InternalMed_Harrison

InternalMed_Harrison. Vasoconstriction, vascular proliferation, thrombosis, and inflammation appear to underlie the development of PAH (Fig. 304-1). In long-standing PH, intimal proliferation and fibrosis, medial hypertrophy, and in situ thrombosis characterize the pathologic findings in the pulmonary vasculature. Vascular remodeling at earlier stages may be confined to the small pulmonary arteries. As the disease advances, intimal proliferation and pathologic remodeling progress, resulting in decreased compliance and increased elastance of the pulmonary vas culature. The outcome is a progressive increase in the right ventricular afterload or total pulmonary vascular resistance (PVR) and, thus, right ventricular work. In subjects with moderate to severe pulmonary vascular disease with significantly increased PVR, as the resting PVR increases, there will be a corresponding increase in mean pulmonary artery pressure (PAP) until the cardiac output (CO) is compromised and starts to fall. With a decline in CO,


InternalMed_Harrison

InternalMed_Harrison. as the resting PVR increases, there will be a corresponding increase in mean pulmonary artery pressure (PAP) until the cardiac output (CO) is compromised and starts to fall. With a decline in CO, the PAP will fall. As CO declines as a result of increased afterload and decreased contractility, tachycardia is a compensatory response. Tachycardia decreases filling time and, thus, preload, and results in a reduced fraction of stroke volume available to distend the pulmonary vascular tree.


InternalMed_Harrison

InternalMed_Harrison. Abnormalities in multiple molecular pathways and genes that regulate the pulmonary vascular endothelial and smooth muscle cells have been identified (Table 304-1). These abnormalities include decreased expression of the voltage-regulated potassium channel, mutations in the bone morphogenetic protein receptor-2, increased tissue factor expression, overactivation of the serotonin transporter, hypoxia-induced activation of hypoxia-inducible factor-1α, and activation of nuclear factor of activated T cells. As a result, there is a decrease in apoptosis of the smooth muscle cells and the emergence of apoptosis-resistant endothelial cells that promote their accumulation and can obliterate the vascular lumen. In addition, thrombin deposition in the pulmonary vasculature from the prothrombotic state that develops as an independent abnormality or as a result of endothelial dysfunction may amplify vascular cell proliferation and the obliterative arteriopathy.


InternalMed_Harrison

InternalMed_Harrison. The diagnosis of PH can be missed without a reasonable index of suspicion. Dyspnea is the most common presenting symptom, but this complaint is far from specific for the diagnosis of PH. PH symptoms are insidious and overlap considerably with many common conditions, including asthma and other lung disease and cardiac disease. The symptoms of PH are often nonspecific and variable. Most patients will present with dyspnea and/or fatigue, whereas edema, chest pain, presyncope, and frank syncope are less common and associated with more advanced disease. On examination, there may be evidence of right ventricular failure with elevated jugular venous pressure, lower extremity edema, and ascites. Additionally, the cardiovascular examination may reveal an accentuated P2 component of the second heart sound, a right-sided S3 or S4, and a holosystolic tricuspid regurgitant murmur. It is also important to seek signs of the diseases that are often concurrent with PH: clubbing may be seen in some


InternalMed_Harrison

InternalMed_Harrison. sound, a right-sided S3 or S4, and a holosystolic tricuspid regurgitant murmur. It is also important to seek signs of the diseases that are often concurrent with PH: clubbing may be seen in some chronic lung diseases, sclerodactyly and telangiectasia may signify scleroderma, and crackles and systemic hypertension may be clues to left-sided systolic or diastolic heart failure.


InternalMed_Harrison

InternalMed_Harrison. Once clinical suspicion is raised, a systematic approach to diagnosis and assessment is essential. An echocardiogram with (if indicated) a bubble study is the most important screening test. Echocardiography is important for the diagnosis of PH and often essential for determining the cause. All forms of PH may demonstrate a hypertrophied and FIGURE 304-1 The left panels show examples of plexogenic pulmonary arteriopathy. These are obstructive and proliferative lesions of the small muscular pulmonary arteries, composed primarily of endothelial cells with intermixed inflammatory cells, myofibroblasts, and connective tissue components. The lower left panel demonstrates proliferating cells (red PCNA stained cells). Panels on the right demonstrate medial hypertrophy of muscular pulmonary arteries. (Photographs on the left are courtesy of Dr. Stephen Archer, Queen’s University School of Medicine, Kingston,


InternalMed_Harrison

InternalMed_Harrison. Ontario, Canada.) dilated right ventricle (Fig. 304-2) with elevated estimated pulmonary artery systolic pressure. Important additional information can be gleaned about specific etiologies of PH such as valvular disease, left ventricular systolic and diastolic function, intracardiac shunts, and other cardiac diseases.


InternalMed_Harrison

InternalMed_Harrison. Although the accuracy of Doppler echocardiography is often debated, a high-quality echocardiogram that is absolutely normal may obviate the need for further evaluation for PH. An echocardiogram is a screening test, whereas invasive hemodynamic monitoring is the gold standard for diagnosis and assessment of disease severity. With a normal echo-cardiogram, there may still be some concern for PH; this is particularly true if there is unexplained dyspnea or hypoxemia. In this setting, it is reasonable to proceed to right heart catheterization for definitive diagnosis. Alternatively, if the patient has a reasonable functional capacity, a cardiopulmonary exercise test may help to identify a true physiologic limitation as well as differentiate between cardiac and pulmonary causes of dyspnea. If this test is normal, there is no indication for a right heart catheterization. If a cardiovascular limitation to exercise is found, a right heart catheterization should be pursued.


InternalMed_Harrison

InternalMed_Harrison. If the echocardiogram or cardiopulmonary exercise test (CPET) suggests PH and the diagnosis is confirmed by catheterization, a reasonable effort must be made to establish the etiology because this will largely determine the therapeutic approach. A stepwise approach to evaluation is outlined below.


InternalMed_Harrison

InternalMed_Harrison. Chest imaging and lung function tests are essential because lung disease is an important cause of PH. A sign of PH that may be evident on chest x-ray include enlargement of the central pulmonary arteries associated with “vascular pruning,” a relative paucity of peripheral vessels (Fig. 304-3). Cardiomegaly, with specific evidence of right atrial and ventricular enlargement, can often be observed. The chest x-ray may also demonstrate significant interstitial lung disease or suggest hyperinflation from obstructive lung disease, which may be the underlying cause or contributor to the development of PH. High-resolution computed tomography (CT) may provide additional useful information. Classic findings of PH on CT include those found on chest x-ray: enlarged pulmonary arteries (Fig. 304-4), peripheral pruning of the small vessels, and enlarged right ventricle and atrium. However, high-resolution CT may also reveal signs of venous congestion including centrilobular ground-glass infiltrate


InternalMed_Harrison

InternalMed_Harrison. pruning of the small vessels, and enlarged right ventricle and atrium. However, high-resolution CT may also reveal signs of venous congestion including centrilobular ground-glass infiltrate and thickened septal lines. In the absence of left heart disease, these findings suggest pulmonary veno-occlusive disease, a rare cause of PAH that can be quite challenging to diagnose.


InternalMed_Harrison

InternalMed_Harrison. CT angiograms are commonly used to evaluate acute thromboembolic disease and have demonstrated excellent sensitivity and specificity for that purpose. Ventilation-perfusion (V/Q) scanning has traditionally been used for screening because of its high sensitivity and its role in qualifying patients for surgical intervention. The role of CT angiograms in the diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) remains controversial, even with the advent of spiral CT. Although a negative V/Q virtually rules out CTEPH, some cases may be missed through the use of CT angiograms. Pulmonary function tests are an important component of the evaluation. Although an isolated reduction in DLCO is the classic finding in PAH, results of pulmonary function tests may also suggest restrictive or obstructive lung diseases as the cause of dyspnea or PH. The 6-minute walk test Alterations in regulators of proliferation


InternalMed_Harrison

InternalMed_Harrison. Alterations in regulators of proliferation Abbreviations: PDGF, platelet-derived growth factor; EGF, epidermal-derived growth factor; FGF, fetal-derived growth factor; VEGF, vascular endothelial-derived growth factor; MCP-1, monocyte chemoattractant protein-1; IL, interleukin. FIGURE 304-2 A. Representative echocardiogram showing the apical four-chamber view from a patient with pulmonary hypertension demonstrating an enlarged right atrium and ventricle with some compression of the left side of the heart. B. Same echocardiographic view showing a normal echocardiogram. is also important to evaluate the degree of exertional hypoxemia and 1657 limitation and to monitor progression and response to therapy.


InternalMed_Harrison

InternalMed_Harrison. Sleep-disordered breathing is another important cause of PH, but a sleep study is generally necessary only when indicated by the patient’s history. Nocturnal desaturation is a common finding in PH, even in the absence of sleep-disordered breathing. Thus, all patients should undergo nocturnal oximetry screening, regardless of whether classic symptoms of obstructive sleep apnea or obesity-hypoventilation syndrome are observed. Laboratory tests that are important for screening include an HIV test when clinically indicated. In addition, all patients should have antinuclear antibodies, rheumatoid factor, and scl-70 antibodies assessed to screen for the most common rheumatologic diseases associated with PH if clinically indicated. Liver function and hepatitis serology tests are important to screen for underlying liver disease. Finally, there is an increasing role for brain natriuretic peptide (BNP) testing in the diagnosis and management of PH. BNP and the N-terminus of its propeptide


InternalMed_Harrison

InternalMed_Harrison. screen for underlying liver disease. Finally, there is an increasing role for brain natriuretic peptide (BNP) testing in the diagnosis and management of PH. BNP and the N-terminus of its propeptide (NT-proBNP) correlate with right ventricular function, hemodynamic severity, and functional status in PAH.


InternalMed_Harrison

InternalMed_Harrison. Right heart catheterization with pulmonary vasodilator testing remains the gold standard both to establish the diagnosis of PH and to enable selection of appropriate medical therapy. The definition of precapillary PH or PAH requires (1) an increased mean pulmonary artery pressure (mPAP ≥25 mmHg); (2) a pulmonary capillary wedge pressure (PCWP), left atrial pressure, or left ventricular end-diastolic pressure ≤15 mmHg; and (3) PVR >3 Wood units. Postcapillary PH is differentiated from precapillary PH by a PCWP of ≥15 mmHg; this is further differentiated into passive, based on a transpulmonary gradient <12 mmHg, or reactive, based on a transpulmonary gradient >12 mmHg and an increased PVR. In either case, the CO may be normal or reduced.


