Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

16. Chronic Obstructive Pulmonary Disease

Sharya V. Bourdet and Dennis M. Williams


KEY CONCEPTS

 Images Chronic obstructive pulmonary disease (COPD) is a treatable and preventable disease characterized by progressive airflow limitation that is not fully reversible and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases.

 Images COPD is historically described as either chronic bronchitis or emphysema. Chronic bronchitis is defined in clinical terms, whereas emphysema is defined in terms of anatomic pathology. Because most patients exhibit some features of each disease, the appropriate emphasis of COPD pathophysiology is on small airway disease and parenchymal damage that contributes to chronic airflow limitation.

 Images Mortality from COPD has increased steadily over the past three decades; it currently is the third leading cause of death in the United States.

 Images The primary cause of COPD is cigarette smoking, implicated in 85% of diagnosed cases. Other risks include a genetic predisposition, environmental exposures (including occupational dusts and chemicals), and air pollution.

 Images Smoking cessation, and avoidance of other known toxins causing COPD, are the only management strategies proven to slow the progression.

 Images Oxygen therapy has been shown to reduce mortality in selected patients with COPD. Oxygen therapy is indicated for patients with a resting PaO2 of less than 55 mm Hg or a PaO2 of less than 60 mm Hg and evidence of right-sided heart failure, polycythemia, or impaired neurologic function.

 Images Bronchodilators represent the mainstay of drug therapy for COPD. Pharmacotherapy is used to relieve patient symptoms and improve quality of life. Guidelines recommend short-acting bronchodilators as initial therapy for patients with mild or intermittent symptoms.

 Images For the patient who experiences chronic symptoms, long-acting bronchodilators are appropriate. Either a β2-agonist or an anticholinergic offers significant benefits. Combining long-acting bronchodilators is recommended if necessary, despite limited data.

 Images The role of inhaled corticosteroid therapy in COPD is controversial. International guidelines suggest that patients with severe COPD and frequent exacerbations may benefit from inhaled corticosteroids.

 Images Acute exacerbations of COPD have a significant impact on disease progression and mortality. Treatment of acute exacerbations includes intensification of bronchodilator therapy and a short course of systemic corticosteroids.

 Images Antimicrobial therapy should be used during acute exacerbations of COPD if the patient exhibits at least two of the following: increased dyspnea, increased sputum volume, and increased sputum purulence.


Images Chronic obstructive pulmonary disease (COPD) is a common lung disease characterized by airflow limitation that is not fully reversible and is both chronic and progressive.1 COPD is preventable and treatable and causes significant extrapulmonary effects that contribute to disease severity in a subset of patients. The prevalence and mortality of COPD have increased substantially over the past 2 decades. Currently, COPD is the third leading cause of death in the United States, with 6/3% of adults reporting a physician diagnosis of COPD.2 By 2020, it is estimated that COPD will rank fifth in burden of disease and third as a cause of death throughout the world.

Although national guidelines for management have been available for over 2 decades, questions have been raised concerning their quality and supporting evidence. In order to standardize the care of patients with COPD and present evidence-based recommendations, the National Heart, Lung, and Blood Institute (NHLBI) and the World Health Organization (WHO) launched the Global Initiative for Chronic Obstructive Lung Disease (GOLD) in 2001. This report was most recently revised in December 2013.1 The goals of the GOLD organization are to increase awareness of COPD and reduce morbidity and mortality associated with the disease. International guidelines have also been developed through a collaborative effort of the American College of Physicians (ACP), the American College of Chest Physicians (ACCP), the American Thoracic Society (ATS), and the European Respiratory Society (ERS) and are widely available.3 These two guidelines are generally concordant in their recommendations.

COPD is differentiated from asthma in that the airflow limitation that is present is not fully reversible. In a subset of patients, it is fixed with minimal improvement in response to a bronchodilator or with optimal treatment. However, the natural course of the disease is quite variable among patients. The chronic and progressive nature of COPD is associated with an abnormal inflammatory response of the lungs to noxious particles or gases.1 Nonetheless, COPD is preventable and treatable. In recent years, there has been an increased appreciation for the impact of the systemic consequences of chronic inflammatory diseases, including COPD, and for the impact of comorbidities in individual patients that can complicate COPD management.

For many years, clinicians and researchers have exhibited a nihilistic attitude toward the value of treatments for COPD. This was based on the paucity of effective therapies, the destructive nature of the condition, and the fact that the common etiology is cigarette smoking, a modifiable health risk. There is now a renewed interest in evaluating the value of treatments and prevention based on the availability of new therapeutic options for pharmacotherapy and guidelines based on evidence. The international guidelines emphasize the terms preventable and treatable to support a positive approach to managing the patient with COPD. Support is also reflected in the availability of research funding to improve understanding about this disease and its management. This includes NHLBI funding of Specialized Centers of Clinically Oriented Research (SCCOR) programs in COPD that have an objective to promote multidisciplinary research on clinically relevant questions enabling basic science findings to be more rapidly applied to clinical problems.4

Images The term COPD has historically been used to describe various pulmonary diseases with a fixed component of airflow limitation. The two principal conditions are chronic bronchitis and emphysema. Chronic bronchitis is associated with chronic or recurrent excessive mucus secretion into the bronchial tree with cough that is present on most days for at least 3 months of the year for at least 2 consecutive years in a patient in whom other causes of chronic cough have been excluded.3 While chronic bronchitis is defined in clinical terms, emphysema is defined in terms of anatomic pathology. Emphysema historically was defined on histologic examination at autopsy. Because this histologic definition is of limited clinical value, emphysema also has been defined as abnormal permanent enlargement of the airspaces distal to the terminal bronchioles accompanied by destruction of their walls, yet without obvious fibrosis.3

Differentiating COPD as either chronic bronchitis or emphysema as descriptive subsets of COPD is no longer considered relevant. This is based on the observation that the majority of COPD is caused by a common risk factor (cigarette smoking) and most patients exhibit features of both chronic bronchitis and emphysema. Currently, emphasis is placed on the pathophysiologic features of small airways disease and parenchymal destruction as contributors to chronic airflow limitation. Most patients with COPD demonstrate features of both chronic bronchitis and emphysema. Chronic inflammation affects the integrity of the airways and causes damage and destruction of the parenchymal structures. The underlying problem is persistent exposure to noxious particles or gases that sustain the inflammatory response. The airways of both the lung and the parenchyma are susceptible to inflammation, and the result is the chronic airflow limitation that characterizes COPD (see Fig. 16-1).

Images

FIGURE 16-1 Mechanisms for developing chronic airflow limitation in COPD. (From reference 1.)

EPIDEMIOLOGY

The true prevalence of COPD is likely underreported in the United States. Data from the National Health Interview Survey in 2001 indicate that 12.1 million people over age 25 years have COPD.5 Over 9 million of these individuals have chronic bronchitis; the remaining number have emphysema or a combination of both diseases. According to national surveys, the true prevalence of people with symptoms of chronic airflow obstruction may exceed 24 million.6The burden may be even greater because more than one third of adults in the United States reported respiratory complaints compatible with symptomatic COPD in some surveys.7

Images COPD is the fourth leading cause of death in the United States, exceeded only by cancer, heart disease, and cerebrovascular accidents. In 2005, COPD accounted for 126,005 deaths in the United States, representing 1 in every 20 deaths. Deaths attributed to COPD increased 8% from 2000 to 2005.8 It is the only leading cause of death to increase over the past 30 years and is projected to be the third leading cause by 2020.9 Overall, the mortality rate is higher in males; however, the female death rate has doubled over the past 25 years, and the number of female deaths exceeded male deaths in each year since 2000. The mortality rate is higher in whites compared with that in blacks.9

Cigarette smoking is the primary cause of COPD and, although the prevalence of cigarette smoking has declined compared with 1965, approximately 25% of individuals in the United States currently smoke. The trend of increasing COPD mortality likely reflects the long latency period between smoking exposure and complications associated with COPD.

The mortality of COPD is significant; however, morbidity associated with the disease also has a significant impact on patients, their families, and the healthcare system. COPD represents the second leading cause of disability in the United States. In the last 20 years, COPD has been responsible for nearly 50 million hospital visits nationwide.10 In recent years, a diagnosis of COPD accounts for over 15 million physician office visits, 1.5 million emergency room visits, and 700,000 hospitalizations annually. A survey by the American Lung Association revealed that among COPD patients, 51% reported that their condition limits their ability to work, 70% were limited in normal physical activity, 56% were limited in performing household chores, and 50% reported that sleep was affected adversely.11

The economic impact of COPD continues to increase as well. It was estimated at $23 billion in 2000 and rose to $37.2 billion in 2004, including $20.9 billion in direct costs and $16.3 billion in indirect morbidity and mortality costs.9,12 By 2020, COPD will be the fifth most burdensome disease, as measured by disability-adjusted life years lost due to illness. The cost of care for COPD patients is high compared with that for patients without the disease. There is a relationship among the severity of COPD, resources consumed, and the costs of care.13

ETIOLOGY

Images Cigarette smoking is the most common risk factor and accounts for 85% to 90% of cases of COPD.1 Components of tobacco smoke activate inflammatory cells, which produce and release the inflammatory mediators characteristic of COPD. Smokers are 12 to 13 times more likely to die from COPD than nonsmokers.14 Although the risk is lower in pipe and cigar smokers, it is still higher than in nonsmokers. Age of starting, total pack-years, and current smoking status are predictive of COPD mortality.

However, only 15% to 20% of all smokers go on to develop COPD, and not all smokers who have equivalent smoking histories develop the same degree of pulmonary impairment, suggesting that other host and environmental factors contribute to the degree of lung dysfunction. Nevertheless, the rate of loss of lung function is determined primarily by smoking status and history.3 Children and spouses of smokers have increased risk of developing significant pulmonary dysfunction through passive smoking, also known as environmental tobacco smoke or secondhand smoke.

In addition to cigarette smoking, COPD is attributed to a combination of risk factors that results in lung injury and tissue destruction. Risk factors can be divided into host factors and environmental factors (Table 16-1), and, commonly, the interaction between these risks leads to expression of the disease. Host factors, such as genetic predisposition, may not be modifiable but are important for identifying patients at high risk of developing the disease.

TABLE 16-1 Risk Factors for Development of Chronic Obstructive Pulmonary Disease (COPD)

Images

Environmental factors, such as tobacco smoke and occupational dust and chemicals, are modifiable factors that, if avoided, may reduce the risk of disease development. Environmental exposures associated with COPD are particles that are inhaled by the individual, which result in inflammation and cell injury. Exposure to multiple environmental toxins increases the risk of COPD. Thus, the total burden of inhaled particles (e.g., cigarette smoke as well as occupational and environmental particles and pollutants) can play a significant role in the development of COPD. In such cases, it is helpful to assess an individual’s total burden of inhaled particles. For example, an individual who smokes and works in a textile factory has a higher total burden of inhaled particles than an individual who smokes and has no occupational exposure.

In nonindustrialized countries, occupational exposures may be a more common risk than cigarette smoking. These exposures include dust and chemicals such as vapors, irritants, and fumes. Reduced lung function and deaths from COPD are higher for individuals who work in gold and coal mining, in the glass or ceramic industries with exposure to silica dust, and in jobs that expose them to cotton dust or grain dust, toluene diisocyanate, or asbestos. Other occupational risk factors include chronic exposure to open cooking or heating fires.

It is unclear whether air pollution alone is a significant risk factor for the development of COPD in smokers and nonsmokers with normal lung function. However, in individuals with existing pulmonary dysfunction, significant air pollution worsens symptoms. As evidence for this, emergency department visits are increased during higher-intensity periods of air pollution.

