the most common complaint; however, its absence does not exclude the diagnosis, as pharyngeal collapse may occur without tissue vibration. Gasping or snorting during sleep may also be reported, reflecting termination of individual apneas with abrupt airway opening. Dyspnea is unusual, and its absence generally distinguishes OSAHS from paroxysmal nocturnal dyspnea, nocturnal asthma, and acid reflux with laryngospasm. Patients also may describe frequent awakening or sleep disruption, which is more common among women and older adults. The most common daytime symptom is sleepiness. This symptom can be difficult to elicit and may be hard to distinguish from exercise-related fatigue, deconditioning, and malaise. In contrast to true sleepiness, the latter symptoms generally improve with rest. Other symptoms include a dry mouth, nocturnal heartburn, diaphoresis of the chest and neck, nocturia,


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InternalMed_Harrison. and malaise. In contrast to true sleepiness, the latter symptoms generally improve with rest. Other symptoms include a dry mouth, nocturnal heartburn, diaphoresis of the chest and neck, nocturia, morning headaches, trouble concentrating, irritability, and mood disturbances. Several questionnaires that evaluate snoring frequency, self-reported apneas, and daytime sleepiness can facilitate OSAHS screening. The predictive ability of a questionnaire can be enhanced by a consideration of whether the patient is male or has risk factors such as obesity or hypertension.


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InternalMed_Harrison. Physical findings often reflect the etiologic factors for the disorder as well as comorbid conditions, particularly vascular disease. On examination, patients may exhibit hypertension and regional (central) obesity, as indicated by a large waist and neck circumference. The oropharynx may reveal a small orifice with crowding due to an enlarged tongue, a low-lying soft palate with a bulky uvula, large tonsils, a high arched palate, and/or micro/retrognathia. Since high-level nasal resistance can increase pharyngeal collapsibility, the nasal cavity should be inspected for polyps, septal deviation, and other signs of obstruction. Because patients with heart failure are at increased risk for both OSAHS and CSA, a careful cardiac examination should be conducted to detect possible leftor right-sided cardiac dysfunction. Evidence of cor pulmonale suggests severe OSAHS or a comorbid cardiopulmonary condition. A neurologic evaluation is needed to evaluate for conditions such as neuromuscular


InternalMed_Harrison

InternalMed_Harrison. cardiac dysfunction. Evidence of cor pulmonale suggests severe OSAHS or a comorbid cardiopulmonary condition. A neurologic evaluation is needed to evaluate for conditions such as neuromuscular and cerebrovascular diseases, which increase OSAHS risk.


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InternalMed_Harrison. predict the severity of sleep-related breathing disturbances, specific diagnosis and categorization of OSAHS severity require objective measurement of breathing during the period of sleep. The gold standard for diagnosis of OSAHS is an overnight polysomnogram (PSG). A negative in-laboratory PSG rules out OSAHS except in unusual circumstances—e.g., with insufficient REM sleep or supine sleep. Home sleep tests that record only a few respiratory and cardiac channels commonly are used as a cost-effective means a high pretest probability of OSAHS. However, a home study may yield a false-negative result if sleep time is not accurately estimated, and further evaluation may therefore be required.


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InternalMed_Harrison. The key physiological information collected during a sleep study for OSAHS assessment includes measurement of breathing (changes in airflow, respiratory excursion), oxygenation (hemoglobin oxygen saturation), body position, and cardiac rhythm. In addition, PSGs stages (by electroencephalography, chin electromyography, and electro-oculography), limb movements (by leg sensors), and snor ing intensity. This information is used to quantify the frequency and subtypes of abnormal respiratory events during sleep as well as associated changes in oxygen saturation, arousals, and sleep stage distributions. Tables 319-1 and 319-2 define the respiratory events scored and the severity guidelines employed during a sleep study. Figure 319-2 shows examples of sleep-related respiratory events. A typical sleep study report provides quantitative data such as the


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InternalMed_Harrison. Figure 319-2 shows examples of sleep-related respiratory events. A typical sleep study report provides quantitative data such as the AHI and the profile of oxygen saturation over the night (mean, nadir, time at low levels). Reports may also include the respira tory disturbance index, which includes the number of respiratory effort–related arousals in addition to the number of apneas plus hypopneas. In-laboratory PSG also quantifies sleep latency (time from “lights off ” to first sleep onset), sleep efficiency (percentage of • Apnea: Cessation of airflow for ≥10 sec during sleep, accompanied by: respiratory effort (obstructive apneas, Fig. 319-2A), or of respiratory effort (central apneas, Fig. 319-2B) • Hypopnea:


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InternalMed_Harrison. Cessation of airflow for ≥10 sec during sleep, accompanied by: respiratory effort (obstructive apneas, Fig. 319-2A), or of respiratory effort (central apneas, Fig. 319-2B) • Hypopnea: A ≥30% reduction in airflow for at least 10 sec during sleep that is accompanied by either a ≥3% desaturation or an arousal (Fig. 319-2C) effort–related arousal (RERA): A partially obstructed breath that does not meet the criteria for hypopnea but provides evidence of increasing inspiratory effort (usually through pleural pressure monitoring) punctuated by an arousal (Fig. 319-2D) breath: A partially obstructed breath, typically within a hypopnea or RERA, identified by a flattened or “scooped-out” inspiratory flow shape (Fig. 319-3) oBStruCtiVe SLeep apnea/hypopnea SynDroMe (oSahS): QuantifiCation anD SeVerity SCaLe • Apnea-hypopnea index (AHI):a Number of apneas plus hypopneas per hour • Respiratory disturbance index (RDI): Number of apneas plus hypopneas plus RERAs per hour of sleep


InternalMed_Harrison

InternalMed_Harrison. RERAs per hour of sleep OSAHS: AHI of 5–14 events/h OSAHS: AHI of 15–29 events/h OSAHS: AHI of ≥30 events/h aEach level of AHI can be further quantified by level of sleepiness and associated hypoxemia. time asleep relative to time in bed), arousal index (number of cortical arousals per hour of sleep), time in each sleep stage, and periodic limb movement index. OSAHS severity can be further characterized according to the degree of sleep fragmentation associated with respiratory disturbances. Relevant metrics include the frequency of cortical micro-arousals or awakenings per sleep hour, reduction in sleep continuity (low sleep efficiency), reduction of time in deeper stages of sleep (stage N3 and REM sleep) and increases in light sleep (stage N1). The detection of autonomic arousals, such as surges in blood pressure, changes in heart rate, and abnormalities in cardiac rhythm, also provides relevant information on OSAHS severity.


InternalMed_Harrison

InternalMed_Harrison. Other Laboratory Findings Various imaging studies, including cephalometric radiography, MRI, CT, and fiberoptic endoscopy, can be used to identify anatomic risk factors for OSAHS. Cardiac testing may yield evidence of impaired systolic or diastolic ventricular function or abnormal cardiac structure. Overnight blood pressure monitoring often displays a “non-dipping” pattern (absence of the typical 10-mmHg fall during sleep from blood pressure while awake). Arterial blood gas measurements made during wakefulness are usually normal. Waking hypoxemia or hypercarbia suggests coexisting lung disease or hypoventilation syndrome. Patients with severe nocturnal hypoxemia may have elevated hemoglobin values. A multiple sleep latency test or a maintenance of wakefulness test can be useful in quantifying sleepiness and helping to distinguish OSAHS from narcolepsy.


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InternalMed_Harrison. Health Consequences and Comorbidities OSAHS is a major contributor to cardiac, cerebrovascular, and metabolic disorders as well as to premature death. It is the most common medical cause of daytime sleepiness and negatively influences quality of life. This broad range of health effects is attributable to the impact of sleep fragmentation, cortical arousal, and intermittent hypoxemia on vascular, cardiac, metabolic, and neurologic functions. OSAHS-related respiratory events stimulate sympathetic overactivity, leading to acute blood pressure surges during sleep, endothelial damage, and nocturnal as well as daytime hypertension. OSAHS-related hypoxemia also stimulates release of acute-phase proteins and reactive oxygen species that exacerbate insulin resistance and lipolysis and cause an augmented prothrombotic and proinflammatory state. Inspiratory effort against an occluded airway causes large intrathoracic negative pressure swings, altering cardiac preload and afterload and resulting


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InternalMed_Harrison. prothrombotic and proinflammatory state. Inspiratory effort against an occluded airway causes large intrathoracic negative pressure swings, altering cardiac preload and afterload and resulting in cardiac remodeling and reduced cardiac function. Hypoxemia and sympathetic-parasympathetic imbalance also may cause electrical remodeling of the heart and myocyte injury.