InternalMed_Harrison

InternalMed_Harrison. Vasodilators with a short duration of action, such as inhaled nitric oxide, inhaled epoprostenol, or intravenous adenosine, are preferred for vasodilator testing. A decrease in mPAP by ≥10 mmHg to an absolute level of ≤40 mmHg without a decrease in CO is defined as a positive pulmonary vasodilator response, and responders are considered for long-term treatment with calcium channel blockers (CCBs). Less than 12% of patients are deemed vasoreactive during testing, and even fewer exhibit long-term responsiveness to CCBs. Acute vasodilator-induced reductions in PVR and mPAP predict better long-term survival even among patients not treated with CCBs. The need for invasive hemodynamic measurements to diagnose PH accurately poses an additional problem when evaluating older patients. Physicians are often reluctant to refer older patients for invasive procedures. However, the diagnosis of PH is increasing in the older population, at least in part because of increased awareness of this disease


InternalMed_Harrison

InternalMed_Harrison. often reluctant to refer older patients for invasive procedures. However, the diagnosis of PH is increasing in the older population, at least in part because of increased awareness of this disease in the elderly and increased use of screening echocardiograms. Furthermore, the increased availability of oral and less complicated therapeutic options has encouraged the referral of older patients for evaluation and treatment.


InternalMed_Harrison

InternalMed_Harrison. FIGURE 304-3 Posteroanterior (left) and lateral (right) chest radiograph showing enlarged pulmonary arteries (black arrows) and pruning of the distal pulmonary vasculature (white arrow) commonly seen with advanced pulmonary arterial hypertension.


InternalMed_Harrison

InternalMed_Harrison. PAH is just one of a number of disease classifications that affect the pulmonary vascular bed. PH was previously classified as primary or secondary, but as understanding of the various contributing diseases has increased, classification systems have attempted to group these diseases by clinical features to aid in diagnosis. The World Health Organization (WHO) formulated a clinical classification of the various manifestations of PH, of which PAH is a subgroup, according to similarities in pathophysiologic mechanisms and clinical presentation. PH is a diverse mix of pathologies in which the only unifying theme is elevated PAP relative to left atrial pressure. The categorization of PH was designed by convenience for the purpose of facilitating novel treatments to be tested across different presentations and is not based on a molecular understanding of the pathology and is not a guide for management decisions.


InternalMed_Harrison

InternalMed_Harrison. FIGURE 304-4 Representative computed tomography scan of the chest demonstrating enlarged main pulmonary arteries. There is also a mosaic pattern evident in both lungs. The current classification system, last revised in 2013 during the Fifth World Symposium on Pulmonary Hypertension, recognizes five categories of PH, including PAH, PH due to left heart disease, PH due to chronic lung disease, PH associated with chronic thromboemboli, and a group of miscellaneous diseases that only rarely cause PH.


InternalMed_Harrison

InternalMed_Harrison. Pulmonary Arterial Hypertension WHO Group I PH, pulmonary arterial hypertension (PAH), is a relatively rare cause of PH. PAH includes a group of diseases that result in pulmonary arterial precapillary remodeling marked by intimal fibrosis, increased medial thickness, pulmonary arteriolar occlusion, and classic plexiform lesions. PAH is defined as a sustained elevation in resting mPAP ≥25�mmHg, PVR>240�dyne·s/cm5, and PCWP or left ventricle end-diastolic pressure of ≤15�mmHg based on a right heart catheterization. With a normal PCWP and an elevated mPAP, these diseases demonstrate an increased transpulmonary gradient (mPAP – PCWP); in addition, the PVR is elevated.


InternalMed_Harrison

InternalMed_Harrison. Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disease that leads to right heart failure and death. It is typically seen in young women. The National Institutes of Health registry, the first large registry of patients with PAH, reported that the average age at diagnosis was 36 years, with only 9% of patients with IPAH over the age of 60 at diagnosis. However, the more current clinical data suggest that the patient demographics are changing. The Pulmonary Hypertension Connection registry found that the average age of diagnosis for IPAH was 45 years, with 8.5% of patients older than 70 years at diagnosis. This finding is supported by data from the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL), the largest cohort of PAH to date, which reported that the average age at diagnosis of IPAH was 44.9±0.6 years.


InternalMed_Harrison

InternalMed_Harrison. Other forms of PAH that deserve specific consideration in patients are those associated with HIV, connective tissue disease, and portal hypertension. Although HIV is a rare cause of PAH, this form of PAH is indistinguishable from IPAH and is an important cause of mortality in the HIV-infected population. Importantly, there is no correlation between the stage of HIV infection and the development of PAH. Among connective tissue diseases, the prevalence of PAH has been established only for systemic sclerosis, especially in those with limited cutaneous scleroderma. Although the average age of scleroderma onset is 30 to 50 years old, patients who eventually develop sclerodermaassociated PAH tend to be older at the time of scleroderma diagnosis. Outcomes of scleroderma are closely linked to the development of PAH and are associated with a poor prognosis, although modern therapies have improved outcomes.


InternalMed_Harrison

InternalMed_Harrison. Portopulmonary hypertension occurs in 2–10% of patients with established portal hypertension. Its occurrence appears to be independent of the cause of liver disease and is observed in patients with nonhepatic causes of portal hypertension. A hyperdynamic circulatory state is common, as in most patients with advanced liver disease; however, the same pulmonary vascular remodeling observed in other forms of PAH is seen in the pulmonary vascular bed in portopulmonary hypertension. It is important to distinguish this process from hepatopulmonary syndrome, which can also manifest with dyspnea and hypoxemia but is pathophysiologically distinct from portopulmonary hypertension in that abnormal vasodilation of the pulmonary vasculature leads to intrapulmonary shunting.


InternalMed_Harrison

InternalMed_Harrison. Pulmonary Hypertension Associated with Left Heart Disease WHO Group II PH includes patients with left heart systolic failure, aortic and mitral valve disease, and heart failure with preserved ejection fraction (HFpEF). PH can develop as a result of all of these conditions. The hallmark of Group II PH (i.e., PH due to left heart disease) is elevated left atrial pressure with resulting pulmonary venous hypertension. In general, the transpulmonary gradient and PVR remain normal. Although this phenomenon is well described in both left-sided valvular disease and left-sided systolic heart failure, studies suggest that HFpEF may carry a higher overall risk of PH.


InternalMed_Harrison

InternalMed_Harrison. Whatever the cause of elevated left atrial pressure (i.e., systolic or diastolic heart failure or valvular disease), the increased pulmonary venous pressure indirectly leads to a rise in pulmonary arterial pressure. The presence of PH portends a poor prognosis in all forms of heart failure. In particular, chronic pulmonary venous hypertension may lead to a reactive pulmonary arterial vasculopathy, seen as an elevated transpulmonary gradient (>12 mmHg) and elevated PVR (>3 Wood units). Pathologically, this process is marked by pulmonary arteriolar remodeling with intimal fibrosis and medial hyperplasia akin to that seen in PAH.


InternalMed_Harrison

InternalMed_Harrison. Pulmonary Hypertension Associated with Lung Disease Intrinsic lung disease is the second most common cause of PH, although its actual prevalence is difficult to ascertain. PH has been observed in both chronic obstructive lung disease and interstitial lung disease. It can also be seen in diseases with mixed obstructive/restrictive physiology: bronchiectasis, cystic fibrosis, mixed obstructive restrictive disease marked by fibrosis in the lower lung zones, and emphysema predominantly in the upper lung zones. As in patients with left heart disease, PH associated with chronic lung disease is usually modest; however, some of these patients appear to have PH “out of proportion” to their parenchymal lung disease, suggesting intrinsic pulmonary arterial disease. These patients typically have more severe PH, with results of pulmonary function tests demonstrating a very low DLCO.


InternalMed_Harrison

InternalMed_Harrison. Although PH is described in most forms of interstitial lung disease, it has been most extensively studied in idiopathic pulmonary fibrosis; however, the individual studies have been small. Early echocardiographic data suggested that the prevalence of PH in interstitial lung diseases was high, but invasive hemodynamic monitoring suggests that the incidence is considerably lower than originally believed. The diagnosis of PH portends poor outcome in pulmonary fibrosis. Also included in Group III PH is sleep-disordered breathing. Sleep apnea has long been associated with PH. However, PH associated with sleep-disordered breathing is generally mild.


InternalMed_Harrison

InternalMed_Harrison. Also included in Group III PH is sleep-disordered breathing. Sleep apnea has long been associated with PH. However, PH associated with sleep-disordered breathing is generally mild. Pulmonary Hypertension Associated with Chronic Thromboembolic Disease The development of PH after chronic thromboembolic obstruction of the pulmonary arteries is well described, but its incidence is not known. The incidence of PH after a single pulmonary embolic event is thought to be quite low and likely increases following recurrent embolism. The risk factors for developing CTEPH are unclear. Many patients have no history of clinical venous thromboembolism. The pathogenesis of CTEPH is poorly understood. Obstruction of the proximal pulmonary vasculature is important and often the dominant factor; however, additional pulmonary vascular remodeling occurs. Approximately 10–15% of patients will develop a disease very similar clinically and pathologically to PAH after resection of the proximal thrombus.


InternalMed_Harrison

InternalMed_Harrison. OTHER DISORDERS AFFECTING THE PULMONARY VASCULATURE Sarcoidosis Patients with sarcoidosis can develop PH as a result of lung involvement. Consequently, patients with sarcoidosis who present with progressive dyspnea and PH require a thorough evaluation. Although the majority of sarcoidosis patients with PH generally do not respond to therapy for PAH, a subset of patients with sarcoidosis and severe PH do have a beneficial response to therapy. Sickle Cell Disease Cardiovascular system abnormalities are prominent in the clinical spectrum of sickle cell disease, including PH. The etiology is multifactorial, including hemolysis, hypoxemia, thromboembolism, chronic high CO, and chronic liver disease. The presence of PH in patients with sickle cell disease is rare.


InternalMed_Harrison

InternalMed_Harrison. Schistosomiasis Globally, schistosomiasis is one of the most com-1659 mon causes of PH. The development of PH occurs in the setting of hepatosplenic disease and portal hypertension. Studies suggest that inflammation from the infection triggers the pulmonary vascular changes that occur. The diagnosis is confirmed by finding the parasite ova in the urine or stool of patients with symptoms, which can be difficult. The efficacy of therapies directed toward PH in these patients is unknown.


InternalMed_Harrison

InternalMed_Harrison. PH was a consistently fatal condition with no effective medical treatment options before 1996; however, since that time, there has been an upsurge in the development of novel therapeutic agents for PAH. There are several approved agents for PAH, including prostacyclin and prostacyclin analogues, phosphodiesterase-5 inhibitors, a soluble guanylyl cyclase stimulator, and endothelin receptor antagonists, that have improved the outlook dramatically. Although there is no cure for PAH, current pharmacologic therapies improve morbidity and, in some cases, mortality.


InternalMed_Harrison

InternalMed_Harrison. In PAH, endothelial dysfunction and platelet activation cause an imbalance of arachidonic acid metabolites with reduced prostacyclin levels and increased thromboxane A2 production. Prostacyclin (PGI2) activates cyclic adenosine monophosphate (cAMP)-dependent pathways that mediate vasodilation. PGI2 also has antiproliferative effects on vascular smooth muscle and inhibits platelet aggregation. Protein levels of prostacyclin synthase are decreased in pulmonary arteries of patients with PAH. This imbalance of mediators is addressed by the exogenous administration of prostanoids as therapy in advanced PAH.