Individuals exposed to the same environmental risk factors do not have the same chance of developing COPD, suggesting that host factors play an important role in pathogenesis.1,3 While many not-yet-identified genes may influence the risk of developing COPD, the best documented genetic factor is a hereditary deficiency of α1-antitrypsin (AAT). AAT-associated emphysema is an example of a pure genetic disorder inherited in an autosomal recessive pattern. Inheritance is sometimes described as autosomal codominant by some researchers, because heterozygotes can also have decreased concentrations of AAT enzyme.15 The consequences of AAT deficiency are discussed in the following section as protease–antiprotease imbalance. True AAT deficiency accounts for less than 1% of COPD cases.3

AAT is a 42 kDa plasma protein that is synthesized in hepatocytes. A primary role of AAT is to protect cells, especially those in the lung, from destruction by elastase released by neutrophils. In fact, AAT may be responsible for 90% of the inhibition of this destructive enzyme.16 In individuals with the most common allele (M), plasma levels of AAT are approximately 20 to 50 μmol (100 to 350 mg/dL). The protective effect of AAT in the lungs is significantly diminished when plasma levels are less than 11 μmol (80 mg/dL).16 AAT is an acute-phase reactant, and the serum concentration can be quite variable.

Several types of AAT deficiency have been identified and are due to mutations in the AAT gene. Two main gene variants, S and Z, have been identified. For patients who are homozygous with the S variant, AAT levels are at least 60% of those of normal individuals. These patients usually do not have an increased risk of COPD compared with normal individuals. Patients with homozygous Z deficiency (ZZ) represent 95% of clinical cases15 and have AAT levels that are 10% of those of normal individuals, while patients with heterozygous Z variant (SZ) have levels closer to 40% of those of normal individuals. Homozygous Z patients have a higher risk of developing COPD compared with heterozygous Z patients. A history of cigarette smoking increases this risk. A small number of patients have a null phenotype and are at high risk for developing emphysema because they produce virtually no AAT.

Patients with AAT deficiency develop COPD at an early age (20 to 50 years) primarily owing to an accelerated decline in lung function. Compared with an average annual decline in forced expiratory volume in 1 second (FEV1) of 25 mL/y in healthy nonsmokers, patients with homozygous Z deficiency have been reported to have declines of 54 mL/y for nonsmokers and 108 mL/y for current smokers. Effective diagnosis is dependent on clinical suspicion, diagnostic testing of serum concentrations, and genotype confirmation.15 Patients developing COPD at an early age or those with a strong family history of COPD should be screened for AAT deficiency. If the concentration is low, genotype testing (DNA) should be performed.

Other genes have been implicated with increased risk of developing COPD, including chromosome 2q, transforming growth factor β1, microsomal epoxide hydrolase 1, and tumor necrosis factor-α (TNF-α). However, there are no definite conclusions about an association other than AAT. One genetic factor that may reduce the risk of developing COPD is a polymorphism in the gene encoding for matrix metalloproteinase 12 (MMP12). A cohort of smokers with the polymorphism exhibited a lower risk for developing COPD (0.63).17

Two additional host factors that may influence the risk of COPD include airway hyperresponsiveness and lung growth. Individuals with airway hyperresponsiveness to various inhaled particles may have an accelerated decline in lung function compared with those without airway hyperresponsiveness. Additionally, individuals who do not attain maximal lung growth owing to low-birth-weight, prematurity at birth, or childhood illnesses may be at risk for COPD in the future.1

PATHOPHYSIOLOGY

COPD is characterized by chronic inflammatory changes that lead to destructive changes and the development of chronic airflow limitation. The inflammatory process is widespread and not only involves the airways but also extends to the pulmonary vasculature and lung parenchyma. The inflammation of COPD is often referred to as neutrophilic in nature, but macrophages and CD8+ lymphocytes also play major roles.1820 The inflammatory cells release a variety of chemical mediators, of which TNF-α, interleukin 8 (IL-8), and leukotriene B4 (LTB4) play major roles.1,21 The actions of these cells and mediators are complementary and redundant, leading to the widespread destructive changes. The stimulus for activation of inflammatory cells and mediators is an exposure to noxious particles and gas through inhalation. The most common etiologic factor is exposure to environmental tobacco smoke, although other chronic inhalational exposures can lead to similar inflammatory changes.

Other processes that have been proposed to play a major role in the pathogenesis of COPD include oxidative stress and an imbalance between aggressive and protective defense systems in the lungs (proteases and antiproteases).18These processes may be the result of ongoing inflammation or occur as a result of environmental pressures and exposures (Fig. 16-2).

Images

FIGURE 16-2 Pathogenesis of COPD.

An altered interaction between oxidants and antioxidants present in the airways is responsible for the increased oxidative stress present in COPD. Increases in markers (e.g., hydrogen peroxide and nitric oxide) of oxidants are seen in the epithelial lining fluid.1 The increased oxidants generated by cigarette smoke react with and damage various proteins and lipids, leading to cell and tissue damage. Oxidants also promote inflammation directly and exacerbate the protease–antiprotease imbalance by inhibiting antiprotease activity.

The consequences of an imbalance between proteases and antiproteases in the lungs were described over 40 years ago when the hereditary deficiency of the protective antiprotease AAT was discovered to result in an increased risk of developing emphysema prematurely. This enzyme (AAT) is responsible for inhibiting several protease enzymes, including neutrophil elastase. In the presence of unopposed activity, elastase attacks elastin, a major component of alveolar walls.1

In the inherited form of emphysema, there is an absolute deficiency of AAT. In cigarette smoking–associated emphysema, the imbalance is likely associated with increased protease activity or reduced activity of antiproteases. Activated inflammatory cells release several proteases other than AAT, including cathepsins and metalloproteinases (MMPs). In addition, oxidative stress reduces antiprotease (or protective) activity.

It is helpful to differentiate inflammation occurring in COPD from that present in asthma because the response to antiinflammatory therapy differs. The inflammatory cells that predominate differ between the two conditions, with neutrophils playing a major role in COPD and eosinophils and mast cells in asthma. Mediators of inflammation also differ leukotriene B4 (LTB4), interleukin 8 (IL-8), and tumor necrosis factor alpha (TNF-α) predominating in COPD, compared with leukotriene D4 (LTD4), interleukin 4 (IL-4), and interleukin 5 (IL-5) among the numerous mediators modulating inflammation in asthma.1Characteristics of inflammation for the two diseases are summarized in Table 16-2.

TABLE 16-2 Features of Inflammation in COPD Compared with Asthma

Images

Pathologic changes of COPD are widespread, affecting large and small airways, lung parenchyma, and the pulmonary vasculature.1 An inflammatory exudate is often present that leads to an increase in the number and size of goblet cells and mucus glands. Mucus secretion is increased, and ciliary motility is impaired. There is also a thickening of smooth muscle and connective tissue in the airways. Inflammation is present in central and peripheral airways. The chronic inflammation results in a repeated injury and repair process that leads to scarring and fibrosis. Diffuse airway narrowing is present and is more prominent in smaller peripheral airways. The decrease in FEV1 is attributed to the presence of inflammation in the airways, while the blood gas abnormalities result from impaired gas transfer due to parenchymal damage.

Parenchymal changes affect the gas-exchanging units of the lungs, including the alveoli and pulmonary capillaries. The distribution of destructive changes varies depending on the etiology. Most commonly, smoking-related disease results in centrilobular emphysema that primarily affects respiratory bronchioles. Panlobular emphysema is seen in AAT deficiency and extends to the alveolar ducts and sacs.

The vascular changes of COPD include a thickening of pulmonary vessels and often are present early in the disease. Increased pulmonary pressures early in the disease are due to hypoxic vasoconstriction of pulmonary arteries. If persistent, the presence of chronic inflammation may lead to endothelial dysfunction of the pulmonary arteries. Later, structural changes lead to an increase in pulmonary pressures, especially during exercise. In severe COPD, secondary pulmonary hypertension leads to the development of right-sided heart failure.

Mucus hypersecretion is present early in the course of the disease and is associated with an increased number and size of mucus-producing cells. The presence of chronic inflammation perpetuates the process, although the resulting airflow obstruction and chronic airflow limitation may be reversible or irreversible. The various causes of airflow obstruction are summarized in Table 16-3.

TABLE 16-3 Etiology of Airflow Limitation in COPD

Images

Thoracic overinflation is a relevant feature in the pathophysiology of COPD, because it is a central factor in causing dyspnea. Chronic airflow obstruction leads to air trapping, resulting in thoracic hyperinflation that can be detected on chest radiograph. This problem results in several dynamic changes in the chest, including flattening of diaphragmatic muscles. Under normal circumstances, the diaphragms are dome-shaped muscles tethered at the base of the lungs. When the diaphragm contracts, the muscle becomes shorter and flatter, which creates the negative inspiratory force through which air flows into the lung during inspiration. In the presence of thoracic hyperinflation, the diaphragmatic muscle is placed at a disadvantage and is a less efficient muscle of ventilation. The increased work required by diaphragmatic contractions predisposes the patient to muscle fatigue, especially during periods of exacerbations.

The other consequence of thoracic hyperinflation is a change in lung volumes. For patients with COPD who exhibit thoracic hyperinflation, there is an increase in the functional residual capacity (FRC), which is the amount of air left in the lung after exhalation at rest. Therefore, these patients are breathing at higher lung volumes, which perturbs gas exchange. In addition, the increased FRC limits the inspiratory reserve capacity, which is the amount of air that the patient can inhale to fill the lungs. The increased FRC also limits the duration of inhalation time, and this has been associated with an increase in dyspnea complaints by patients.22 Drug therapy for COPD, especially bronchodilators, can reduce thoracic hyperinflation by reducing airflow obstruction. This may partially explain the improvement in symptoms reported by patients with COPD despite minimal improvements in lung function with drug therapy.

Airflow limitation is assessed through spirometry, which represents the “gold standard” for diagnosing and monitoring COPD. The hallmark of COPD is a reduction in the ratio of FEV1 to forced vital capacity (FVC) to less than 70%.1,3 The FEV1 generally is reduced, except in very mild disease, and the rate of FEV1 decline is greater in COPD patients compared with that in normal subjects.

The impact of the numerous pathologic changes in the lung perturbs the normal gas-exchange and protective functions of the lung. Ultimately, these are exhibited through the common symptoms of COPD, including dyspnea and a chronic cough productive of sputum. As the disease progresses, abnormalities in gas exchange lead to hypoxemia and/or hypercapnia, although there often is not a strong relationship between pulmonary function and arterial blood gas (ABG) results.

Significant changes in ABGs usually are not present until the FEV1 is less than 1 L.1 In these patients, hypoxemia and hypercapnia can become chronic problems. Initially, when hypoxemia is present, it usually is associated with exercise. However, as the disease progresses, hypoxemia at rest develops. Patients with severe COPD can have a low arterial oxygen tension (pressure exerted by oxygen gas in arterial blood [PaO2] = 45 to 60 mm Hg) and an elevated arterial carbon dioxide tension (pressure exerted by carbon dioxide gas in arterial blood [PaCO2] = 50 to 60 mm Hg). The hypoxemia is attributed to hypoventilation Images of lung tissue relative to perfusion Images of the area. This low Images ratio will progress over a period of several years, resulting in a consistent decline in the PaO2. Some COPD patients lose the ability to increase the rate or depth of respiration in response to persistent hypoxemia. Although this is not completely understood, the decreased ventilatory drive may be due to abnormal peripheral or central respiratory receptor responses. This relative hypoventilation subsequently leads to hypercapnia. In this case, the central respiratory response to a chronically increased PaCO2 can be blunted. These changes in PaO2 and PaCO2 are subtle and progress over a period of many years. As a result, the pH usually is nearly normal because the kidneys compensate by retaining bicarbonate. If acute respiratory distress develops, such as might be seen in pneumonia or a COPD exacerbation with impending respiratory failure, the PaCO2 may rise sharply, and the patient presents with an uncompensated respiratory acidosis.