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InternalMed_Harrison. HYPERTENSION OSAHS can raise blood pressure to prehypertensive and hypertensive ranges, increase the prevalence of a non-dipping overnight blood pressure pattern, and increase the risk of resistant hypertension. Elevations in blood pressure are due to augmented sympathetic nervous system activation as well as alterations in the rennin–angiotensin–aldosterone system and fluid balance. Treatment of OSAHS with nocturnal continuous positive airway pressure (CPAP) has been shown to reduce 24-h ambulatory blood pressure. Although the overall impact of CPAP on blood pressure levels is relatively modest (averaging 2–4 mmHg), larger improvements are observed among patients with high AHIs and sleepiness. t. flow snore flown. p. flow t. flowchest n. p. flow abdomen


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InternalMed_Harrison. t. flow snore flown. p. flow t. flowchest n. p. flow abdomen FIGURE 319-2 A. Obstructive apnea. There are 30 sec of no airflow, as shown in the nasal pressure (n. p. flow) and thermistor-measured flow (t. flow). Note the presence of chest-abdomen motion, indicating respiratory effort against an occluded airway. B. Central apnea in a patient with Cheyne-Stokes respiration due to congestive heart failure. The flat chest-abdomen tracings indicate the absence of inspiratory effort during the central apneas. C. Hypopnea. Partial obstruction of the pharyngeal airway can limit ventilation, leading to desaturation (a mild decrease in this patient, from 93% to 90%) and arousal. D. Respiratory effort–related arousal (RERA). Minimal flow reduction terminated by an arousal (Ar) without desaturation constitutes a RERA. EEG, electroencephalogram; EOG, electro-oculogram; EKG, electrocardiogram.


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InternalMed_Harrison. CARDIOVASCULAR, CEREBROVASCULAR, AND METABOLIC DISEASES Among the SLEEPINESS More than 50% of patients with moderate to severe most serious health consequences of OSAHS is its impact on cardiac OSAHS report daytime sleepiness. Patients with OSAHS symptoms and metabolic functions. Strong epidemiologic evidence indicates that have a twofold increased risk of occupational accidents. Individuals OSAHS significantly increases the risk of coronary artery disease, heart with elevated AHIs are involved in motor vehicle crashes as failure with and without reduced ejection fraction, atrial and ventricu-much as seven times more often than persons with normal AHIs.


InternalMed_Harrison

InternalMed_Harrison. lar arrhythmias, atherosclerosis and coronary artery disease, stroke, Randomized controlled trials have shown that treatment of OSAHS and diabetes. Treatment of OSAHS has been shown to reduce several with nasal CPAP therapy alleviates sleepiness as measured by either markers of cardiovascular risk, improve insulin resistance, decrease the questionnaire or objective testing. However, the degree of improve- recurrence rate of atrial fibrillation, and improve various outcomes in ment varies widely. Residual sleepiness may be due to several factors, patients with active cardiovascular disease. Large-scale trials are under including suboptimal treatment adherence, insufficient sleep time, way to evaluate the role of OSAHS treatment in reducing cardiac event other sleep disorders, or prior hypoxic-mediated damage in brain rates and in prolonging the survival of patients with cardiac disease. areas involved in alertness. Visceral adipose tissue, whose amounts are increased in patients with


InternalMed_Harrison

InternalMed_Harrison. damage in brain rates and in prolonging the survival of patients with cardiac disease. areas involved in alertness. Visceral adipose tissue, whose amounts are increased in patients with OSAHS, releases somnogenic cyto kines that may contribute to sleepiness. Thus, even after treatment, it is important to assess and monitor patients for residual sleepiness and to evaluate the necessity of optimizing treatment adherence, improving sleep patterns, and identifying other disorders contributing to sleepiness.