InternalMed_Harrison

InternalMed_Harrison. Epoprostenol was the first prostanoid available for the management of PAH. Epoprostenol delivered as a continuous intravenous infusion improves functional capacity and survival in PAH. The efficacy of epoprostenol in WHO functional class 3 and 4 PAH patients was demonstrated in a clinical trial that showed improved quality of life, mPAP, PVR, 6-minute walk distance (6MWD), and mortality. Treprostinil has a longer half-life than epoprostenol (~4 h vs ~6 min), which allows for continuous subcutaneous and intravenous administration. Treprostinil has been shown to improve pulmonary hemodynamics, symptoms, exercise capacity, and survival in PAH.


InternalMed_Harrison

InternalMed_Harrison. Inhaled prostacyclins provide the beneficial effects of infused prostacyclin therapy without the inconvenience and side effects (risk of infection and infusion site reactions) of infusion catheters. Both inhaled iloprost and treprostinil have been approved for patients with WHO class 3 and 4 PAH. The main advantage of treprostinil is less frequent administration. Inhaled formulations can be efficacious in moderately symptomatic patients with PAH and may be appropriate when used in combination with an oral medication. Phosphodiesterase-5 (PDE5) inhibitors (e.g., sildenafil) increase cyclic guanosine mono-phosphate (cGMP) levels and activate cGMP-dependent signaling pathways that also mediate vasodilation and platelet inhibition. Thus, the addition of a PDE5 inhibitor augments the pulmonary hemodynamic and functional capacity benefits of prostanoids in PAH.


InternalMed_Harrison

InternalMed_Harrison. Endothelin Receptor Antagonists Endothelin receptor antagonists (ERAs) target endothelin-1 (ET-1), a potent endogenous vasoconstrictor and vascular smooth muscle mitogen that is elevated in PAH patients. Endothelin levels are increased coincident with increased PVR and mPAP and decreased CO and 6MWD. ERAs block the binding of ET-1 to either endothelin receptor A (ET-A) and/or B (ET-B). ET-A receptors found on pulmonary artery smooth muscle cells mediate vasoconstriction. In the normal pulmonary vasculature, ET-B receptors are found on endothelial cells and mediate vasodilation via production of prostacyclin and nitric oxide as well as ET-1 clearance. Three ERAs approved for use in the United States are bosentan and macitentan both, nonselective receptor antagonists, and ambrisentan, a selective ET-A receptor antagonist. Studies have shown that both bosentan and macitentan improve hemodynamics and exercise capacity and delay clinical worsening.


InternalMed_Harrison

InternalMed_Harrison. Studies have shown that both bosentan and macitentan improve hemodynamics and exercise capacity and delay clinical worsening. Route of Generic Name Administration Drug Class Indication stimulator Abbreviations: FDA, U.S. Food and Drug Administration; NYHA, New York Heart Association; PAH, pulmonary arterial hypertension; PDES, phosphodiesterase-5. The randomized, placebo-controlled, phase III Bosentan Randomized Trial of Endothelin Antagonist Therapy (BREATHE)-1 comparing bosentan with placebo demonstrated�improved symptoms, 6MWD, and WHO functional class. The Endothelin Antagonist Trial in Mildly Symptomatic Pulmonary Arterial Hypertension Patients (EARLY) comparing bosentan with placebo demonstrated improved PVR and 6MWD.


InternalMed_Harrison

InternalMed_Harrison. Several studies, including the phase III, placebo-controlled Ambrisentan in Pulmonary Arterial Hypertension-1 (ARIES-1) trial, suggest that ambrisentan improves exercise tolerance, WHO functional class, hemodynamics, and quality of life in patients with PAH. There are no trial data to evaluate whether the selective ET-A receptor antagonism of ambrisentan has any advantage over the nonselective ET receptor antagonism of bosentan.


InternalMed_Harrison

InternalMed_Harrison. Phosphodiesterase Type-5 Inhibitors Nitric oxide derived from endothelial cells activates guanylyl cyclase, which, in turn, generates cGMP in vascular smooth muscle cells and platelets. cGMP is a second messenger that induces vasodilation through relaxation of the arterial smooth muscle cells and inhibits platelet activation. PDE5 enzymes metabolize cGMP. Therefore, cGMP PDE5 inhibitors prolong the vasodilatory effect of nitric oxide, especially within the pulmonary arterial bed where high concentrations of cGMP are found. There are currently two PDE5 inhibitors used for the treatment of PAH, sildenafil and tadalafil. Both agents have been shown to improve hemodynamics and 6MWD. Recently, the oral soluble guanylyl cyclase stimulator, riociguat, was approved for the treatment of both PAH and CTEPH.


InternalMed_Harrison

InternalMed_Harrison. Unmet and Future Research Needs in Pulmonary Hypertension Presently there are only three classes of therapy for patients with PAH, and even with therapy, the median survival for a person with PAH is only 5–6 years (Table 304-2). Although there are five subtypes of PH, current approved therapies only address one subtype. Not only do we need to expand the treatment options for patients with PAH, we also need to develop effective therapies for all patients with PH. Limited survival is, in part, a result of delay in diagnosis. Improved awareness among clinicians and patients could lead to more timely diagnosis that will affect the response to therapy and survival. PH needs to be diagnosed in a timely manner so that therapy can be initiated as soon as possible. Patients should also have the option of referral to a specialty center that focuses on treatment of patients with pulmonary vascular disease, which will ensure their access to state-of-the-art care and a multidisciplinary approach


InternalMed_Harrison

InternalMed_Harrison. of referral to a specialty center that focuses on treatment of patients with pulmonary vascular disease, which will ensure their access to state-of-the-art care and a multidisciplinary approach to care. Finally, there need to be continued efforts at developing new therapies that target the increasingly complex and overlapping pathways involved in the various forms of PH.


InternalMed_Harrison

InternalMed_Harrison. approach to the patient with 305 Disease of the respiratory System Patricia A. Kritek, Augustine M. K. Choi


InternalMed_Harrison

InternalMed_Harrison. Patricia A. Kritek, Augustine M. K. Choi The majority of diseases of the respiratory system fall into one of three major categories: (1) obstructive lung diseases; (2) restrictive disorders; and (3) abnormalities of the vasculature. Obstructive lung diseases are most common and primarily include disorders of the airways, such as asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, and bronchiolitis. Diseases resulting in restrictive pathophysiology include parenchymal lung diseases, abnormalities of the chest wall and pleura, and neuromuscular disease. Disorders of the pulmonary vasculature include pulmonary embolism, pulmonary hypertension, and pulmonary veno-occlusive disease. Although many specific diseases fall into these major categories, both infective and neoplastic processes can affect the respiratory system and result in myriad pathologic findings, including those listed in the three categories above (Table 305-1).


InternalMed_Harrison

InternalMed_Harrison. Disorders can also be grouped according to gas exchange abnormalities, including hypoxemic, hypercarbic, or combined impairment. However, many diseases of the lung do not manifest as gas exchange abnormalities. As with the evaluation of most patients, the approach to a patient with disease of the respiratory system begins with a thorough history and a focused physical examination. Many patients will subsequently undergo pulmonary function testing, chest imaging, blood and sputum analysis, a variety of serologic or microbiologic studies, and diagnostic procedures, such as bronchoscopy. This stepwise approach is discussed in detail below.


InternalMed_Harrison

InternalMed_Harrison. HISTORY Dyspnea and Cough The cardinal symptoms of respiratory disease are dyspnea and cough (Chaps. 47e and 48). Dyspnea has many causes, some of which are not predominantly due to lung pathology. The words a patient uses to describe shortness of breath can suggest certain etiologies for dyspnea. Patients with obstructive lung disease often complain of “chest tightness” or “inability to get a deep breath,” whereas patients with congestive heart failure more commonly report “air hunger” or a sense of suffocation.


InternalMed_Harrison

InternalMed_Harrison. The tempo of onset and the duration of a patient’s dyspnea are likewise helpful in determining the etiology. Acute shortness of breath is usually associated with sudden physiologic changes, such as laryngeal edema, bronchospasm, myocardial infarction, pulmonary embolism, or pneumothorax. Patients with COPD and idiopathic pulmonary fibrosis (IPF) experience a gradual progression of dyspnea on exertion, punctuated by acute exacerbations of shortness of breath. In contrast, most asthmatics have normal breathing the majority of the time with recurrent episodes of dyspnea that are usually associated with specific triggers, such as an upper respiratory tract infection or exposure to allergens.


InternalMed_Harrison

InternalMed_Harrison. Specific questioning should focus on factors that incite dyspnea as well as on any intervention that helps resolve the patient’s shortness of breath. Asthma is commonly exacerbated by specific triggers, although this can also be true of COPD. Many patients with lung disease report dyspnea on exertion. Determining the degree of activity that results in shortness of breath gives the clinician a gauge of the patient’s degree of disability. Many patients adapt their level of activity to accommodate progressive limitation. For this reason, it is important, particularly in older patients, to delineate the activities in which they engage and how these activities have changed over time. Dyspnea on exertion is often an early symptom of underlying lung or heart disease and warrants a thorough evaluation.


InternalMed_Harrison

InternalMed_Harrison. Cough generally indicates disease of the respiratory system. The clinician should inquire about the duration of the cough, whether or not it is associated with sputum production, and any specific triggers that induce it. Acute cough productive of phlegm is often a symptom of infection of the respiratory system, including processes affecting the upper airway (e.g., sinusitis, tracheitis), the lower airways (e.g., bronchitis, bronchiectasis), and the lung parenchyma (e.g., pneumonia). Both the quantity and quality of the sputum, including whether it is blood-streaked or frankly bloody, should be determined. Hemoptysis warrants an evaluation as delineated in Chap. 48.


InternalMed_Harrison

InternalMed_Harrison. Chronic cough (defined as that persisting for >8 weeks) is commonly associated with obstructive lung diseases, particularly asthma and chronic bronchitis, as well as “nonrespiratory” diseases, such as gastroesophageal reflux and postnasal drip. Diffuse parenchymal lung diseases, including IPF, frequently present as a persistent, nonproductive cough. As with dyspnea, all causes of cough are not respiratory in origin, and assessment should encompass a broad differential, including cardiac and gastrointestinal diseases as well as psychogenic causes.