The consequences of long-standing COPD and chronic hypoxemia include the development of secondary pulmonary hypertension that progresses slowly if appropriate treatment of COPD is not initiated. Pulmonary hypertension is the most common cardiovascular complication of COPD and can result in cor pulmonale, or right-sided heart failure.23

The elevated pulmonary artery pressures are attributed to vasoconstriction (in response to chronic hypoxemia), vascular remodeling, and loss of pulmonary capillary beds. If elevated pulmonary pressures are sustained, cor pulmonale can develop, characterized by hypertrophy of the right ventricle in response to increases in pulmonary vascular resistance.

The risks of cor pulmonale include venous stasis with the potential for thrombosis and pulmonary embolism. Another important systemic consequence of COPD is a loss of skeletal muscle mass and general decline in the overall health status.

While airway inflammation is prominent for patients with COPD, there is also evidence of systemic inflammation.24 A consequence is widespread skeletal muscle dysfunction, especially in the leg muscles involved with ambulation.25 The systemic manifestations can have devastating effects on overall health status and comorbidities. These include cardiovascular events associated with ischemia, cachexia, osteoporosis, anemia, and muscle wasting. There is some interest in the role of measuring C-reactive protein as a parameter to assess systemic inflammation and its impact on COPD severity; however, it is premature to recommend this strategy currently.26

PATHOPHYSIOLOGY OF EXACERBATION

The natural history of COPD is characterized by recurrent exacerbations associated with increased symptoms and a decline in overall health status. An exacerbation is defined as a change in the patient’s baseline symptoms (dyspnea, cough, or sputum production) beyond day-to-day variability sufficient to warrant a change in management.1,3 Exacerbations have a significant impact on the natural course of COPD and occur more frequently for patients with more severe chronic disease. Because many patients experience chronic symptoms, the diagnosis of an exacerbation is based, in part, on subjective measures and clinical judgment. Repeated exacerbations, especially those requiring hospitalization, are associated with an increased mortality risk.

There are limited data about pathology during exacerbations owing to the nature of the disease and the condition of patients. However, inflammatory mediators including neutrophils and eosinophils are increased in the sputum. Chronic airflow limitation is a feature of COPD and may not change remarkably even during an exacerbation.1 The lung hyperinflation present in chronic COPD is worsened during an exacerbation, which contributes to worsening dyspnea and poor gas exchange.

The primary physiologic change is often a worsening of ABG results due to poor gas exchange and increased muscle fatigue. For a patient experiencing a severe exacerbation, profound hypoxemia and hypercapnia can be accompanied by respiratory acidosis and respiratory failure.


CLINICAL PRESENTATION

Symptoms

    • Chronic cough

    • Sputum production

    • Dyspnea

Exposure to Risk Factors

    • Tobacco smoke

    • α1-Antitrypsin deficiency

    • Occupational hazards

Physical Examination

    • Cyanosis of mucosal membranes

    • Barrel chest

    • Increased resting respiratory rate

    • Shallow breathing

    • Pursed lips during expiration

    • Use of accessory respiratory muscles

Diagnostic Tests

    • Spirometry with reversibility testing

    • Radiograph of chest

    • Arterial blood gas (not routine)

CLINICAL PRESENTATION

The diagnosis of COPD is made based on the patient’s symptoms, including cough, sputum production, and dyspnea, and a history of exposure to risk factors such as tobacco smoke and occupational exposures. Patients may have these symptoms for several years before dyspnea develops and often will not seek medical attention until dyspnea is significant. A diagnosis of COPD should be considered for any patient, age 40 years or older, with persistent or progressive dyspnea, with chronic cough productive of sputum, and who exhibits an unusual or abnormal decline in activity, especially in the presence of positive cigarette smoke exposure. In addition, the presence of genetic factors, including AAT deficiency, and occupational exposures should be evaluated because approximately 15% of patients with COPD do not have a history of cigarette smoking.

The presence of airflow limitation should be confirmed with spirometry. Spirometry represents a comprehensive assessment of lung volumes and capacities. The hallmark of COPD is an FEV1:FVC ratio of less than 70%, which indicates airway obstruction, and a postbronchodilator FEV1 of less than 80% of predicted confirms the presence of airflow limitation that is not fully reversible.1 There is an increased awareness that the use of a fixed ratio of less than 70% may be problematic because normal aging may affect this result; however, it continues to be the current standard. An improvement in FEV1 of less than 12% following inhalation of a rapid-acting bronchodilator is considered to be evidence of irreversible airflow obstruction. Reversibility of airflow limitation is measured by a bronchodilator challenge, which is described in Table 16-4. The use of peak expiratory flow measurements is not adequate for the diagnosis of COPD owing to low specificity and the high degree of effort dependence; however, a low peak expiratory flow is consistent with COPD. A comprehensive discussion about spirometry can be found in Chapter 15.

TABLE 16-4 Procedures for Reversibility Testing

Images

Spirometry combined with a physical examination improves the diagnostic accuracy of COPD.7 Spirometry also is useful to determine the severity of airflow limitation. Patients with all levels of severity of COPD exhibit the hallmark finding of airflow obstruction, that is, a reduction in the FEV1:FVC ratio to less than 70%. FVC is the total amount of air exhaled after a maximal inhalation. Currently, the GOLD consensus guidelines suggest a four-grade classification of airflow limitation (see Table 16-5). Patients in GOLD 3 or 4 have the most significant airflow limitation and are at the highest risk for future exacerbations, while patients in GOLD 1 and 2 have less airflow limitation and are at lower risk for exacerbations.

TABLE 16-5 Classification of Severity of Airflow Obstruction (Based on Postbronchodilator FEV1)

Images

Dyspnea is typically the most troublesome complaint for the patient with COPD and often is the stimulus for the patient seeking medical attention. It can impair exercise performance and functional capacity and is frequently associated with depression and anxiety. Together, these have a significant effect on health-related quality of life.22 As a subjective symptom, dyspnea is often difficult for the clinician to assess. Various tools are available to evaluate the severity of dyspnea. The modified Medical Research Council (mMRC) scale is commonly employed and categorizes dyspnea grades from 0 to 4 (see Table 16-6).27 The effect of COPD on overall well-being can be assessed using the COPD Assessment Test (CAT), which includes eight statements about symptoms and activities. The patient scores each statement on a scale of 0 to 5 and the impact of COPD is assessed by the cumulative score (see Table 16-7).28

TABLE 16-6 Modified Medical Research Council (MRC) Dyspnea Scale

Images

TABLE 16-7 Staging Acute Exacerbations of COPDa

Images

Previously, guidelines have defined disease severity solely by spirometry. Observations that patients with similar spirometric parameters exhibit variations in symptom severity and risk of adverse health events, such as exacerbations, have led to a revision in severity classification. In order to incorporate multiple factors that contribute to disease risk, the revised GOLD consensus guidelines recommend that three separate parameters be assessed when classifying disease severity. Parameters include an assessment of airflow limitation by spirometry, measurement of symptom severity, and an assessment of exacerbation frequency. Symptom assessment should be measured using either CAT or mMRC. Frequency of exacerbations can be assessed either by predicted risk of future exacerbations based on classification of airflow limitation or through a review of exacerbation history for the past 12 months. Patients with at least two exacerbations in the last 12 months would be considered high risk for future exacerbations. If both methods of exacerbation risk are assessed, the method with the highest risk result should be used to classify the patient (see Fig. 16-3).

Images

FIGURE 16-3 Groups of COPD classification.

While a physical examination is appropriate in the diagnosis and assessment of COPD, most patients who present in the milder stages of COPD will have a normal physical examination. In later stages of the disease, when airflow limitation is severe, patients may have cyanosis of mucosal membranes, development of “barrel chest” due to hyperinflation of the lungs, an increased respiratory rate and shallow breathing, and changes in breathing mechanics such as pursing of the lips to help with expiration or use of accessory respiratory muscles.

Classification Based on Severity

In 2011, the GOLD guidelines included a modified system for classifying COPD based on severity. As discussed above, the new system is based on numerous factors that have a significant impact on the patient, including the degree of airflow obstruction, the frequency and severity of symptoms, and the frequency of exacerbations (see Fig. 16-3). A patient can first be classified according to the severity of airflow obstruction into grades ranging from 1 to 4 (Table 16-5). Then the patient is placed into a group (A, B, C, or D) based on the impact of symptoms and the risk for future exacerbations. The extent of symptoms is assessed using a validated symptom assessment tool (e.g., the mMRC or the CAT). Finally, the risk for an exacerbation is based on previous exacerbations. A patient is categorized based on a history of less than two annual exacerbations, or two or more. This new classification system by group provides an appropriate emphasis for each of the parameters included (see Fig. 16-3). Another advantage is that classifying patients according to these groups informs treatment decisions.

Prognosis

For the patient with COPD, the combination of impaired lung function and recurrent exacerbations promotes a clinical scenario characterized by dyspnea, reduced exercise tolerance and physical activity, and deconditioning. These factors lead to disease progression, poor quality of life, possible disability, and premature mortality.29 COPD is ultimately a fatal disease if it progresses and advanced directives and end-of-life care options are appropriate to consider. The primary causes of death of patients with COPD include respiratory failure, cardiovascular events or diseases, and lung cancer.30

The FEV1 is the most important prognostic indicator for a patient with COPD. The average rate of decline of FEV1 is the most useful objective measure to assess the course of COPD. The average rate of decline in FEV1 for healthy, nonsmoking patients owing to age alone is 25 to 30 mL/y. The rate of decline for smokers is steeper, especially for heavy smokers compared with light smokers. The decline in pulmonary function is a steady curvilinear path. The more severely diminished the FEV1 at diagnosis, the steeper is the rate of decline. Greater numbers of years of smoking and number of cigarettes smoked also correlate with a steeper decline in pulmonary function.27 Conversely, the rate of decline of blood gases has not been shown to be a useful parameter to assess progression of the disease. Patients with COPD should have spirometry performed at least annually to assess disease progression.31

The survival rate of patients with COPD is highly correlated to the initial level of impairment in the FEV1 and age. Other less important factors include degree of reversibility with bronchodilators, resting pulse, perceived physical disability, diffusing capacity for carbon monoxide (DLCO), cor pulmonale, and blood gas abnormalities. A rapid decline in pulmonary function tests indicates a poor prognosis. Median survival is approximately 10 years when the FEV1 is 1.4 L, 4 years when the FEV1 is 1 L, and about 2 years when the FEV1 is 0.5 L.

While ABG measurements are important, they do not carry the prognostic value of pulmonary function tests. Measurement of ABGs is more useful for patients with severe disease and is recommended for all patients with an FEV1 of less than 40% of predicted or those with signs of respiratory failure or right-sided heart failure.1

Asthma is usually differentiated from COPD based on the patient’s medical history, risk factors, and improvements on postbronchodilator spirometry; however, in some cases, asthma patients exhibit COPD-like features and COPD patients exhibit asthma-like features. It is also possible for the two conditions to coexist.