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InternalMed_Harrison. QUALITY OF LIFE AND MOOD Reductions in health-related quality of life are common in patients with OSAHS, with the largest decrements on FIGURE 319-3 Example of flow limitation. The inspiratory flow pat-the physical and vitality subscales. Treatment with CPAP often results tern in a patent airway is rounded and peaks in the middle. In con-in improvement in these patient-reported outcomes. Depression, in trast, a partially obstructed airway exhibits an early peak followed by particular symptoms of somatic depression (irritability, fatigue, lack of mid-inspiratory flattening, yielding a scooped-out appearance. energy) is commonly reported in OSAHS.


InternalMed_Harrison

InternalMed_Harrison. A comprehensive approach to the management of OSAHS is needed to reduce risk factors and comorbidities. The clinician should seek to identify and address lifestyle and behavioral factors as well as comorbidities that may be exacerbating OSAHS. As appropriate, treatment should aim to reduce weight; optimize sleep duration (7–9 hours); regulate sleep schedules (with similar bedtimes and wake times across the week); encourage the patient to avoid sleeping in the supine position; treat nasal allergies; increase physical activity; eliminate alcohol ingestion within 3 h of bedtime; and minimize use of sedating medications. Patients should be counseled to avoid drowsy driving.


InternalMed_Harrison

InternalMed_Harrison. CPAP is the standard medical therapy with the highest level of evidence for efficacy. Delivered through a nasal or nasal-oral mask, CPAP works as a mechanical splint to hold the airway open, thus maintaining airway patency during sleep. An overnight CPAP titration study, performed either in a laboratory or with a home “autotitrating” device, is required to determine the optimal pressure setting that reduces the number of apneas/hypopneas during sleep, improves gas exchange, and reduces arousals. Rates of adherence to CPAP treatment are highly variable (average, 50–80%) and may be improved with support by a skilled health care team who can address side effects (Table 319-3). Despite the limitations of CPAP, controlled studies have demonstrated its beneficial effect on blood pressure, alertness, mood, and insulin sensitivity. Uncontrolled studies also indicate a favorable effect on cardiovascular outcomes, cardiac ejection fraction, atrial fibrillation recurrence, and mortality risk.


InternalMed_Harrison

InternalMed_Harrison. Oral appliances for OSAHS work by advancing the mandible, thus opening the airway by repositioning the lower jaw and pulling the tongue forward. These devices generally work better when customized for patient use; maximal adaptation can take several weeks. Efficacy studies show that these devices can reduce the AHI by γ50% in two-thirds of individuals, although these data are based largely on patients with mild OSAHS. Side effects of oral appliances include temporomandibular joint pain and tooth movement. Oral appliances are most often used for treating patients with mild OSAHS or patients who do not tolerate CPAP. However, since adherence to the use of oral appliances sometimes exceeds CPAP adherence, these devices are under investigation for treatment of more severe disease.


InternalMed_Harrison

InternalMed_Harrison. Upper airway surgery for OSAHS is less effective than CPAP and is mostly reserved for the treatment of patients who snore, have mild OSAHS, and cannot tolerate CPAP. Uvulopalatopharyngoplasty (removal of the uvula and the margin of the soft palate) is the most common surgery and, although results vary greatly, has a success Nasal congestion Provide heated humidification, administer saline/ steroid nasal sprays Claustrophobia Change mask interface (e.g., to nasal prongs), promote habituation (i.e., practice breathing on CPAP while awake) Difficulty exhaling Temporarily reduce pressure, provide bilevel positive airway pressure


InternalMed_Harrison

InternalMed_Harrison. Difficulty exhaling Temporarily reduce pressure, provide bilevel positive airway pressure Bruised nasal ridge Change mask interface, provide protective padding rate similar to or slightly lower than treatment with oral appliances. 1Upper airway surgery is less effective in severe OSAHS and in obese patients. Success rates may be higher for multilevel surgery (involving more than one site/structure) performed by an experienced surgeon, but the selection of patients is an important factor and relies on careful targeting of culprit areas for surgical resection. Bariatric surgery is an option for obese patients with OSAHS and can improve not only OSAHS but also other obesity-associated health conditions. Other procedures that can decrease snoring but have minimal effects on OSAHS include injection of the soft palate (resulting in stiffening), radiofrequency ablation, laser-assisted uvulopalatoplasty, and palatal implants.


InternalMed_Harrison

InternalMed_Harrison. Supplemental oxygen can improve oxygen saturation, but there is little evidence that it improves OSAHS symptoms or the AHI.