InternalMed_Harrison

InternalMed_Harrison. Additional Symptoms Patients with respiratory disease may report wheezing, which is suggestive of airways disease, particularly asthma. Hemoptysis can be a symptom of a variety of lung diseases, including infections of the respiratory tract, bronchogenic carcinoma, and pulmonary embolism. In addition, chest pain or discomfort is often thought to be respiratory in origin. As the lung parenchyma is not innervated with pain fibers, pain in the chest from respiratory disorders usually results from either diseases of the parietal pleura (e.g., pneumothorax) or pulmonary vascular diseases (e.g., pulmonary hypertension). As many diseases of the lung can result in strain on Approach to the Patient with Disease of the Respiratory System 1662 the right side of the heart, patients may also present with symptoms of cor pulmonale, including abdominal bloating or distention and pedal edema (Chap. 279).


InternalMed_Harrison

InternalMed_Harrison. Additional History A thorough social history is an essential component of the evaluation of patients with respiratory disease. All patients should be asked about current or previous cigarette smoking, as this exposure is associated with many diseases of the respiratory system, most notably COPD and bronchogenic lung cancer but also a variety of diffuse parenchymal lung diseases (e.g., desquamative interstitial pneumonitis and pulmonary Langerhans cell histiocytosis). For most disorders, longer duration and greater intensity of exposure to cigarette smoke increases the risk of disease. There is growing evidence that “second-hand smoke” is also a risk factor for respiratory tract pathology; for this reason, patients should be asked about parents, spouses, or housemates who smoke. Possible inhalational exposures should be explored, including those at the work place (e.g., asbestos, wood smoke) and those associated with leisure (e.g., excrement from pet birds) (Chap. 311). Travel


InternalMed_Harrison

InternalMed_Harrison. inhalational exposures should be explored, including those at the work place (e.g., asbestos, wood smoke) and those associated with leisure (e.g., excrement from pet birds) (Chap. 311). Travel predisposes to certain infections of the respiratory tract, most notably the risk of tuberculosis. Potential exposure to fungi found in specific geographic regions or climates (e.g., Histoplasma capsulatum) should be explored.


InternalMed_Harrison

InternalMed_Harrison. Associated symptoms of fever and chills should raise the suspicion of infective etiologies, both pulmonary and systemic. A comprehensive review of systems may suggest rheumatologic or autoimmune disease presenting with respiratory tract manifestations. Questions should focus on joint pain or swelling, rashes, dry eyes, dry mouth, or constitutional symptoms. In addition, carcinomas from a variety of primary sources commonly metastasize to the lung and cause respiratory symptoms. Finally, therapy for other conditions, including both irradiation and medications, can result in diseases of the chest.


InternalMed_Harrison

InternalMed_Harrison. Physical Examination The clinician’s suspicion of respiratory disease often begins with a patient’s vital signs. The respiratory rate is often informative, whether elevated (tachypnea) or depressed (hypopnea). In addition, pulse oximetry should be measured, as many patients with respiratory disease have hypoxemia, either at rest or with exertion. The classic structure of the respiratory examination proceeds through inspection, percussion, palpation, and auscultation as described below. Often, however, auscultatory findings will lead the clinician to perform further percussion or palpation in order to clarify these findings.


InternalMed_Harrison

InternalMed_Harrison. The first step of the physical examination is inspection. Patients with respiratory disease may be in distress, often using accessory muscles of respiration to breathe. Severe kyphoscoliosis can result in restrictive pathophysiology. Inability to complete a sentence in conversation is generally a sign of severe impairment and should result in an expedited evaluation of the patient. Percussion of the chest is used to establish diaphragm excursion and lung size. In the setting of decreased breath sounds, percussion is used to distinguish between pleural effusions (dull to percussion) and pneumothorax (hyper-resonant note). The role of palpation is limited in the respiratory examination. Palpation can demonstrate subcutaneous air in the setting of barotrauma. It can also be used as an adjunctive assessment to determine whether an area of decreased breath sounds is due to consolidation (increased tactile fremitus) or a pleural effusion (decreased tactile fremitus).


InternalMed_Harrison

InternalMed_Harrison. The majority of the manifestations of respiratory disease present as abnormalities of auscultation. Wheezes are a manifestation of airway obstruction. While most commonly a sign of asthma, peribronchial edema in the setting of congestive heart failure can also result in diffuse wheezes, as can any other process that causes narrowing of small airways. For this reason, clinicians must take care not to attribute all wheezing to asthma. Rhonchi are a manifestation of obstruction of medium-sized airways, most often with secretions. In the acute setting, this manifestation may be a sign of viral or bacterial bronchitis. Chronic rhonchi suggest bronchiectasis or COPD. Stridor, a high-pitched, focal inspiratory wheeze, usually heard over the neck, is a manifestation of upper airway obstruction and should prompt expedited evaluation of the patient, as it can precede complete upper airway obstruction and respiratory failure.


InternalMed_Harrison

InternalMed_Harrison. Crackles, or rales, are commonly a sign of alveolar disease. A variety of processes that fill the alveoli with fluid may result in crackles. Pneumonia can cause focal crackles. Pulmonary edema is associated with crackles, generally more prominent at the bases. Interestingly, diseases that result in fibrosis of the interstitium (e.g., IPF) also result in crackles often sounding like Velcro being ripped apart. Although some clinicians make a distinction between “wet” and “dry” crackles, this distinction has not been shown to be a reliable way to differentiate among etiologies of respiratory disease.


InternalMed_Harrison

InternalMed_Harrison. One way to help distinguish between crackles associated with alveolar fluid and those associated with interstitial fibrosis is to assess for egophony. Egophony is the auscultation of the sound “AH” instead of “EEE” when a patient phonates “EEE.” This change in note is due to abnormal sound transmission through consolidated parenchyma and is present in pneumonia but not in IPF. Similarly, areas of alveolar filling have increased whispered pectoriloquy as well as transmission of larger-airway sounds (i.e., bronchial breath sounds in a lung zone where vesicular breath sounds are expected). The lack or diminution of breath sounds can also help determine the etiology of respiratory disease. Patients with emphysema often have a quiet chest with diffusely decreased breath sounds. A pneumothorax or pleural effusion may present with an area of absent breath sounds.


InternalMed_Harrison

InternalMed_Harrison. Other Systems Pedal edema, if symmetric, may suggest cor pulmonale; if asymmetric, it may be due to deep venous thrombosis and associated pulmonary embolism. Jugular venous distention may also be a sign of volume overload associated with right heart failure. Pulsus paradoxus is an ominous sign in a patient with obstructive lung disease, as it is associated with significant negative intrathoracic (pleural) pressures required for ventilation and impending respiratory failure. As stated earlier, rheumatologic disease may manifest primarily as lung disease. Owing to this association, particular attention should be paid to joint and skin examination. Clubbing can be found in many lung diseases, including cystic fibrosis, IPF, and lung cancer. Cyanosis is seen in hypoxemic respiratory disorders that result in >5 g of deoxygenated hemoglobin/dL.


InternalMed_Harrison

InternalMed_Harrison. The sequence of studies is dictated by the clinician’s differential diagnosis, as determined by the history and physical examination. Acute respiratory symptoms are often evaluated with multiple tests performed at the same time in order to diagnose any life-threatening diseases rapidly (e.g., pulmonary embolism or multilobar pneumonia). In contrast, chronic dyspnea and cough can be evaluated in a more protracted, stepwise fashion.


InternalMed_Harrison

InternalMed_Harrison. Pulmonary Function Testing (See also Chap. 307) The initial pulmonary function test obtained is spirometry. This study is an effort-dependent test used to assess for obstructive pathophysiology as seen in asthma, COPD, and bronchiectasis. A diminished-forced expiratory volume in 1 sec (FEV1)/forced vital capacity (FVC) (often defined as <70% of the predicted value) is diagnostic of obstruction. In addition to measuring FEV1 and FVC, the clinician should examine the flow-volume loop (which is effort-independent). A plateau of the inspiratory and expiratory curves suggests large-airway obstruction in extrathoracic and intrathoracic locations, respectively.


InternalMed_Harrison

InternalMed_Harrison. Spirometry with symmetric decreases in FEV1 and FVC warrants further testing, including measurement of lung volumes and the diffusion capacity of the lung for carbon monoxide (DLCO). A total lung capacity <80% of the predicted value for a patient’s age, race, sex, and height defines restrictive pathophysiology. Restriction can result from parenchymal disease, neuromuscular weakness, or chest wall or pleural diseases. Restriction with impaired gas exchange, as indicated by a decreased DLCO, suggests parenchymal lung disease. Additional testing, such as measurements of maximal expiratory pressure and maximal inspiratory pressure, can help diagnose neuromuscular weakness. Normal spirometry, normal lung volumes, and a low DLCO should prompt further evaluation for pulmonary vascular disease.


InternalMed_Harrison

InternalMed_Harrison. Arterial blood gas testing is often helpful in assessing respiratory 1663 disease. Hypoxemia, while usually apparent with pulse oximetry, can be further evaluated with the measurement of arterial PO2 and the calculation of an alveolar gas and arterial blood oxygen tension difference ([A–a]DO2). Patients with diseases that cause ventilation-perfusion mismatch or shunt physiology have an increased (A–a) DO2 at rest. Arterial blood gas testing also allows the measurement of arterial PCO2. Hypercarbia can accompany severe airway obstruction (e.g., COPD) or progressive restrictive physiology, as in patients with neuromuscular weakness.


InternalMed_Harrison

InternalMed_Harrison. Chest Imaging (See Chap. 308e) Most patients with disease of the respiratory system undergo imaging of the chest as part of the initial evaluation. Clinicians should generally begin with a plain chest radio-graph, preferably posterior-anterior and lateral films. Several findings, including opacities of the parenchyma, blunting of the costophrenic angles, mass lesions, and volume loss, can be very helpful in determining an etiology. However, many diseases of the respiratory system, particularly those of the airways and pulmonary vasculature, are asso ciated with a normal chest radiograph. CT of the chest is often performed subsequently and allows better delineation of parenchymal processes, pleural disease, masses or nodules, and large airways. If the test includes administration of contrast, the pulmonary vasculature can be assessed with particular utility for determination of pulmonary emboli. Intravenous contrast also allows lymph nodes to be delineated in greater detail.