CLINICAL PRESENTATION OF COPD EXACERBATION

Because of the subjective nature of defining an exacerbation of COPD, the criteria used among clinicians vary widely; however, most rely on a change in one or more of the following clinical findings: worsening symptoms of dyspnea, increase in sputum volume, or increase in sputum purulence. Acute exacerbations have a significant impact of the economics of treating COPD as well, estimated at 35% to 45% of the total costs of the disease in some settings.32

A widely accepted definition of an exacerbation is that it is an event in the natural course of COPD that is characterized by a worsening in baseline dyspnea, cough, and/or sputum that is beyond the normal day-to-day variation, is acute in onset, and may warrant a change in regular medication. With an exacerbation, patients using rapid-acting bronchodilators may report an increase in the frequency of use. Exacerbations are commonly staged as mild, moderate, or severe according to the criteria summarized in Table 16-7.33

An important complication of a severe exacerbation is acute respiratory failure. In the emergency department or hospital, an ABG usually is obtained to assess the severity of an exacerbation. The diagnosis of acute respiratory failure in COPD is made based on an acute change in the ABGs. Defining acute respiratory failure as a PaO2 of less than 50 mm Hg or a PaCO2 of greater than 50 mm Hg often may be incorrect and inadequate because these values may not represent a significant change from a patient’s baseline values. A more precise definition is an acute drop in PaO2 of 10 to 15 mm Hg or any acute increase in PacO2 that decreases the serum pH to 7.3 or less. Additional acute clinical manifestations of respiratory failure include restlessness, confusion, tachycardia, diaphoresis, cyanosis, hypotension, irregular breathing, miosis, and unconsciousness.

Prognosis

COPD exacerbations are associated with significant morbidity and mortality. While mild exacerbations may be managed at home, mortality rates are higher for patients admitted to the hospital. In one study of patients hospitalized with COPD exacerbations, in-hospital mortality was 6% to 8%.34 Many patients experiencing an exacerbation do not have a return to their baseline clinical status for several weeks, significantly affecting their quality of life. Additionally, as many as half the patients originally hospitalized for an exacerbation are readmitted within 6 months.35

There is good evidence that acute exacerbations of COPD have a tremendous impact on disease progression and ultimate mortality. For exacerbations requiring hospitalizations, mortality rates range from 22% to 43% after 1 year, and 36% to 49% in 2 years.34,36,37

TREATMENT

Chronic Obstructive Pulmonary Disease

Desired Outcome

Given the nature of COPD, a major focus in healthcare should be on prevention. However, for patients with a diagnosis of COPD, the primary goal is to prevent or minimize progression. Specific goals of management are listed in Table 16-8. The primary goal of pharmacotherapy has been relief of symptoms, including dyspnea. However, more recently there has been increased interest in the value of therapeutic interventions that reduce exacerbation frequency and severity, as well as reduce mortality. In fact, a reduction in exacerbation frequency is an important outcome measure to consider when evaluating the role and benefit of individual chronic therapies used in COPD management.

TABLE 16-8 Goals of COPD Management

Images

Optimally, these goals can be accomplished with minimal risks or side effects. The therapy of the patient with COPD is multifaceted and includes pharmacologic and nonpharmacologic strategies. Appropriate measures of effectiveness of the management plan include continued smoking cessation, symptom improvement, reduction in FEV1 decline, reduction in the number of exacerbations, improvements in physical and psychological well-being, and reduction in mortality, hospitalizations, and days lost from work.


CLINICAL PRESENTATION Features of COPD Exacerbation

Symptoms

    • Increased sputum volume

    • Acutely worsening dyspnea

    • Chest tightness

    • Presence of purulent sputum

    • Increased need for bronchodilators

    • Malaise, fatigue

    • Decreased exercise tolerance

Physical Examination

    • Fever

    • Wheezing, decreased breath sounds

Diagnostic Tests

    • Sputum sample for Gram stain and culture

    • Chest radiograph to evaluate for new infiltrates

Unfortunately, most treatments for COPD have not been shown to improve survival or to slow the progressive decline in lung function. However, many therapies do improve pulmonary function and quality of life and reduce exacerbations and duration of hospitalization. Several disease-specific quality-of-life measures are available to assess the overall efficacies of therapies for COPD, including the CAT, Chronic Respiratory Questionnaire (CRQ), and the St. George’s Respiratory Questionnaire (SGRQ). These questionnaires measure the impact of various therapies on such disease variables as severity of dyspnea and level of activity. They do not measure impact of therapies on survival. While early studies of COPD therapies focused primarily on improvements in pulmonary function measurements such as FEV1, there is a trend toward greater use of these disease-specific quality-of-life measures to evaluate the benefits of therapy on larger clinical outcomes.

General Approach to Treatment

To be effective, the clinician should address four primary components of management: assess and monitor the condition, avoid or reduce exposure to risk factors, manage stable disease, and treat exacerbations. These components are addressed through a variety of nonpharmacologic and pharmacologic approaches.

Nonpharmacologic Therapy

Patients with COPD should receive education about their disease, treatment plans, and strategies to slow progression and prevent complications.1 Advice and counseling about smoking cessation are essential, if applicable, and should be addressed for patients in all stages of the disease. Because the natural course of the disease leads to respiratory failure, the clinician should address end-of-life decisions and advanced directives prospectively with the patient and family.38

Smoking Cessation

Images Smoking cessation represents the single most important intervention in preventing the development, as well as the progression, of COPD. A primary component of COPD management is avoidance of or reduced exposure to risk factors. Exposure to environmental tobacco smoke is a major risk factor, and smoking cessation is the most effective strategy to reduce the risk of developing COPD and to slow or stop disease progression. The cost-effectiveness of smoking-cessation interventions compares favorably with interventions made for other major chronic diseases.39 The importance of smoking cessation cannot be overemphasized. Smoking cessation leads to decreased symptomatology and slows the rate of decline of pulmonary function even after significant abnormalities in pulmonary function tests have been detected (FEV1:FVC <60%).31 As confirmed by the Lung Health Study, smoking cessation is the only intervention proven at this time to affect long-term decline in FEV1 and slow the progression of COPD.40 In this 5-year prospective trial, smokers with early COPD were randomly assigned to one of the following three groups: smoking-cessation intervention plus inhaled ipratropium three times a day, smoking-cessation intervention alone, or no intervention. During an 11-year followup, the rate of decline in FEV1 among subjects who continued to smoke was more than twice the rate in sustained quitters. Smokers who underwent smoking-cessation intervention had fewer respiratory symptoms and a smaller annual decline in FEV1 compared with smokers who had no intervention. However, this study also demonstrated the difficulty in achieving and sustaining successful smoking cessation.

Tobacco cessation has mortality benefits beyond those related to COPD. A followup analysis of the Lung Health Study data conducted more than 14 years later demonstrated an 18% reduction in all-cause mortality in patients who received the intervention compared with usual care.41 Intervention patients had lower death rates due to coronary artery disease (the leading cause of mortality), cardiovascular diseases, and lung cancer, although all categories did not reach clinical significance.

Every clinician has a responsibility to assist smokers in smoking-cessation efforts. A clinical practice guideline for treating tobacco dependence from the U.S. Public Health Service (PHS) was updated in 2008.42 The major findings and recommendations of that report are summarized in Table 16-9. An earlier report from the Surgeon General in 2004 on the health consequences of smoking broadened the scope of the detrimental effects of cigarette smoking, indicating that “Smoking harms nearly every organ of the body, causing many diseases and reducing the health of smokers in general.”14

TABLE 16-9 Key Guideline Recommendations Regarding Tobacco Use and Dependence42

Images

All clinicians should take an active role in assisting patients with tobacco dependence in order to reduce the burden on the individual, his or her family, and the healthcare system. It is estimated that over 75% of smokers want to quit and that one-third have made a serious effort. Yet complete and permanent tobacco cessation is difficult.40 Counseling that is provided by clinicians is associated with greater success rates than self-initiated efforts.42

The PHS guidelines recommend that clinicians take a comprehensive approach to smoking-cessation counseling. Advice should be given to smokers even if they have no symptoms of smoking-related disease or if they are receiving care for reasons unrelated to smoking. Clinicians should be persistent in their efforts because relapse is common among smokers owing to the chronic nature of dependence. Brief interventions (3 minutes) of counseling are proven effective. However, it must be recognized that the patient must be ready to stop smoking because there are several stages of decision making. Based on this, a five-step intervention program is proposed (Table 16-10).

TABLE 16-10 Five-Step Strategy for Smoking-Cessation Program (5 A’s)

Images

There is strong evidence to support the use of pharmacotherapy to assist in smoking cessation. In fact, it should be offered to most patients as part of a cessation attempt. In general, available therapies will double the effectiveness of a cessation effort. Agents that are considered first line are listed in Table 16-11. The usual duration of therapy is 8 to 12 weeks, although some individuals may require longer courses of treatment. Precautions to consider before using bupropion include a history of seizures or an eating disorder. Nicotine replacement therapies are contraindicated for patients with unstable coronary artery disease, active peptic ulcers, or recent myocardial infarction or stroke. Nicotine patch, bupropion, and the combination of bupropion and the nicotine patch were compared with placebo in a controlled trial.43 The treatment groups that received bupropion had higher rates of smoking cessation than the groups that received placebo or the nicotine patch. The addition of the nicotine patch to bupropion slightly improved the smoking-cessation rate compared with bupropion monotherapy. Recently, a new agent became available to assist in tobacco cessation attempts. Varenicline is a nicotine acetylcholine receptor partial agonist that has shown benefit in tobacco cessation.44 It relieves physical withdrawal symptoms and reduces the rewarding properties of nicotine. Nausea and headache are the most frequent complaints associated with varenicline. Currently, varenicline has not been studied in combination with other tobacco cessation therapies. Second-line agents are less effective or associated with greater side effects; however, they may be useful in selected clinical situations. These therapies include clonidine and nortriptyline, a tricyclic antidepressant.

TABLE 16-11 First-Line Pharmacotherapies for Smoking Cessation

Images

Behavioral modification techniques or other forms of psychotherapy also may be helpful in assisting in smoking cessation. Programs that address the many issues associated with smoking (i.e., learned behaviors, environmental influences, and chemical dependence) using a team approach are more likely to be successful. The role of alternative medicine therapies in smoking cessation is controversial. Hypnosis may aid in improving abstinence rates when added to a smoking-cessation program but appears to give little benefit when used alone. Acupuncture has not been shown to contribute to smoking cessation and is not recommended.3

Other Environmental Triggers

Although cigarette smoke represents the overwhelming majority of risk for developing COPD, exposure to other environmental toxins also confers risks.45,46 Exposures to occupational dusts and fumes have been implicated as a cause of COPD in 19% of smokers and 31% of nonsmokers with COPD in the United States. In the case of known environmental hazards, primary prevention is appropriate. Policies to limit airborne exposures in the workplace and outdoors, as well as education efforts of workers and policy makers, are recommended.

Pulmonary Rehabilitation

Exercise training is beneficial in the treatment of COPD to improve exercise tolerance and to reduce symptoms of dyspnea and fatigue.1 Pulmonary rehabilitation programs are an integral component in the management of COPD and should include exercise training along with smoking cessation, breathing exercises, optimal medical treatment, psychosocial support, and health education. Pulmonary rehabilitation has no direct effect on lung function or gas exchange. Instead, it optimizes other body systems so that the impact of poor lung function is minimized. Exercise training reduces the CNS response to dyspnea, ameliorates anxiety and depression, reduces thoracic hyperinflation, and improves skeletal muscle function.25 High-intensity training (70% maximal workload) is possible even in advanced COPD patients, and the level of intensity improves peripheral muscle and ventilatory function. Studies have demonstrated that pulmonary rehabilitation with exercise three to seven times per week can produce long-term improvement in activities of daily living, quality of life, exercise tolerance, and dyspnea for patients with moderate-to-severe COPD.47 Improvements in dyspnea can be achieved without concomitant improvements in spirometry. While rehabilitation programs vary based on length of program, and exercise frequency and intensity, those with longer length and more frequent sessions have demonstrated the best clinical benefit.

Immunizations

Vaccines can be considered as pharmacologic agents; however, their role is described here in reducing risk factors for COPD exacerbations. Because influenza is a common complication in COPD that can lead to exacerbations and respiratory failure, an annual vaccination with the inactivated intramuscular influenza vaccine is recommended. Immunization against influenza can reduce serious illness and death by 50% in COPD patients.48 Influenza vaccine should be administered in the fall of each year (October and November) during regular medical visits or at vaccination clinics. There are few contraindications to influenza vaccine except for a patient with a serious allergy to eggs. An oral antiinfluenza agent (oseltamivir) can be considered for patients with COPD during an outbreak for patients who have not been immunized; however, this therapy is less effective and causes more side effects.49

The polyvalent pneumococcal vaccine, usually administered one time, is widely recommended for people from 2 to 64 years of age who have chronic lung disease and for all people older than 65 years. Thus, COPD patients at any age are candidates for vaccination. Although evidence for the benefit of the pneumococcal vaccine in COPD is not strong, the argument for continued use is that the current vaccine provides coverage for 85% of pneumococcal strains causing invasive disease and the increasing rate of resistance of pneumococcus to selected antibiotics. Currently, administering the vaccine remains the standard of practice and is recommended by the Centers for Disease Control and Prevention and the American Lung Association. Repeated vaccination with the 23-valent product is not recommended for patients aged 2 to 64 years with chronic lung disease; however, revaccination is recommended for patients over 65 years of age if the first vaccination was more than 5 years earlier and the patient was younger than age 65. The GOLD guidelines recommend pneumococcal vaccine for all COPD patients 65 years and older and for patients less than 65 years only if the FEV1 is less than 40% predicted.50,51 In 2009, the CDC broadened their recommendations for the pneumococcal polysaccharide vaccine to include all persons aged 18 and over who smoke based on a higher risk of pneumococcal infection in these patients.

Long-Term Oxygen Therapy

Images The use of supplemental oxygen therapy increases survival in COPD patients with chronic hypoxemia. Although long-term oxygen has been used for many years for patients with advanced COPD, it was not until 1980 that data became available documenting its benefits. At that time, the Nocturnal Oxygen Therapy Trial Group published its data comparing nocturnal oxygen therapy (NOT), 12 hours/day, with continuous oxygen therapy (COT), average of 20 hours/day.52 Among patients who were followed for at least 12 months, the results revealed a mortality rate in the NOT group that was nearly double that of the COT group (51% vs. 26%). Statistical estimates of the COT group suggest that COT may have added 3.25 years to a COPD patient’s life. Additional data from the Nocturnal Oxygen Therapy Trial Group revealed that COT patients had fewer (but statistically insignificant) hospitalizations, improved quality of life and neuropsychological function, reduced hematocrit, and decreased pulmonary vascular resistance.52

The decline in mortality with oxygen therapy was further substantiated in 1981 in a study by the British Medical Research Council that compared 15 hours/day of oxygen versus no supplemental oxygen in COPD patients.53Patients receiving oxygen therapy for at least part of the day had lower rates of mortality than those not receiving oxygen. Long-term oxygen therapy provides even more benefit in terms of survival after at least 5 years of use, and it improves the quality of life of these patients by increasing walking distance and neuropsychological condition and reducing time spent in the hospital.54 Before patients are considered for long-term oxygen therapy, they should be stabilized in the outpatient setting, and pharmacotherapy should be optimized. Once this is accomplished, long-term oxygen therapy should be instituted if either of the following two conditions is observed and documented twice in a 3-week period:

   1. A resting PaO2 of less than 55 mm Hg or SaO2 less than 88% with or without hypercapnia

   2. A resting PaO2 between 55 and 60 mm Hg or SaO2 less than 88% with evidence of right-sided heart failure, polycythemia, or pulmonary hypertension

The most practical means of administering long-term oxygen is with the nasal cannula, at 1 to 2 L/min, which provides 24% to 28% oxygen. The goal is to raise the PaO2 above 60 mm Hg. Patient education about flow rates and avoidance of flames (i.e., smoking) is of the utmost importance.

There are three different ways to deliver oxygen, including (a) in liquid reservoirs, (b) compressed into a cylinder, and (c) via an oxygen concentrator. Although conventional liquid oxygen and compressed oxygen are quite bulky, smaller, portable tanks are available to permit greater patient mobility. Oxygen concentrator devices separate nitrogen from room air and concentrate oxygen. These are the most convenient and the least expensive method of oxygen delivery. Oxygen-conservation devices are available that allow oxygen to flow only during inspiration, making the supply last longer. These may be particularly useful to prolong the oxygen supply for mobile patients using portable cylinders. However, the devices are bulky and subject to failure.

Adjunctive Therapies

In addition to supplemental oxygen, adjunctive therapies to consider as part of a pulmonary rehabilitation program are psychoeducational care and nutritional support. Psychoeducational care (such as relaxation) has been associated with improvement in the functioning and well-being of adults with COPD.1,3 The role of nutritional support for patients with COPD is controversial. Several studies have shown an association among malnutrition, low body mass index (BMI), and impaired pulmonary status among patients with COPD. However, a meta-analysis suggests that the effect of nutritional support on outcomes in COPD is small and not associated with improved anthropometric measures, lung function, or functional exercise capacity.55

Pharmacologic Therapy

Results from numerous recent clinical trials have improved insight and understanding about the respective roles of various medications used in chronic COPD management; yet, some controversies still exist related to both effectiveness and safety. In contrast to the survival benefit conferred by supplemental oxygen therapy, there is no medication available for the treatment of COPD that has been conclusively shown to modify the progressive decline in lung function or prolong survival.1 There is limited evidence that chronic treatment with long-acting inhaled β-agonists, inhaled corticosteroids (ICs), or the combination can reduce the rate of decline in spirometry in a subset of patients with more severe disease.56 Currently, the primary goal of pharmacotherapy is to control patient symptoms and reduce complications, including the frequency and severity of exacerbations and improving the overall health status and exercise tolerance of the patient.

International guidelines recommend a stepwise approach to the use of pharmacotherapy based on disease severity,1,3 which is determined by the results of spirometry, nature of symptoms, and exacerbation rates. The impact of recurrent exacerbations on accelerating disease progression is increasingly recognized as an important factor to be considered. The primary goals of pharmacotherapy are to control symptoms (including dyspnea), reduce exacerbations, and improve exercise tolerance and health status. Currently, there is inadequate evidence to support the use of more aggressive pharmacotherapy early in the course of disease because of the lack of a disease-modifying benefit. Because of the progressive nature of COPD, pharmacotherapy tends to be chronic and cumulative and step-down approaches in stable patients are not successful. Patients exhibit variable responses to available therapies and the treatment approach should be individualized.

Pharmacotherapy of COPD typically involves the use of inhaled medications, requiring patient knowledge, understanding, and skills using the various inhalation devices. Several delivery devices are available (e.g., metered-dose inhalers [MDIs], dry powder inhalers [DPIs], nebulizers, and ancillary devices such as holding chambers), and the instructions about proper use vary. Comorbidities that are common for patients with COPD, including physical and mental conditions, can have a significant effect on the patient’s ability to use the devices. Periodic and frequent reinforcement and observation by the clinician is required for the patient’s benefit.

Images Pharmacotherapy focuses on the use of bronchodilators to control symptoms. Bronchodilators relax bronchial smooth muscle, improve lung emptying, reduce thoracic hyperinflation at rest and during exercise, and improve exercise tolerance.1 These effects can be seen in the absence of objective improvements on spirometry. There are several classes of bronchodilators to choose from, and no single class has been proven to provide superior benefit over other available agents. The initial and subsequent choice of medications should be based on the specific clinical situation and patient characteristics. Medications can be used as needed or on a scheduled basis depending on the clinical situation, and additional therapies should be added in a stepwise manner depending on the response and severity of disease. Considerations should be given to individual patient response, tolerabilility, adherence, and economic factors. Recommendations for management of COPD have been proposed based on a combined assessment of airflow limitation, symptoms, and risk of exacerbations, according to the new classification system for disease severity (Fig. 16-4). This schema provides clearer guidance on management compared with previous recommendations, and also allows for the individualization of pharmacotherapy based on patient-specific factors of lung function, symptom frequency and severity, and exacerbation risk.

Images

FIGURE 16-4 Pharmacotherapy recommendations based on group classification.

According to the guidelines, patients with intermittent symptoms and low risk for exacerbations (Group A) should be treated with short-acting bronchodilators as needed. When symptoms become more persistent (Group B), long-acting bronchodilators should be initiated. For patients at high risk for exacerbations (Groups C and D), ICs should be considered. Short-acting bronchodilators relieve symptoms and increase exercise tolerance. Long-acting bronchodilators relieve symptoms, reduce exacerbation frequency, and improve quality of life and health status. Patients have a variety of choices in using inhalational therapies, including MDIs, DPIs, or nebulizers. There is no clear advantage of one delivery method over another, and it is recommended that patient-specific factors and preferences should be considered in selecting the device.57

The benefit of individual therapies in reducing the severity and frequency of exacerbations has been a major focus for the past several years. Each of the agents typically used in the long-term treatment of COPD has been shown to reduce exacerbation frequency, and each does so to a similar degree. In a meta-analysis that included many clinical trials, it was reported that exacerbations were reduced by long-acting inhaled β2-agonists (LABAs) (23%), tiotropium (29%), ICs (22%), and ICs plus LABAs (28%).58 There were no significant differences between the agents. These exacerbation reduction rates are consistent with those seen in the large clinical trials for tiotropium (Understanding Potential Long-term Impacts on Function with Tiotropium [UPLIFT] and Towards a Revolution in COPD Health [TORCH] [ICs plus LABAs]).

Bronchodilators

Bronchodilator classes available for the treatment of COPD include β2-agonists, anticholinergics, and methylxanthines. There is no clear benefit to one agent or class over others, although inhaled therapy generally is preferred. In general, it can be more difficult for patients with COPD to use inhalation devices effectively compared with other populations owing to advanced age and the presence of other comorbidities. Clinicians should advise, counsel, and observe patient technique with the devices frequently and consistently.

Bronchodilators generally work by reducing the tone of airway smooth muscle (relaxation), thus minimizing airflow limitation. For patients with COPD, the clinical benefits of bronchodilators include increased exercise capacity, decreased air trapping in the lungs, and relief of symptoms such as dyspnea. However, use of bronchodilators may not be associated with significant improvements in pulmonary function measurements such as FEV1. In clinical studies, regular use of a long-acting inhaled bronchodilator (LABA or anticholinergic) or ipratropium is associated with improved health status. Regular use of tiotropium also reduces exacerbation rates. In general, side effects of bronchodilator medications are related to their pharmacologic effects and are dose dependent. Because COPD patients are older and more likely to have comorbid conditions, the risk for side effects and drug interactions is higher compared with patients with asthma.

Short-Acting Bronchodilators The initial therapy for COPD patients who experience symptoms intermittently is short-acting bronchodilators. Among these agents, the choices are a short-acting β2-agonist or an anticholinergic. Either class of agents has a relatively rapid onset of action, relieves symptoms, and improves exercise tolerance and lung function. In general, both classes are equally effective.