InternalMed_Harrison

InternalMed_Harrison. Depending on the clinician’s suspicion, a variety of other studies may be done. Concern about large-airway lesions may warrant bronchoscopy. This procedure may also be used to sample the alveolar space with bronchoalveolar lavage or to obtain nonsurgical lung biopsies. Blood testing may include assessment for hypercoagulable states in the setting of pulmonary vascular disease, serologic testing for infectious or rheumatologic disease, or assessment of inflammatory markers or leukocyte counts (e.g., eosinophils). Sputum evaluation for malignant cells or microorganisms may be appropriate. An echocardiogram to assess rightand left-sided heart function is often obtained. Finally, at times, a surgical lung biopsy is needed to diagnose certain diseases of the respiratory system. All of these studies will be guided by the preceding history, physical examination, pulmonary function testing, and chest imaging. Approach to the Patient with Disease of the Respiratory System


InternalMed_Harrison

InternalMed_Harrison. Disturbances of Respiratory Function Edward T. Naureckas, Julian Solway The primary functions of the respiratory system—to oxygenate blood and eliminate carbon dioxide—require virtual contact between blood 306e and fresh air, which facilitates diffusion of respiratory gases between blood and gas. This process occurs in the lung alveoli, where blood flowing through alveolar wall capillaries is separated from alveolar gas by an extremely thin membrane of flattened endothelial and epithelial cells, across which respiratory gases diffuse and equilibrate. Blood flow through the lung is unidirectional via a continuous vascular path, along which venous blood absorbs oxygen from and loses CO2 to inspired gas. The path for airflow, in contrast, reaches a dead end at the alveolar walls; thus the alveolar space must be ventilated tidally, with inflow of fresh gas and outflow of alveolar gas alternating periodically at the respiratory rate (RR). To provide an enormous alveolar surface area


InternalMed_Harrison

InternalMed_Harrison. the alveolar space must be ventilated tidally, with inflow of fresh gas and outflow of alveolar gas alternating periodically at the respiratory rate (RR). To provide an enormous alveolar surface area (typically 70 m2) for blood-gas diffusion within the modest volume of a thoracic cavity (typically 7 L), nature has distributed both blood flow and ventilation among millions of tiny alveoli through multigenerational branching of both pulmonary arteries and bronchial airways. As a consequence of variations in tube lengths and calibers along these pathways as well as the effects of gravity, tidal pressure fluctuations, and anatomic constraints from the chest wall, the alveoli vary in their relative ventilations and perfusions. Not surprisingly, for the lung to be most efficient in exchanging gas, the fresh gas ventilation of a given alveolus must be matched to its perfusion.


InternalMed_Harrison

InternalMed_Harrison. For the respiratory system to succeed in oxygenating blood and eliminating CO2, it must be able to ventilate the lung tidally and thus to freshen alveolar gas; it must provide for perfusion of the individual alveolus in a manner proportional to its ventilation; and it must allow adequate diffusion of respiratory gases between alveolar gas and capillary blood. Furthermore, it must accommodate severalfold increases in the demand for oxygen uptake or CO2 elimination imposed by metabolic needs or acid-base derangement. Given these multiple requirements for normal operation, it is not surprising that many diseases disturb respiratory function. This chapter considers in some detail the physiologic determinants of lung ventilation and perfusion, elucidates how the matching distributions of these processes and rapid gas diffusion allow normal gas exchange, and discusses how common diseases derange these normal functions, thereby impairing gas exchange—or at least increasing the work required


InternalMed_Harrison

InternalMed_Harrison. processes and rapid gas diffusion allow normal gas exchange, and discusses how common diseases derange these normal functions, thereby impairing gas exchange—or at least increasing the work required by the respiratory muscles or heart to maintain adequate respiratory function.


InternalMed_Harrison

InternalMed_Harrison. It is useful to think about the respiratory system as three independently functioning components: the lung, including its airways; the neuromuscular system; and the chest wall, which includes everything that is not lung or active neuromuscular system. Accordingly, the mass of the respiratory muscles is part of the chest wall, while the force these muscles generate is part of the neuromuscular system; the abdomen (especially an obese abdomen) and the heart (especially an enlarged heart) are, for these purposes, part of the chest wall. Each of these three components has mechanical properties that FIguRE 306e-1 Pressure-volume curves of the isolated lung, isolated chest wall, combined respiratory system, inspiratory muscles, and expiratory muscles. FRC, functional residual capacity; RV, residual volume; TLC, total lung capacity.


InternalMed_Harrison

InternalMed_Harrison. relate to its enclosed volume (or—in the case of the neuromuscular 306e-1 system—the respiratory system volume at which it is operating) and to the rate of change of its volume (i.e., flow).


InternalMed_Harrison

InternalMed_Harrison. Volume-Related Mechanical Properties—Statics Figure 306e-1 shows the volume-related properties of each component of the respiratory system. Due both to surface tension at the air-liquid interface between alveolar wall lining fluid and alveolar gas and to elastic recoil of the lung tissue itself, the lung requires a positive transmural pressure difference between alveolar gas and its pleural surface to stay inflated; this difference is called the elastic recoil pressure of the lung, and it increases with lung volume. The lung becomes rather stiff at high volumes, so that relatively small volume changes are accompanied by large changes in transpulmonary pressure; in contrast, the lung is compliant at lower volumes, including those at which tidal breathing normally occurs. At zero inflation pressure, even normal lungs retain some air in the alveoli because the small peripheral airways are tethered open by radially outward pull from inflated lung parenchyma attached to adventitia; as the


InternalMed_Harrison

InternalMed_Harrison. pressure, even normal lungs retain some air in the alveoli because the small peripheral airways are tethered open by radially outward pull from inflated lung parenchyma attached to adventitia; as the lung deflates during exhalation, those small airways are pulled open progressively less, and eventually they close, trapping some gas in the alveoli. This effect can be exaggerated with age and especially with obstructive airway diseases, resulting in gas trapping at quite large lung volumes.


InternalMed_Harrison

InternalMed_Harrison. The elastic behavior of the passive chest wall (i.e., in the absence of neuromuscular activation) differs markedly from that of the lung. Whereas the lung tends toward full deflation with no distending (transmural) pressure, the chest wall encloses a large volume when pleural pressure equals body surface (atmospheric) pressure. Furthermore, the chest wall is compliant at high enclosed volumes, readily expanding even further in response to increases in transmural pressure. The chest wall also remains compliant at small negative transmural pressures (i.e., when pleural pressure falls slightly below atmospheric pressure), but as the volume enclosed by the chest wall becomes quite small in response to large negative transmural pressures, the passive chest wall becomes stiff due to squeezing together of ribs and intercostal muscles, diaphragm stretch, displacement of abdominal contents, and straining of ligaments and bony articulations. Under normal circumstances, the lung and the passive


InternalMed_Harrison

InternalMed_Harrison. of ribs and intercostal muscles, diaphragm stretch, displacement of abdominal contents, and straining of ligaments and bony articulations. Under normal circumstances, the lung and the passive chest wall enclose essentially the same volume, the only difference being the volumes of the pleural fluid and of the lung parenchyma (both quite small). For this reason and because the lung and chest wall function in mechanical series, the pressure required to displace the passive respiratory system (lungs plus chest wall) at any volume is simply the sum of the elastic recoil pressure of the lungs and the transmural pressure across the chest wall. When plotted against respiratory system volume, this relationship assumes a sigmoid shape, exhibiting stiffness at high lung volumes (imparted by the lung), stiffness at low lung volumes (imparted by the chest wall or sometimes by airway closure), and compliance in the middle range of lung volumes.


InternalMed_Harrison

InternalMed_Harrison. CHAPTER 306e Disturbances of Respiratory Function FIguRE 306e-2 Spirogram demonstrating a slow vital capacity maneuver and various lung volumes. In addition, a passive resting point of the respiratory system is attained when alveolar gas pressure equals body surface pressure (i.e., when the transrespiratory system pressure is zero). At this volume (called the functional residual capacity [FRC]), the outward recoil of the chest wall is balanced exactly by the inward recoil of the lung. As these recoils are transmitted through the pleural fluid, the lung is pulled both outward and inward simultaneously at FRC, and thus its pressure falls below atmospheric pressure (typically, −5 cmH2O).


InternalMed_Harrison

InternalMed_Harrison. The normal passive respiratory system would equilibrate at the FRC and remain there were it not for the actions of respiratory muscles. The inspiratory muscles act on the chest wall to generate the equivalent of positive pressure across the lungs and passive chest wall, while the expiratory muscles generate the equivalent of negative transrespiratory pressure. The maximal pressures these sets of muscles can generate vary with the lung volume at which they operate. This variation is due to length-tension relationships in striated muscle sarcomeres and to changes in mechanical advantage as the angles of insertion change with lung volume (Fig. 306e-1). Nonetheless, under normal conditions, the respiratory muscles are substantially “overpowered” for their roles and generate more than adequate force to drive the respiratory system to its stiffness extremes, as determined by the lung (total lung capacity [TLC]) or by chest wall or airway closure (residual volume [RV]); the airway closure


InternalMed_Harrison

InternalMed_Harrison. force to drive the respiratory system to its stiffness extremes, as determined by the lung (total lung capacity [TLC]) or by chest wall or airway closure (residual volume [RV]); the airway closure always prevents the adult lung from emptying completely under normal circumstances. The excursion between full and minimal lung inflation is called vital capacity (VC; Fig. 306e-2) and is readily seen to be the difference between volumes at two unrelated stiffness extremes—one determined by the lung (TLC) and the other by the chest wall or airways (RV). Thus, although VC is easy to measure (see below), it provides little information about the intrinsic properties of the respiratory system. As will become clear, it is much more useful for the clinician to consider TLC and RV individually.


InternalMed_Harrison

InternalMed_Harrison. Flow-Related Mechanical Properties—Dynamics The passive chest wall and active neuromuscular system do exhibit mechanical behaviors related to the rate of change of volume, but these behaviors become quantitatively important only at markedly supraphysiologic breathing frequencies (e.g., during high-frequency mechanical ventilation) and thus will not be addressed here. In contrast, the dynamic airflow properties of the lung substantially affect its ability to ventilate and contribute importantly to the work of breathing, and these properties are often deranged by disease. Understanding dynamic airflow properties is therefore worthwhile.


InternalMed_Harrison

InternalMed_Harrison. As with the flow of any fluid (gas or liquid) in any tube, maintenance of airflow within the pulmonary airways requires a pressure gradient that falls along the direction of flow, the magnitude of which is determined by the flow rate and the frictional resistance to flow. During quiet tidal breathing, the pressure gradients driving inspiratory or expiratory flow are small owing to the very low frictional resistance of normal pulmonary airways (Raw, normally <2 cmH2O/L per second). However, during rapid exhalation, another phenomenon reduces flow below that which would have been expected if frictional resistance were the only impediment to flow. This phenomenon is called dynamic FIguRE 306e-3 Luminal area versus transmural pressure relationship. Transmural pressure represents the pressure difference across the airway wall from inside to outside.