Short-Acting Sympathomimetics (β2-Agonists) A number of sympathomimetic agents are available in the United States. They vary in selectivity, route of administration, and duration of action. In COPD management, sympathomimetic agents with β2-selectivity, or β2-agonists, should be used as bronchodilators. β2-Agonists cause bronchodilation by stimulating the enzyme adenyl cyclase to increase the formation of cyclic adenosine monophosphate (cAMP). cAMP is responsible for mediating relaxation of bronchial smooth muscle, leading to bronchodilation. In addition, β2-agonists may improve mucociliary clearance. Although shorter-acting and less selective β-agonists are still used widely (e.g., metaproterenol, isoetharine, isoproterenol, and epinephrine), they should not be used owing to their shorter duration of action and increased cardiostimulatory effects. Short-acting, selective β2-agonists such as albuterol, levalbuterol, and pirbuterol are preferred for therapy.

Sympathomimetics are available in inhaled, oral, and parenteral dosage forms. The preferred route of administration is by inhalation. The use of oral and parenteral β-agonists in COPD is discouraged because they are no more effective than a properly used MDI or DPI, and the incidence of systemic adverse effects such as tachycardia and hand tremor is greater. Administration of β2-agonists in the outpatient and emergency room settings via inhalers (MDIs or DPIs) is at least as effective as nebulization therapy and usually favored for reasons of cost and convenience.57 Chapter 15 includes a complete description of the devices used for delivering aerosolized medication and a comparison of β2-agonist therapies.

Albuterol is the most frequently used β2-agonist. It is available as an oral and inhaled preparation. Albuterol is a racemic mixture of (R)-albuterol, which is responsible for the bronchodilator effect, and (S)-albuterol, which has no therapeutic effect. (S)-Albuterol is considered by some clinicians to be inert, whereas others believe that it may be implicated in worsening airway inflammation and antagonizing the response to (R)-albuterol. Levalbuterol is a single-isomer formulation of (R)-albuterol. A retrospective evaluation of levalbuterol versus albuterol use for patients with asthma and COPD concluded that levalbuterol offered significant advantages over albuterol for hospitalized patients.59 Other clinicians feel that there are no significant differences between the products and that the use of levalbuterol is not justified owing to its higher acquisition cost.60 The effects of a single dose of levalbuterol have been compared with those of albuterol and ipratropium plus albuterol for patients with COPD. No significant differences in pulmonary function improvements or adverse effects were noted.61

In COPD patients, β2-agonists exert a rapid onset of effect, although the response generally is less than that seen in asthma. Short-acting inhaled β2-agonists cause only a small improvement in FEV1 acutely but may improve respiratory symptoms and exercise tolerance despite the small improvement in spirometric measurements.62 Patients with COPD can use quick-onset β2-agonists as needed for relief of symptoms or on a scheduled basis to prevent or reduce symptoms. The duration of action of short-acting β2-agonists is 4 to 6 hours.

Inhaled β2-agonists are generally well tolerated. They can cause sinus tachycardia and rhythm disturbances in predisposed patients, but these are rarely reported. Skeletal muscle tremors can occur initially but subside as tolerance develops.

Short-Acting Anticholinergics When given by inhalation, anticholinergics such as ipratropium or atropine produce bronchodilation by competitively inhibiting cholinergic receptors in bronchial smooth muscle. This activity blocks acetylcholine, with the net effect being a reduction in cyclic guanosine monophosphate (cGMP), which normally acts to constrict bronchial smooth muscle. Muscarinic receptors on airway smooth muscle include M1, M2, and M3subtypes. Activation of M1 and M3 receptors by acetylcholine results in bronchoconstriction; however, activation of M2 receptors inhibits further acetylcholine release.

Ipratropium is the primary short-acting anticholinergic agent used for COPD in the United States. Atropine has a tertiary structure and is absorbed readily across the oral and respiratory mucosa, whereas ipratropium has a quaternary structure that is absorbed poorly. The lack of systemic absorption of ipratropium greatly diminishes the anticholinergic side effects such as blurred vision, urinary retention, nausea, and tachycardia associated with atropine. Ipratropium bromide is available as an MDI and a solution for inhalation. The MDI was recently reformulated with an HFA propellant and delivers 17 mcg per puff. Ipratropium is also available as an MDI in combination with albuterol and as a solution for nebulization at 200 mcg/mL. It provides a peak effect in 1.5 to 2 hours and has a duration of effect of 4 to 6 hours. Ipratropium has a slower onset of action and a more prolonged bronchodilator effect compared with standard β2-agonists. Because of the slower onset of effect (15 to 20 minutes compared with 5 minutes for albuterol), it may be less suitable for as-needed use; however, it is often prescribed in that manner. The role of inhaled anticholinergics in COPD is well established.6365 However, results from the Lung Health Study showed that treatment with ipratropium did not affect the progressive decline in lung function.40 Studies comparing ipratropium with inhaled β2-agonists have generally reported similar improvements in pulmonary function. Others report a modest benefit with ipratropium, including a lower incidence of side effects such as tachycardia.63,64

Although the recommended dose of ipratropium is 2 puffs four times a day, there is evidence for a dose–response, so the dose can be titrated upward often to 24 puffs a day. Ipratropium has been shown to increase maximum exercise performance in stable COPD patients with doses of 8 to 12 puffs prior to exercise but not with doses of 4 puffs or less.65,66 During sleep, ipratropium also has been shown to improve arterial oxygen saturation and sleep quality.67 Ipratropium is well tolerated. The most frequent patient complaints are dry mouth, nausea, and an occasional metallic taste.

Clinicians differ about preference in choosing the initial short-acting bronchodilator therapy for the patient with COPD. Both a short-acting β2-agonist and ipratropium represent reasonable choices for initial therapy.

Images Long-Acting Bronchodilators For patients with moderate-to-severe COPD who experience symptoms on a regular and consistent basis, or in whom short-acting therapies do not provide adequate relief, long-acting bronchodilator therapies are the recommended treatment. Long-acting inhaled bronchodilator therapy can be administered as an inhaled β2-agonist (LABA) or an anticholinergic. Long-acting, inhaled bronchodilator therapy is more convenient and effective, compared with short-acting agents, for patients with chronic symptoms. There are superior outcomes in lung function as measured by spirometry, symptoms including dyspnea, and, importantly, reductions in exacerbation frequency and improved quality of life.

Long-Acting Inhaled β2-Agonists LABAs offer the convenience and benefit of a long duration of action for patients with persistent symptoms. Most of the currently available agents, salmeterol, formoterol, and arformoterol, are dosed every 12 hours and provide sustained bronchodilation. An ultra-long-acting agent, indacaterol, requires only once-daily dosing and was recently approved in July 2011. Arformoterol, formoterol, and indacaterol have an onset of action similar to albuterol (less than 5 minutes), whereas salmeterol has a slower onset (15 to 20 minutes); however, none of these agents are recommended for acute relief of symptoms. There is no dose titration for any of these agents; the starting dose is the effective and recommended dose for all patients. The clinical benefits of LABAs compared with short-acting therapies include similar or superior improvements in lung function and symptoms, as well as reduced exacerbation rates in some studies.6871 The use of the long-acting agents should be considered for patients with frequent and persistent symptoms. When patients require short-acting β2-agonists on a scheduled basis, LABAs are more convenient based on dosing frequency but are also more expensive. Salmeterol, indacaterol, and formoterol are available in dry powder inhalation devices, and formoterol and arformoterol as solutions for nebulization. LABAs are also useful to reduce nocturnal symptoms and improve quality of life. When compared with short-acting bronchodilators or theophylline, both salmeterol and formoterol improve lung function, symptoms, exacerbation frequency, and quality of life.70These benefits are apparent even for patients with poorly reversible lung function and are related to improvements in inspiratory capacity.72 Both salmeterol and formoterol have been compared with ipratropium. In separate studies, each agent improved FEV1 compared with ipratropium and, in addition, the LABA was more effective for other selected outcomes (e.g., prolonged time to exacerbation for salmeterol while formoterol reduced symptoms and rescue inhaler use).73,74 Comparative data for indacaterol and other bronchodilators are limited. Available studies have demonstrated similar effects with indacaterol on FEV1 and symptoms compared with other long-acting bronchodilators; however, the effect on other outcomes such as exacerbation frequency has not been evaluated.

Long-Acting Anticholinergics Tiotropium bromide, a long-acting quaternary anticholinergic agent, has been available in the United States since 2004. This agent blocks the effects of acetylcholine by binding to muscarinic receptors in airway smooth muscle and mucus glands, blocking the cholinergic effects of bronchoconstriction and mucus secretion. Tiotropium is more selective than ipratropium at blocking important muscarinic receptors. It dissociates slowly from M1 and M3 receptors, allowing prolonged bronchodilation. The dissociation from M2 receptors is much faster, allowing inhibition of acetylcholine release. Binding studies of tiotropium in the human lung show that it is approximately 10-fold more potent than ipratropium and protects against cholinergic bronchoconstriction for greater than 24 hours.75

When inhaled, tiotropium is minimally absorbed into the systemic circulation and results in bronchodilation within 30 minutes, with a peak effect in 3 hours. Bronchodilation persists for at least 24 hours, allowing for a once-daily dosing. There is no titration of tiotropium dose; a regimen of 18 mcg inhaled once daily is recommended for all patients. In the United States, it is delivered via the HandiHaler, a single-load, dry powder, breath-actuated device. Because it acts locally, tiotropium is well tolerated, with the most common complaint being a dry mouth. Other anticholinergic side effects that are reported include constipation, urinary retention, tachycardia, blurred vision, and precipitation of narrow-angle glaucoma symptoms.

The benefits of tiotropium have been evaluated in numerous trials of patients with COPD. Similar to long-acting β-agonists, tiotropium improves lung function and dyspnea, exacerbation frequency, and health-related quality of life.76 Benefits have been demonstrated compared with placebo77 and with ipratropium.78 Tiotropium therapy is associated with a decreased risk of exacerbations compared with placebo or ipratropium, and equal or superior efficacy compared with LABAs in various studies.79 The tolerance that is demonstrated with chronic use of β-agonists does not occur with tiotropium therapy, as improvements in lung function are sustained with long-term therapy.80

As a long-acting bronchodilator, tiotropium is an option to consider in addition to LABAs for COPD management. Once-daily tiotropium has been compared with twice-daily salmeterol in two placebo-controlled trials of 6 months’ duration. Tiotropium reduced asthma exacerbations and hospital admissions and improved quality of life, whereas both active treatments improved lung function and reduced dyspnea.78 In another 6-month randomized controlled trial of patients with COPD, patients were randomized to receive tiotropium once daily by DPI, salmeterol twice daily by MDI, or placebo.81 Patients receiving tiotropium had greater improvements in trough FEV1 and dyspnea scores than those receiving salmeterol. Patients also were more likely to have improvements in quality-of-life indicators with tiotropium than with salmeterol. However, no differences in frequency of exacerbations were noted among the three groups.

The most notable study involving the use of tiotropium in recent years for patients with COPD was the UPLIFT trial.82 This was a randomized, double-blind study of 4 years’ duration. A total of 5,993 subjects received either tiotropium 18 mcg daily inhaled via a HandiHaler device or a matching placebo. All other COPD therapies were allowed except for other anticholinergic therapies (e.g., ipratropium). The mean postbronchodilator FEV1 among subjects was 1.32 L, and the primary outcome was the rate of decline in FEV1 on spirometry. The results showed that tiotropium treatment resulted in prebronchodilator FEV1 improvement of 87 to 103 mL, and postbronchodilator improvement of 47 to 65 mL, both of which were statistically significant. However, the rate of decline in the mean FEV1 result was not statistically significant between the groups. Tiotropium-treated subjects benefited from treatment as reflected in improved quality-of-life scores, reduced exacerbation rates, fewer hospitalizations, and instances of respiratory failure. Tiotropium was associated with a lower overall risk of mortality, including deaths from respiratory and cardiac causes.