InternalMed_Harrison

InternalMed_Harrison. airflow limitation, and it occurs because the bronchial airways through which air is exhaled are collapsible rather than rigid (Fig. 306e-3). An important anatomic feature of the pulmonary airways is its treelike branching structure. While the individual airways in each successive generation, from most proximal (trachea) to most distal (respiratory bronchioles), are smaller than those of the parent generation, their number increases exponentially such that the summed cross-sectional area of the airways becomes very large toward the lung periphery. Because flow (volume/time) is constant along the airway tree, the velocity of airflow (flow/summed cross-sectional area) is much greater in the central airways than in the peripheral airways. During exhalation, gas leaving the alveoli must therefore gain velocity as it proceeds toward the mouth. The energy required for this “convective” acceleration is drawn from the component of gas energy manifested as its local pressure, which reduces


InternalMed_Harrison

InternalMed_Harrison. gain velocity as it proceeds toward the mouth. The energy required for this “convective” acceleration is drawn from the component of gas energy manifested as its local pressure, which reduces intraluminal gas pressure, airway transmural pressure, airway size (Fig. 306e-3), and flow. This is the Bernoulli effect, the same effect that keeps an airplane airborne, generating a lifting force by decreasing pressure above the curved upper surface of the wing due to acceleration of air flowing over the wing. If an individual tries to exhale more forcefully, the local velocity increases further and reduces airway size further, resulting in no net increase in flow. Under these circumstances, flow has reached its maximum possible value, or its flow limit. Lungs normally exhibit such dynamic airflow limitation. This limitation can be assessed by spirometry, in which an individual inhales fully to TLC and then forcibly exhales to RV. One useful spirometric measure is the volume of air exhaled


InternalMed_Harrison

InternalMed_Harrison. limitation. This limitation can be assessed by spirometry, in which an individual inhales fully to TLC and then forcibly exhales to RV. One useful spirometric measure is the volume of air exhaled during the first second of expiration (FEV1), as discussed later. Maximal expiratory flow at any lung volume is determined by gas density, airway cross-section and distensibility, elastic recoil pressure of the lung, and frictional pressure loss to the flow-limiting airway site. Under normal conditions, maximal expiratory flow falls with lung volume (Fig. 306e-4), primarily because of the dependence of lung recoil pressure on lung volume (Fig. 306e-1). In pulmonary fibrosis, lung recoil pressure is increased at any lung volume, and thus the maximal expiratory flow is elevated when considered in relation to lung volume. Conversely, in emphysema, lung recoil pressure is reduced; this reduction is a principal mechanism by which maximal expiratory flows fall. Diseases that narrow the airway lumen


InternalMed_Harrison

InternalMed_Harrison. to lung volume. Conversely, in emphysema, lung recoil pressure is reduced; this reduction is a principal mechanism by which maximal expiratory flows fall. Diseases that narrow the airway lumen at any transmural pressure (e.g., asthma or chronic bronchitis) or that cause excessive airway collapsibility (e.g., tracheomalacia) also reduce maximal expiratory flow.


InternalMed_Harrison

InternalMed_Harrison. The Bernoulli effect also applies during inspiration, but the more negative pleural pressures during inspiration lower the pressure outside of airways, thereby increasing transmural pressure and promoting airway expansion. Thus inspiratory airflow limitation seldom occurs due to diffuse pulmonary airway disease. Conversely, extrathoracic airway narrowing (e.g., due to a tracheal adenoma or post-tracheostomy stricture) can lead to inspiratory airflow limitation (Fig. 306e-4). The Work of Breathing In health, the elastic (volume change–related) and dynamic (flow-related) loads that must be overcome to ventilate the lungs at rest are small, and the work required of the respiratory muscles is minimal. However, the work of breathing can


InternalMed_Harrison

InternalMed_Harrison. A BC This volume is called the anatomic 306e-3 dead space (VD). Quiet breathing with tidal volumes smaller than the anatomic dead space introduces no fresh gas into the alveoli at all; only that part of the inspired tidal volume (VT) that is greater than the VD introduces fresh gas into the alveoli. The dead space can be further increased functionally if some of the inspired tidal volume is delivered to a part of the lung that receives no pulmonary blood flow and ˜ Increasing volume thus cannot contribute to gas exchange (e.g., the portion of the lung distal to a FIguRE 306e-4 Flow-volume loops. A. Normal. B. Airflow obstruction. C. Fixed central airway large pulmonary embolus). In this situ- obstruction. RV, residual volume; TLC, total lung capacity. E˙V(exhaled minute ventilationation,


InternalMed_Harrison

InternalMed_Harrison. VT × RR) includes a component of dead increase considerably due to a metabolic requirement for substantially increased ventilation, an abnormally increased mechanical load, or both. As discussed below, the rate of ventilation is primarily set by the need to eliminate carbon dioxide, and thus ventilation increases during exercise (sometimes by more than twentyfold) and during metabolic acidosis as a compensatory response. Naturally, the work rate required to overcome the elasticity of the respiratory system increases with both the depth and the frequency of tidal breaths, while the work required to overcome the dynamic load increases with total ventilation. A modest increase of ventilation is most efficiently achieved by increasing tidal volume but not respiratory rate, which is the normal ventilatory response to lower-level exercise. At high levels of exercise, deep breathing persists, but respiratory rate also increases. The pattern chosen by the respiratory controller minimizes the


InternalMed_Harrison

InternalMed_Harrison. ventilatory response to lower-level exercise. At high levels of exercise, deep breathing persists, but respiratory rate also increases. The pattern chosen by the respiratory controller minimizes the work of breathing.


InternalMed_Harrison

InternalMed_Harrison. The work of breathing also increases when disease reduces the compliance of the respiratory system or increases the resistance to airflow. The former occurs commonly in diseases of the lung parenchyma (interstitial processes or fibrosis, alveolar filling diseases such ˙VA ( a component of fresh gas alveolar ventilation


InternalMed_Harrison

InternalMed_Harrison. CO2 elimination from the alveoli is equal to ˙VA times the difference in CO2 fraction between inspired air (essentially zero) and alveolar gas (typically ~5.6% after correction for humidification of inspired air, corresponding to 40 mmHg). In the steady state, the alveolar fraction of CO2 is equal to metabolic CO2 production divided by alveolar ventilation. Because, as discussed below, alveolar and arterial CO2 tensions are equal, and because the respiratory controller normally strives to maintain arterial PCO (PaCO2) at ~40 mmHg, the adequacy of alveolar ventilation is reflected in PaCO2. If the PaCO2 falls much below 40 mmHg, alveolar hyperventilation is present; if the PaCO2 exceeds 40 mmHg, then alveolar hypoventilation is present. Ventilatory failure is characterized by extreme alveolar hypoventilation.


InternalMed_Harrison

InternalMed_Harrison. As a consequence of oxygen uptake of alveolar gas into capillary blood, alveolar oxygen tension falls below that of inspired gas. The rate of oxygen uptake (determined by the body’s metabolic oxygen consumption) is related to the average rate of metabolic CO2 production, = [VT – VD] × RR). ˙VO2 / and their ratio—the “respiratory quotient” (R = ˙ largely on the fuel being metabolized. For a typical American diet, )—depends


InternalMed_Harrison

InternalMed_Harrison. CHAPTER 306e Disturbances of Respiratory Function as pulmonary edema or pneumonia, or substantial lung resection), and the latter occurs in obstructive airway diseases such as asthma, chronic bronchitis, emphysema, and cystic fibrosis. Furthermore, severe airflow obstruction can functionally reduce the compliance of the respiratory system by leading to dynamic hyperinflation. In this scenario, expiratory flows slowed by the obstructive airways disease may be insufficient to allow complete exhalation during the expiratory phase of tidal breathing; as a result, the “functional residual capacity” from which the next breath is inhaled is greater than the static FRC. With repetition of incomplete exhalations of each tidal breath, the operating FRC becomes dynamically elevated, sometimes to a level that approaches TLC. At these high lung volumes, the respiratory system is much less compliant than at normal breathing volumes, and thus the elastic work of each tidal breath is also increased.


InternalMed_Harrison

InternalMed_Harrison. that approaches TLC. At these high lung volumes, the respiratory system is much less compliant than at normal breathing volumes, and thus the elastic work of each tidal breath is also increased. The dynamic pulmonary hyperinflation that accompanies severe airflow obstruction causes patients to sense difficulty in inhaling—even though the root cause of this pathophysiologic abnormality is expiratory airflow obstruction.


InternalMed_Harrison

InternalMed_Harrison. Adequacy of Ventilation As noted above, the respiratory control system that sets the rate of ventilation responds to chemical signals, including arterial CO2 and oxygen tensions and blood pH, and to volitional needs, such as the need to inhale deeply before playing a long phrase on the trumpet. Disturbances in ventilation are discussed in Chap. 318. The focus of this chapter is on the relationship between ventilation of the lung and CO2 elimination. At the end of each tidal exhalation, the conducting airways are filled with alveolar gas that had not reached the mouth when expiratory flow stopped. During the ensuing inhalation, fresh gas immediately enters the airway tree at the mouth, but the gas first entering the alveoli at the start of inhalation is that same alveolar gas in the conducting airways that had just left the alveoli. Accordingly, fresh gas does not enter the alveoli until the volume of the conducting airways has been inspired.


InternalMed_Harrison

InternalMed_Harrison. R is usually around 0.85, and more oxygen is absorbed than CO2 is excreted. Together, these phenomena allow the estimation of alveolar oxygen tension, according to the following relationship, known as the alveolar gas equation: The alveolar gas equation also highlights the influences of inspired oxygen fraction (Fi ), barometric pressure (P ), and vapor pressure of water (PH2O = 47 mmHg at 37°C) in addition to alveolar ventilation (which sets Pa ) in determining Pa . An implication of the alveolar gas equation is that severe arterial hypoxemia rarely occurs as a pure consequence of alveolar hypoventilation at sea level while an individual is breathing air. The potential for alveolar hypoventilation to induce severe hypoxemia with otherwise normal lungs increases as falls with increasing altitude.