The safety of tiotropium documented in the UPLIFT trial is reassuring. Recently, retrospective analysis have reported an increased risk of cardiovascular events associated with ipratropium83 and tiotropium use.84,85 However, the UPLIFT study, which was a prospective trial over 4 years, did not report an increased cardiovascular risk associated with tiotropium use.82

Recently, another long-acting agent has been approved. Aclidinium bromide is expected to have a similar role to tiotropium. In one clinical trial, aclidinium administered at 400 mcg twice daily provided similar improvements in spirometry and COPD symptom scores compared with tiotropium.86

Combination Anticholinergics and β-Agonists Combination regimens of bronchodilators are used often in the treatment of COPD, especially as the disease progresses and symptoms worsen over time. Combining bronchodilators with different mechanisms of action allows the lowest possible effective doses to be used and reduces potential adverse effects from individual agents.1 Combinations of both short- and long-acting β2-agonists with ipratropium have been shown to provide added symptomatic relief and improvements in pulmonary function.8688 A combination of albuterol and ipratropium (Combivent) is available as an MDI in the United States for chronic maintenance therapy of COPD. This product offers the obvious convenience of two classes of bronchodilators in a single inhaler.

Although clinical practice guidelines recommend that combinations of long-acting bronchodilators are appropriate for patients who do not receive adequate benefit from a single agent, data to support the use of these combinations have been lacking. These approaches have been the focus of more recent research. A recent Cochrane review evaluated five trials comparing combination long-acting bronchodilators (LABA plus tiotropium) versus tiotropium alone. Combination therapy resulted in significant improvement in FEV1 and quality-of-life measures compared with tiotropium alone, although no difference was shown for frequency of exacerbations or symptom scores.89 Future combination inhalation products may contain long-acting β2-agonists with tiotropium to reduce the need for frequent dosing.

Methylxanthines Methylxanthines, including theophylline and aminophylline, have been available for the treatment of COPD for at least 5 decades and at one time were considered first-line therapy. However, with the availability of LABAs and inhaled anticholinergics, the role of methylxanthine therapy is significantly limited. Inhaled bronchodilator therapy is preferred for COPD. Because of the risk for drug interactions and the significant intrapatient and interpatient variability in dosage requirements, theophylline therapy generally is considered for patients who are intolerant or unable to use an inhaled bronchodilator. Theophylline is still an alternative to commonly used inhaled therapies partially due to the potential for multiple mechanisms (bronchodilation and antiinflammatory) and the possible benefit that systemic administration may exert on peripheral airways.90

The methylxanthines may produce bronchodilation through numerous mechanisms, including (a) inhibition of phosphodiesterase, thereby increasing cAMP levels, (b) inhibition of calcium ion influx into smooth muscle, (c) prostaglandin antagonism, (d) stimulation of endogenous catecholamines, (e) adenosine receptor antagonism, and (f) inhibition of release of mediators from mast cells and leukocytes.91

Chronic theophylline use for patients with COPD has been shown to exert improvements in lung function, including vital capacity (VC), FEV1, minute ventilation, and gas exchange.90 Subjectively, theophylline has been shown to reduce dyspnea, increase exercise tolerance, and improve respiratory drive in COPD patients.90,91 Other nonpulmonary effects of theophylline that may contribute to improved overall functional capacity for patients with COPD include improved cardiac function and decreased pulmonary artery pressure.

Regular use of methylxanthines has not been shown to have either a beneficial or a detrimental effect on the progression of COPD. However, methylxanthines may be added to the treatment plan of patients who have not achieved an optimal clinical response to inhaled bronchodilators. Studies suggest that adding theophylline to a combination of albuterol and ipratropium provides added benefit for stable COPD patients, supporting the hypothesis that there is a synergistic bronchodilator effect.9294 The efficacy of combination therapy with salmeterol and theophylline for patients with COPD was reported to improve pulmonary function and reduce dyspnea better than either treatment alone.95 Combination treatment also was associated with a reduced number of exacerbations only when compared with the theophylline group, suggesting that the salmeterol component was responsible for this beneficial effect.

As is the case with other bronchodilator therapy, parameters other than objective measurements, such as FEV1, should be monitored to assess efficacy of theophylline in COPD. Subjective parameters, such as perceived improvements in symptoms of dyspnea and exercise tolerance, become increasingly important in assessing the acceptability of methylxanthines for COPD patients. Although objective improvement may be minimal, patients may experience an improvement in clinical symptoms, and thus benefit to the individual may be meaningful.

Although theophylline is available in a variety of oral dosage forms, sustained-release preparations are most appropriate for the long-term management of COPD. These products have the advantages of improving patient compliance and achieving more consistent serum concentrations over rapid-release theophylline and aminophylline preparations. However, caution must be used in switching from one sustained-release preparation to another because there are considerable variations in sustained-release characteristics.91 Aside from IV aminophylline, there is no need to use any of the various salt forms of theophylline.

Therapy can be initiated at 200 mg twice daily and titrated upward every 3 to 5 days to the target dose. Most patients required daily doses of 400 to 900 mg. Dosage adjustments generally should be made based on serum concentration results. Traditionally, the therapeutic range of theophylline was identified as 10 to 20 mcg/mL; however, because of the frequency of dose-related side effects and the relatively minor benefit of higher concentrations, a more conservative therapeutic range of 8 to 15 mcg/mL often is targeted. This is especially preferable for the elderly. When concentrations are measured, trough measurements are most appropriate.

Once a dose is established, serum concentrations should be monitored once or twice a year unless the patient’s disease worsens, medications that interfere with theophylline metabolism are added to therapy, or toxicity is suspected. The most common side effects of theophylline therapy are related to the GI system, the cardiovascular system, and the CNS. Side effects are dose related; however, there is overlap in side effects between the therapeutic and toxic ranges. Minor side effects include dyspepsia, nausea, vomiting, diarrhea, headache, dizziness, and tachycardia. More serious toxicities, especially at toxic concentrations, include arrhythmias and seizures.

Factors that decrease theophylline clearance and lead to reduced maintenance dose requirements include advanced age, bacterial or viral pneumonia, left or right ventricular failure, liver dysfunction, hypoxemia from acute decompensation, and use of drugs such as cimetidine, macrolides, and fluoroquinolone antibiotics. Factors that may enhance theophylline clearance and result in the need for higher maintenance doses include tobacco and marijuana smoking, hyperthyroidism, and the use of such drugs as phenytoin, phenobarbital, and rifampin.

In summary, there are decades of experience with theophylline and other methylxanthine products in the management of patients with COPD. However, inhalation therapy is currently preferred based on superior efficacy and safety, as well as ease of use by the clinician. Theophylline is a challenging medication to dose, monitor, and manage due to the significant intrapatient and interpatient variability in pharmacokinetics and the potential for drug interactions and toxicities.

Corticosteroids

Images Corticosteroid therapy has been studied and debated in COPD therapy for half a century; however, owing to the poor risk-to-benefit ratio, chronic systemic corticosteroid therapy should be avoided if possible.1 Because of the potential role of inflammation in the pathogenesis of the disease, clinicians hoped that corticosteroids would be promising agents in COPD management. However, their use continues to be debated, especially in the management of stable COPD.

The antiinflammatory mechanisms whereby corticosteroids exert their beneficial effect in COPD include (a) reduction in capillary permeability to decrease mucus, (b) inhibition of release of proteolytic enzymes from leukocytes, and (c) inhibition of prostaglandins. Unfortunately, the clinical benefits of systemic corticosteroid therapy in the chronic management of COPD are often not evident, and the risk of toxicity is extensive and far-reaching. Currently, the appropriate situations to consider corticosteroids in COPD include (a) short-term systemic use for acute exacerbations and (b) inhalation therapy for chronic stable COPD.

The role of oral steroid use in chronic stable COPD patients was evaluated in a meta-analysis over a decade ago.96 Investigators concluded that only a small fraction (10%) of COPD patients treated with steroids showed clinically significant improvement in baseline FEV1 (increase of 20%) compared with those treated with placebo. While a small number of COPD patients are considered responders to oral steroids, many of these patients actually may have an asthmatic, or reversible, component to their disease. The best predictors for response to oral steroids are the presence of eosinophils on sputum examination (≥3%) and a significant response to sympathomimetics on pulmonary function tests.97 Both the presence of eosinophils in sputum and the responsiveness to sympathomimetics suggest an asthmatic component to the disease process and thus may explain the clinical benefit seen with steroids.

Previously, a common clinical practice was to administer a short course (2 weeks) of oral corticosteroids as a trial to predict which patients would benefit from chronic oral or ICs. There is now sufficient evidence suggesting that this practice is not effective in predicting a long-term response to ICs and should not be recommended.98

Long-term adverse effects associated with systemic corticosteroid therapy include osteoporosis, muscular atrophy, thinning of the skin, development of cataracts, and adrenal suppression and insufficiency. The risks associated with long-term steroid therapy are much greater than the clinical benefits. If a decision to treat with long-term systemic corticosteroids is made, the lowest possible effective dose should be given once per day in the morning to minimize the risk of adrenal suppression. If therapy with oral agents is required, an alternate-day schedule should be used.

The use of chronic IC therapy has been of interest for the past decade. Their use has been common despite the lack of firm evidence about significant clinical benefit until recently. ICs have an improved risk-to-benefit ratio compared with systemic corticosteroid therapy. Using the model for asthma, it was hoped that the inhalation of potent corticosteroid would result in high local efficacy and limited systemic exposure and toxicity. In the latter part of the 1990s, several large international trials were initiated to evaluate the effect on ICs in COPD. Unfortunately, the results of these major clinical trials failed to demonstrate any benefit from chronic treatment with ICs in modifying long-term decline in lung function that is characteristic of COPD.99 Therefore, the role of ICs in COPD continues to be debated in the literature, unlike in asthma, where their use is clearly advocated. Much of the debate centers on the appropriate outcome measures in this population of patients.

During the last decade, several studies of ICs in COPD were designed to detect a benefit on slowing the progressive loss of lung function, but the results were disappointing.100105 None of the large national or international trials were able to demonstrate a benefit of high-dose IC therapy on this primary outcome. However, ICs have been associated with other important benefits in some patients, including a decrease in exacerbation frequency and improvements in overall health status.101,105,106 Clinicians continue to debate the most appropriate and relevant outcome measure to evaluate in COPD studies. A meta-analysis evaluating randomized clinical trials involving ICs for patients with COPD indicated that treatment was associated with a relative risk reduction in exacerbation frequency of 33%. The report indicated that 12 patients would require treatment for 20.8 months to prevent one exacerbation episode. The benefit was evident for patients with moderate-to-severe COPD.107 This meta-analysis did not detect a mortality benefit.