InternalMed_Harrison

InternalMed_Harrison. gAS EXCHANgE Diffusion For oxygen to be delivered to the peripheral tissues, it must pass from alveolar gas into alveolar capillary blood by diffusing through alveolar membrane. The aggregate alveolar membrane is highly optimized for this process, with a very large surface area and minimal thickness. Diffusion through the alveolar membrane is so efficient in the human lung that in most circumstances a red blood cell’s hemoglobin becomes fully oxygen saturated by the time the cell has traveled just one-third the length of the alveolar capillary. Thus the uptake of alveolar oxygen is ordinarily limited by the amount of blood transiting the alveolar capillaries rather than by the rapidity with which oxygen can diffuse across the membrane; consequently, oxygen uptake from the lung is said to be “perfusion limited.” CO2 also equilibrates rapidly across the alveolar membrane. Therefore, the oxygen and CO2 tensions in capillary blood leaving a normal alveolus are essentially equal to those


InternalMed_Harrison

InternalMed_Harrison. be “perfusion limited.” CO2 also equilibrates rapidly across the alveolar membrane. Therefore, the oxygen and CO2 tensions in capillary blood leaving a normal alveolus are essentially equal to those in alveolar gas. Only in rare circumstances (e.g., at high altitude or in high-performance athletes exerting maximal effort) is exiting ventilated units increases only slightly, as hemoglobin will oxygen uptake from normal lungs diffusion limited. Diffusion limita-already have been nearly fully saturated and the solubility of oxygen in tion can also occur in interstitial lung disease if substantially thickened plasma is quite small. alveolar walls remain perfused. A more common occurrence than the two extreme examples given above is a widening of the distribution of ventilation/perfusion ratios;


InternalMed_Harrison

InternalMed_Harrison. Ventilation/Perfusion Heterogeneity As noted above, for gas exchange to be most efficient, ventilation to each individual alveolus (among the millions of alveoli) should match perfusion to its accompanying capil lung disease.ofconsequencea commonisQ˙heterogeneity /˙Vsuch In this circumstance, perfusion of relatively underventilated alveoli laries. Because of the differential effects of gravity on lung mechanics and blood flow throughout the lung and because of differences in airway and vascular architecture among various respiratory paths, results in the incomplete oxygenation of exiting blood. When mixed Q˙regions, this partially /with well-oxygenated blood leaving higher ˙V reoxygenated blood disproportionately lowers arterial PaO2, although to a lesser extent than does a similar perfusion fraction of bloodthere is minor ventilation/perfusion heterogeneity even in the nor-


InternalMed_Harrison

InternalMed_Harrison. Q˙heterogeneity can be particularly marked in /mal lung; however, ˙V disease. Two extreme examples are (1) ventilation of unperfused lung leaving regions of pure shunt. In addition, in contrast to shunt regions, inhalation of supplemental oxygen does raise the PAO2, even in rela Q˙regions, and so the arterial hypoxemia /tively underventilated low ˙V distal to a pulmonary embolus, in which ventilation of the physiologic dead space is “wasted” in the sense that it does not contribute to gas exchange; and (2) perfusion of nonventilated lung (a “shunt”), which allows venous blood to pass through the lung unaltered. When mixed with fully oxygenated blood leaving other well-ventilated lung units, shunted venous blood disproportionately lowers the mixed arterial PaO2 as a result of the nonlinear oxygen content versus PO2 relationship of hemoglobin (Fig. 306e-5). Furthermore, the resulting arterial Q˙heterogeneity is typically responsive to oxygen therapy /induced by ˙V (Fig. 306e-5).


InternalMed_Harrison

InternalMed_Harrison. Q˙heterogeneity is typically responsive to oxygen therapy /induced by ˙V (Fig. 306e-5). In sum, arterial hypoxemia can be caused by substantial reduc tion of inspired oxygen tension; by severe alveolar hypoventilation; by perfusion of relatively underventilated (low ˙ unventilated (shunt) lung regions; and, in unusual circumstances, by limitation of gas diffusion. hypoxemia is refractory to supplemental inspired oxygen. The reason is that (1) raising the inspired FiO2 has no effect on alveolar gas ten-PATHOPHYSIOLOgY sions in nonventilated alveoli and (2) while raising inspired FiO2 does Although many diseases injure the respiratory system, this system increase PaCO2 in ventilated alveoli, the oxygen content of blood responds to injury in relatively few ways. For this reason, the pattern of


InternalMed_Harrison

InternalMed_Harrison. FIO2 = 0.21 FIO2 = 1 99 mmHg 40 mmHg40 mmHg (75%) 40 mmHg (75%) 55 mmHg (87.5%) 40 mmHg (75%) 99 mmHg (100%) 650 mmHg 40 mmHg 40 mmHg (75%) 40 mmHg (75%) 56 mmHg (88%) 40 mmHg (75%) 650 mmHg (100%) 99 mmHg 40 mmHg40 mmHg (75%) 45 mmHg (79%) 40 mmHg (75%) 99 mmHg (100%) FIO2 = 0.21 650 mmHg 200 mmHg40 mmHg (75%) 200 mmHg (100%) 40 mmHg (75%) 650 mmHg (100%) FIO2 = 1V/QHeterogeneity.. 58 mmHg 350 mmHg (89.5%) (100%) FIguRE 306e-5 Influence of air versus oxygen breathing on mixed arterial oxygenation in shunt and ventilation/perfusion heterogeneity. Partial pressure of oxygen (mmHg) and oxygen saturations are shown for mixed venous blood, for end capillary blood (normal versus affected alveoli), and for mixed arterial blood. FIO2, fraction of inspired oxygen; ˙V/Q˙ , ventilation/perfusion.


InternalMed_Harrison

InternalMed_Harrison. CHAPTER 306e Flow Volume Flow Volume Flow Volume Flow Volume Flow Volume FIguRE 306e-6 Common abnormalities of pulmonary function (see text). Pulmonary function values are expressed as a percentage of normal predicted values, except for Raw, which is expressed as cmH2O/L per sec (normal, <2 cmH2O/L per second). The figures at the bottom of each column show the typical configuration of flow-volume loops in each condition, including the flow-volume relationship during tidal breathing. b.d., bronchodilator; DL co, diffusion capacity of lung for carbon monoxide; FEV1, forced expiratory volume in 1 sec; FRC, functional residual capacity; FVC, forced vital capacity; Raw, airways resistance; RV, residual volume; TLC, total lung capacity. physiologic abnormalities may or may not provide sufficient information by which to discriminate among conditions.


InternalMed_Harrison

InternalMed_Harrison. physiologic abnormalities may or may not provide sufficient information by which to discriminate among conditions. Figure 306e-6 lists abnormalities in pulmonary function testing that are typically found in a number of common respiratory disorders and highlights the simultaneous occurrence of multiple physiologic abnormalities. The coexistence of some of these respiratory disorders results in more complex superposition of these abnormalities. Methods to measure respiratory system function clinically are described later in this chapter.


InternalMed_Harrison

InternalMed_Harrison. Ventilatory Restriction Due to Increased Elastic Recoil—Example: Idiopathic Pulmonary Fibrosis Idiopathic pulmonary fibrosis raises lung recoil at all lung volumes, thereby lowering TLC, FRC, and RV as well as forced vital capacity (FVC). Maximal expiratory flows are also reduced from normal values but are elevated when considered in relation to lung volumes. Increased flow occurs both because the increased lung recoil drives greater maximal flow at any lung volume and because airway diameters are relatively increased due to greater radially outward traction exerted on bronchi by the stiff lung parenchyma. For the same reason, airway resistance is also normal. Destruction of the pulmonary capillaries by the fibrotic process results in a marked reduction in diffusing capacity (see below). Oxygenation is often severely reduced by persistent perfusion of alveolar units that are relatively underventilated due to fibrosis of nearby (and mechanically linked) lung. The flow-volume loop (see


InternalMed_Harrison

InternalMed_Harrison. Oxygenation is often severely reduced by persistent perfusion of alveolar units that are relatively underventilated due to fibrosis of nearby (and mechanically linked) lung. The flow-volume loop (see below) looks like a miniature version of a normal loop but is shifted toward lower absolute lung volumes and displays maximal expiratory flows that are increased for any given volume over the normal tracing.


InternalMed_Harrison

InternalMed_Harrison. Ventilatory Restriction Due to Chest Wall Abnormality—Example: Moderate Obesity As the size of the average American continues to increase, this pattern may become the most common of pulmonary function abnormalities. In moderate obesity, the outward recoil of the chest wall is blunted by the weight of chest wall fat and the space occupied by intraabdominal fat. In this situation, preserved inward recoil of the lung overbalances the reduced outward recoil of the chest wall, and FRC falls. Because respiratory muscle strength and lung recoil remain normal, TLC is typically unchanged (although it may fall in massive obesity) and RV is normal (but may be reduced in massive obesity).


InternalMed_Harrison

InternalMed_Harrison. Mild hypoxemia may be present due to perfusion of alveolar units that are poorly ventilated because of airway closure in dependent portions of the lung during breathing near the reduced FRC. Flows remain normal, as does the diffusion capacity of the lung for carbon monoxide (DlCO), unless obstructive sleep apnea (which often accompanies obesity) and associated chronic intermittent hypoxemia have induced pulmonary arterial hypertension, in which case DlCO may be low.


InternalMed_Harrison

InternalMed_Harrison. Ventilatory Restriction Due to Reduced Muscle Strength—Example: Myasthenia gravis In this circumstance, FRC remains normal, as both lung recoil and passive chest wall recoil are normal. However, TLC is low and RV is elevated because respiratory muscle strength is insufficient to push the passive respiratory system fully toward either volume extreme. Caught between the low TLC and the elevated RV, FVC and FEV1 are reduced as “innocent bystanders.” As airway size and lung vasculature are unaffected, both Raw and DlCO are normal. Oxygenation is normal unless weakness becomes so severe that the patient has insufficient strength to reopen collapsed alveoli during sighs, with resulting atelectasis.


InternalMed_Harrison

InternalMed_Harrison. Airflow Obstruction Due to Decreased Airway Diameter—Example: Acute Asthma During an episode of acute asthma, luminal narrowing due to smooth muscle constriction as well as inflammation and thickening within the smalland medium-sized bronchi raise frictional resistance and reduce airflow. “Scooping” of the flow-volume loop is caused by reduction of airflow, especially at lower lung volumes. Often, airflow obstruction can be reversed by inhalation of β2-adrenergic agonists acutely or by treatment with inhaled steroids chronically. TLC usually remains normal (although elevated TLC is sometimes seen in long-standing asthma), but FRC may be dynamically elevated. RV is often increased due to exaggerated airway closure at low lung volumes, and this elevation of RV reduces FVC. Because central airways are narrowed, Raw is usually elevated. Mild arterial hypoxemia is often present due to perfusion of relatively underventilated alveoli distal to obstructed airways (and is responsive to oxygen


InternalMed_Harrison

InternalMed_Harrison. are narrowed, Raw is usually elevated. Mild arterial hypoxemia is often present due to perfusion of relatively underventilated alveoli distal to obstructed airways (and is responsive to oxygen supplementation), but DlCO is normal or mildly elevated.


InternalMed_Harrison

InternalMed_Harrison. Airflow Obstruction Due to Decreased Elastic Recoil—Example: Severe Emphysema Loss of lung elastic recoil in severe emphysema results in Disturbances of Respiratory Function


InternalMed_Harrison

InternalMed_Harrison. Q˙units has /these circumstances, any venous admixture through low ˙V pulmonary hyperinflation, of which elevated TLC is the hallmark. FRC is more severely elevated due both to loss of lung elastic recoil and to dynamic hyperinflation—the same phenomenon as autoPEEP, which is the positive end-expiratory alveolar pressure that occurs when a new breath is initiated before the lung volume is allowed to return to FRC. Residual volume is very severely elevated because of airway closure and because exhalation toward RV may take so long that RV cannot be reached before the patient must inhale again. Both FVC and FEV1 are markedly decreased, the former because of the severe elevation of RV and the latter because loss of lung elastic recoil reduces the pressure driving maximal expiratory flow and also reduces tethering open of small intrapulmonary airways. The flow-volume loop demonstrates marked scooping, with an initial transient spike of flow attributable largely to expulsion of air from


InternalMed_Harrison

InternalMed_Harrison. also reduces tethering open of small intrapulmonary airways. The flow-volume loop demonstrates marked scooping, with an initial transient spike of flow attributable largely to expulsion of air from collapsing central airways at the onset of forced exhalation. Otherwise, the central airways remain relatively unaffected, so Raw is normal in “pure” emphysema. Loss of alveolar surface and capillaries in the alveolar walls reduces DlCO; however, because poorly ventilated emphysematous acini are also poorly perfused (due to loss of their capillaries), arterial hypoxemia usually is not seen at rest until emphysema becomes very severe. However, during exercise, PaO2 may fall precipitously if extensive destruction of the pulmonary vasculature prevents a sufficient increase in cardiac output and mixed venous oxygen content falls substantially. Under a particularly marked effect in lowering mixed arterial oxygen tension.


InternalMed_Harrison

InternalMed_Harrison. FuNCTIONAL MEASuREMENTS Measurement of Ventilatory Function • Lung voLumes Figure 306e-2 demonstrates a spirometry tracing in which the volume of air entering or exiting the lung is plotted over time. In a slow vital capacity maneuver, the subject inhales from FRC, fully inflating the lungs to TLC, and then exhales slowly to RV; VC, the difference between TLC and RV, represents the maximal excursion of the respiratory system. Spirometry discloses relative volume changes during these maneuvers but cannot reveal the absolute volumes at which they occur. To determine absolute lung volumes, two approaches are commonly used: inert gas dilution and body plethysmography. In the former, a known amount of a nonabsorbable inert gas (usually helium or neon) is inhaled in a single large breath or is rebreathed from a closed circuit; the inert gas is diluted by the gas resident in the lung at the time of inhalation, and its final concentration reveals the volume of resident gas contributing to the


InternalMed_Harrison

InternalMed_Harrison. from a closed circuit; the inert gas is diluted by the gas resident in the lung at the time of inhalation, and its final concentration reveals the volume of resident gas contributing to the dilution. A drawback of this method is that regions of the lung that ventilate poorly (e.g., due to airflow obstruction) may not receive much inspired inert gas and so do not contribute to its dilution. Therefore, inert gas dilution (especially in the single-breath method) often underestimates true lung volumes.


InternalMed_Harrison

InternalMed_Harrison. In the second approach, FRC is determined by measuring the compressibility of gas within the chest, which is proportional to the volume of gas being compressed. The patient sits in a body plethysmograph (a chamber usually made of transparent plastic to minimize claustrophobia) and, at the end of a normal tidal breath (i.e., when lung volume is at FRC), is instructed to pant against a closed shutter, thus periodically compressing air within the lung slightly. Pressure fluctuations at the mouth and volume fluctuations within the body box (equal but opposite to those in the chest) are determined, and from these measurements the thoracic gas volume is calculated by means of Boyle’s law. Once FRC is obtained, TLC and RV are calculated by adding the value for inspiratory capacity and subtracting the value for expiratory reserve volume, respectively (both values having been obtained during spirometry) (Fig. 306e-2). The most important determinants of healthy individuals’ lung volumes are


InternalMed_Harrison

InternalMed_Harrison. the value for expiratory reserve volume, respectively (both values having been obtained during spirometry) (Fig. 306e-2). The most important determinants of healthy individuals’ lung volumes are height, age, and sex, but there is considerable additional normal variation beyond that accounted for by these parameters. In addition, race influences lung volumes; on average, TLC values are ~12% lower in African Americans and 6% lower in Asian Americans than in Caucasian Americans. In practice, a mean “normal” value is predicted by multivariate regression equations using height, age, and sex, and the patient’s value is divided by the predicted value (often with “race correction” applied) to determine “percent predicted.” For most measures of lung function, 85–115% of the predicted value can be normal; however, in health, the various lung volumes tend to scale together. For example, if one is “normal big” with a TLC 110% of the predicted value, then all other lung volumes and spirometry


InternalMed_Harrison

InternalMed_Harrison. be normal; however, in health, the various lung volumes tend to scale together. For example, if one is “normal big” with a TLC 110% of the predicted value, then all other lung volumes and spirometry values will also approximate 110% of their respective predicted values. This pattern is particularly helpful in evaluating airflow, as discussed below.


InternalMed_Harrison

InternalMed_Harrison. Air FLow As noted above, spirometry plays a key role in lung volume determination. Even more often, spirometry is used to measure airflow, which reflects the dynamic properties of the lung. During an FVC maneuver, the patient inhales to TLC and then exhales rapidly and forcefully to RV; this method ensures that flow limitation has been achieved, so that the precise effort made has little influence on actual flow. The total amount of air exhaled is the FVC, and the amount of air exhaled in the first second is the FEV1; the FEV1 is a flow rate, revealing volume change per time. Like lung volumes, an individual’s maximal expiratory flows should be compared with predicted values based on height, age, and sex. While the FEV1/FVC ratio is typically reduced in airflow obstruction, this condition can also reduce FVC by raising RV, sometimes rendering the FEV1/FVC ratio “artifactually normal” with the erroneous implication that airflow obstruction is absent. To circumvent this problem, it is


InternalMed_Harrison

InternalMed_Harrison. can also reduce FVC by raising RV, sometimes rendering the FEV1/FVC ratio “artifactually normal” with the erroneous implication that airflow obstruction is absent. To circumvent this problem, it is useful to compare FEV1 as a fraction of its predicted value with TLC as a fraction of its predicted value. In health, the results are usually similar. In contrast, even an FEV1 value that is 95% of its predicted value may actually be relatively low if TLC is 110% of its respective predictied value. In this case, airflow obstruction may be present, despite the “normal” value for FEV1.


InternalMed_Harrison

InternalMed_Harrison. The relationships among volume, flow, and time during spirometry are best displayed in two plots—the spirogram (volume vs. time) and the flow-volume loop (flow vs. volume) (Fig. 306e-4). In conditions that cause airflow obstruction, the site of obstruction is sometimes correlated with the shape of the flow-volume loop. In diseases that cause lower airway obstruction, such as asthma and emphysema, flows decrease more rapidly with declining lung volumes, leading to a characteristic scooping of the flow-volume loop. In contrast, fixed upper-airway obstruction typically leads to inspiratory and/or expiratory flow plateaus (Fig. 306e-4).


InternalMed_Harrison

InternalMed_Harrison. AirwAys resistAnce The total resistance of the pulmonary and upper airways is measured in the same body plethysmograph used to measure FRC. The patient is asked once again to pant, but this time against a closed and then opened shutter. Panting against the closed shutter reveals the thoracic gas volume as described above. When the shutter is opened, flow is directed to and from the body box, so that volume fluctuations in the box reveal the extent of thoracic gas compression, which in turn reveals the pressure fluctuations driving flow. Simultaneous measurement of flow allows the calculation of lung resistance (as flow divided by pressure). In health, Raw is very low (<2 cmH2O/L per second), and half of the detected resistance resides within the upper airway. In the lung, most resistance originates in the central airways. For this reason, airways resistance measurement tends to be insensitive to peripheral airflow obstruction.


InternalMed_Harrison

InternalMed_Harrison. respirAtory muscLe strength To measure respiratory muscle strength, the patient is instructed to exhale or inhale with maximal effort against a closed shutter while pressure is monitored at the mouth. Pressures greater than ±60 cmH2O at FRC are considered adequate and make it unlikely that respiratory muscle weakness accounts for any other resting ventilatory dysfunction that is identified.


InternalMed_Harrison

InternalMed_Harrison. Measurement of gas Exchange • DiFFusing cApAcity (DL co) This test uses a small (and safe) amount of carbon monoxide (CO) to measure gas exchange across the alveolar membrane during a 10-sec breath hold. CO in exhaled breath is analyzed to determine the quantity of CO crossing the alveolar membrane and combining with hemoglobin in red blood cells. This “single-breath diffusing capacity” (Dlco) value increases with the surface area available for diffusion and the amount of hemoglobin within the capillaries, and it varies inversely with alveolar membrane thickness. Thus, Dlco decreases in diseases that thicken or destroy alveolar membranes (e.g., pulmonary fibrosis, emphysema), curtail the pulmonary vasculature (e.g., pulmonary hypertension), or reduce alveolar capillary hemoglobin (e.g., anemia). Single-breath diffusing capacity may be elevated in acute congestive heart failure, asthma, polycythemia, and pulmonary hemorrhage.


InternalMed_Harrison

InternalMed_Harrison. ArteriAL BLooD gAses The effectiveness of gas exchange can be assessed by measuring the partial pressures of oxygen and CO2 in a sample of blood obtained by arterial puncture. The oxygen content of blood (Ca ) depends upon arterial saturation (%O Sat), which is set by Pa , pH, and PaCO2 according to the oxyhemoglobin dissociation curve. CaO2can also be measured by oximetry (see below): CaO2 (mL/dL) = 1.39 (mL/dL) × [hemoglobin](g) × % O2 Sat + 0.003 (mL/dL/mmHg) × PaO2 (mmHg) If hemoglobin saturation alone needs to be determined, this task can 306e-7 be accomplished noninvasively with pulse oxymetry. The authors wish to acknowledge the contributions of Drs. Steven E. Weinberger and Irene M. Rosen to this chapter in previous editions as well as the helpful contributions of Drs. Mary Strek and Jeffrey Jacobson. CHAPTER 306e Disturbances of Respiratory Function


InternalMed_Harrison

InternalMed_Harrison. CHAPTER 306e Disturbances of Respiratory Function Diagnostic procedures in respiratory Disease Anne L. Fuhlbrigge, Augustine M. K. Choi The diagnostic modalities available for assessing the patient with suspected or known respiratory system disease include imaging stud-307 ies and techniques for acquiring biologic specimens, some of which involve direct visualization of part of the respiratory system. Methods to characterize the functional changes developing as a result of disease, including pulmonary function tests and measurements of gas exchange, are discussed in Chap. 306e.


InternalMed_Harrison

InternalMed_Harrison. Routine chest radiography, including both posteroanterior (PA) and lateral views, is an integral part of the diagnostic evaluation of diseases involving the pulmonary parenchyma, the pleura, and, to a lesser extent, the airways and the mediastinum (see Chaps. 305 and 308e). Lateral decubitus views are useful for determining whether pleural abnormalities represent freely flowing fluid, whereas apical lordotic views can visualize disease at the lung apices better than the standard PA view. Portable equipment is often used for acutely ill patients who cannot be transported to a radiology suite but are more difficult to interpret owing to several limitations: (1) the single anteroposterior (AP) projection obtained; (2) variability in overand underexposure of film; (3) a shorter focal spot-film distance leading to lack of edge sharpness and loss of fine detail; and (4) magnification of the cardiac silhouette and other anterior structures by the AP projection. Common radiographic patterns


InternalMed_Harrison

InternalMed_Harrison. distance leading to lack of edge sharpness and loss of fine detail; and (4) magnification of the cardiac silhouette and other anterior structures by the AP projection. Common radiographic patterns and their clinical correlates are reviewed in Chap. 308e.