Other investigators have reported a reduction in mortality for patients with COPD who were treated with ICs. In an epidemiologic study of a Canadian database, patient mortality 3 months to 1 year following a hospitalization for a COPD exacerbation was evaluated for patients who received ICs in the first 3 months compared with those who did not. For patients over 65 years of age, IC therapy reduced mortality by 25%. Much of the mortality reduction was reflected in deaths due to cardiovascular causes. Conversely, patients who received only bronchodilator therapy trended toward higher mortality rates, although this was not significant.108 A pooled analysis of seven large trials also concluded that ICs reduced all-cause mortality in COPD patients.109

Currently, the recommended role of IC therapy is for patients with severe or very severe COPD and at high risk of exacerbation (Groups C and D) who are not controlled with inhaled bronchodilators. The initial hope that treatment with ICs would prevent or slow the progressive decline in FEV1 remains unproven; however, it is often argued that additional important outcomes for patients with COPD include relief of symptoms, fewer and less severe exacerbations, and improved quality of life.110 ICs do not prolong survival in COPD patients and there is good evidence to suggest that treatment with ICs increases the risk of pneumonia for patients with COPD.111113

Although a dose–response relationship for ICs has not been demonstrated in COPD, the major clinical trials employed moderate to high doses for treatment. Side effects of ICs are relatively mild compared with the toxicity from systemic therapy. Hoarseness, sore throat, oral candidiasis, and skin bruising have been reported in the clinical trials. Severe side effects, such as adrenal suppression, osteoporosis, and cataract formation, have been reported less frequently than with systemic corticosteroids, but clinicians should monitor patients who are receiving high-dose chronic therapy.114,115

There is evidence supporting a dose relationship between IC use and the risk of fractures. In a cohort of over 1,600 subjects with a diagnosis of asthma or COPD (mean age 80 years), the risk of a fracture was 2.53 times higher (CI, 1.65 to 3.89) in those receiving a mean daily dose of IC of 601 mcg or greater.116 However, the data are conflicting about this issue. A meta-analysis found no evidence supporting an increased risk of fractures or decreased bone mineral density with chronic IC use.117 It appears prudent to suggest that, to minimize the risk of fracture, patients should be treated with the lowest effective dose of ICs.118 It may also be helpful to recommend adequate intake of calcium and vitamin D and possibly periodic bone mineral density testing.

Combination Therapy: Bronchodilators and Inhaled Corticosteroids

Following the disappointing results of chronic IC studies and the progressive decline in lung function, investigators became interested in the combination of potent antiinflammatory therapies and long-acting bronchodilators. Subsequently, several studies have shown an additive benefit with long-acting bronchodilators.119122 In various studies, combination therapy with salmeterol plus fluticasone or formoterol plus budesonide was associated with greater improvements in clinical outcomes such as FEV1, health status, and frequency of exacerbations compared with ICs or long-acting bronchodilators alone. The availability of combination inhalers (e.g., salmeterol plus fluticasone and budesonide plus formoterol) makes administration of both ICs and long-acting bronchodilators more convenient for patients and decreases the total number of inhalations needed daily. An IC combined with a long-acting β-agonist is superior to the individual components in reducing exacerbations, improving lung function and overall health status.111 Therefore, there is growing evidence that IC and long-acting β-agonist combinations improve lung function, as well as reduce symptoms of dyspnea and exacerbation frequency.121123

The combination of a long-acting β-agonist and IC has been compared with the long-acting β-agonist therapy alone. In a study involving nearly 1,000 patients with severe but stable COPD, subjects received either salmeterol 50 mcg/fluticasone 500 mcg twice daily or salmeterol 50 mcg twice daily for 44 weeks. Exacerbation frequency was significantly lower in the combination group (334 episodes vs. 464 episodes), which corresponded to a 35% reduction in the annualized rate. The time to the first exacerbation was also delayed with the combination therapy.124 One finding of concern reported in this trial was the increased number of pneumonia cases for patients receiving combination therapy compared with salmeterol alone. There were 23 cases reported compared with 7 in the salmeterol group.124 An increase in the risk for pneumonia was also reported in the TORCH study described below.111

The largest prospective study to date is referred to as the TORCH study.111 This trial consisted of 6,112 patients who received one of four treatments for 3 years. Treatment groups were placebo, salmeterol 50 mcg twice daily, fluticasone 500 mcg twice daily, or the combination of salmeterol and fluticasone in a single inhaler. The primary outcome was death from any cause and secondary outcomes were exacerbation rates, lung function, and health status. None of the active treatments differed significantly from placebo, although the combination of salmeterol and fluticasone trended toward fewer deaths (P = 0.052). The combination also reduced exacerbation rates, and improved lung function and health status compared with the other treatments. Exacerbation rates were also significantly reduced with combination therapy compared with either single agent alone. Both treatment groups that included fluticasone had higher rates of pneumonia. Although this study did not reflect a mortality benefit, the authors indicated the risk of death was reduced by 17.5% with the combination and that the number needed to treat for 1 year to provide a benefit was 4.

In a post hoc analysis of this trial, both individual agents and the combination decreased the rate of spirometry decline in patients with an FEV1 of less than 60% predicted.56 While this observation is interesting, it is in contrast to previous randomized controlled studies that have not demonstrated an effect of pharmacotherapy on rate of disease progression.

In a head-to-head trial, a large study comparing a combination of salmeterol and fluticasone with tiotropium alone showed no difference in the exacerbation rates between the groups, although the combination therapy was associated with a higher study completion rate.125

Combinations of Long-Acting Bronchodilators Compared with Long-Acting Bronchodilators Plus Inhaled Corticosteroids The combination of salmeterol and tiotropium has also been evaluated in a short-term crossover study involving only 22 subjects who received salmeterol (50 mcg twice daily) plus fluticasone (500 mcg twice daily), fluticasone plus tiotropium (18 mcg once daily), or fluticasone, salmeterol, and tiotropium for 1 week. The triple combination provided a significant benefit of improved lung function compared with either of the dual treatments in subjects with moderate-to-severe COPD.126 The benefit of triple therapy was evaluated in a 1-year randomized, double-blind, placebo-controlled study involving 449 subjects with moderate-to-severe COPD. Treatment consisted of tiotropium, tiotropium plus salmeterol, or tiotropium, salmeterol, and fluticasone.127 There was no difference between treatments for the primary outcome of percentage of patients experiencing an exacerbation requiring systemic corticosteroids or antibiotics. The triple-drug regimen improved lung function, quality of life, and reduced hospitalization compared with tiotropium alone, while two-drug therapy did not offer any benefit in lung function improvement or hospitalization rates compared with the single agent. Another small study evaluated the addition of tiotropium for 1 month to a regimen of an IC and a long-acting β-agonist.128The addition of tiotropium improved lung function and quality-of-life scores, apparently by improving dynamics of lung capacity (inspiratory capacity). These effects were reversed when tiotropium therapy was discontinued. These data involving combinations of long-acting bronchodilators are limited and preliminary. More research is required and should include other outcome parameters including relief of symptoms, exacerbation rates, and quality of life. Larger sample sizes and longer durations will provide insight into the value of combinations.

A retrospective cohort study of 42,090 patients in the Veterans Affairs healthcare system evaluated outcomes for patients with COPD who received tiotropium as part of a COPD regimen compared with a cohort of COPD patients who did not receive the medication. Patients who received tiotropium with ICs plus a long-acting β-agonist exhibited a 40% reduction in mortality compared with patients treated with ICs plus a long-acting β-agonist alone (95% CI of 0.45 to 0.79). Triple therapy patients also significantly reduced exacerbations and hospitalization rates. However, this same study demonstrated that tiotropium combined with two other medications (various) increased mortality and morbidity risks.83

Phosphodiesterase Inhibitors

Phosphodiesterase 4 (PDE4) is the major phosphodiesterase found in airway smooth muscle cells and inflammatory cells and is responsible for degrading cAMP. Inhibition of PDE4 results in relaxation of airway smooth muscle cells and decreased activity of inflammatory cells and mediators such as TNF-α and IL-8. One PDE4 inhibitor, roflumilast, was approved in February 2011 to reduce the risk of exacerbations in patients with severe COPD. When either used as monotherapy or added to a maintenance regimen with other inhaled bronchodilators, roflumilast was associated with a modest increase in FEV1 and reduction in rate of exacerbation by approximately 15%. Of note, patients in phase III trials evaluating roflumilast were not allowed to receive ICs as part of their maintenance regimen.

Roflumilast is dosed at 500 mcg orally once a day. Major adverse effects include weight loss and neuropsychiatric effects such as suicidal thoughts, insomnia, anxiety, and new or worsened depression. Weight loss may be of concern in patients with low BMI and drug discontinuation may be necessary if significant weight loss is observed. Both patients and family members should be counseled regarding the potential for mood and behavior changes and to alert healthcare providers if they occur.

Roflumilast is metabolized by CYP3A4 and 1A2 and coadministration with strong inducers of cytochrome P450 is not recommended due to potential for subtherapeutic plasma concentrations. Although there are no recommended dose adjustments, caution should also be used when administering roflumilast with strong inhibitors of cytochrome P450 due to potential for adverse effects.

Given the limited evidence demonstrating long-term clinical benefit and the lack of evidence for coadministration with ICs, the role of roflumilast in the management of COPD is not entirely clear. Current consensus guidelines recommend roflumilast for patients with severe or very severe COPD who are at high risk of exacerbation (Groups C and D) and are not controlled by inhaled bronchodilators. Roflumilast may also be considered for patients who are intolerant or unable to use inhaled bronchodilators or corticosteroids. Given that both theophylline and roflumilast have similar mechanisms of action through inhibition of phosphodiesterases, it is not recommended to use both together for the management of COPD.

α1-Antitrypsin Replacement Therapy

For patients with inherited AAT deficiency–associated emphysema, treatment focuses on reduction of risk factors such as smoking, symptomatic treatment with bronchodilators, and augmentation therapy with replacement AAT. Based on knowledge about the relationship between serum concentrations of AAT and the risk of developing emphysema, the rationale for augmentation therapy is to maintain serum concentrations above the protective threshold throughout the dosing interval.129 Indirect evidence of AAT activity in the interstitium of the lung has been demonstrated by measuring concentrations of the enzyme in epithelial lining fluid obtained during bronchoalveolar lavage. Augmentation therapy consists of weekly infusions of pooled human AAT to maintain AAT plasma levels over 10 μmol/L. Much of the data supporting the use of AAT replacement are based on evidence of biochemical efficacy (e.g., administering the product and demonstrating protective serum concentrations of AAT).

Clinical evidence for slowing lung function decline or improving outcomes with augmentation therapy is sparse. Stated challenges to performing randomized clinical trials include the large sample size and long duration of followup required, and the expense of conducting such a trial. One observational study followed patients in the National Registry of Severe AAT Deficiency over a period of several years and documented clinical outcomes. In this study, patients who received weekly augmentation therapy with purified AAT had slower declines in FEV1 and decreased mortality compared with patients who never received augmentation therapy.130 However, this was an observational study of patients, not a randomized, placebo-controlled trial, and so direct cause-and-effect relationships cannot be concluded. One randomized, placebo-controlled study of patients with severe AAT deficiency (ZZ phenotype) did show a significant reduction in lung tissue loss and destruction as measured by computed tomographic (CT) scan for patients receiving augmentation therapy.131 Other measures of lung function and mortality were not recorded.

The recommended dosing regimen for replacement AAT is 60 mg/kg administered IV once a week at a rate of 0.08 mL/kg/min, adjusted to patient tolerance. It has been estimated that this form of augmentation therapy will cost over $54,000 annually.132 In the absence of alternative treatments, it is difficult to assess the cost-effectiveness using conventional criteria. There have been repeated problems with supply of this biologic replacement therapy (derived from pooled blood donors) related to production difficulty and contamination issues. Currently, there are four products available (Prolastin-C [Talecris], Aralast-NP [Baxter], Zemaira [CSL Behring], and Glassia [Kamata]) that should minimize this problem in the future. Drug development research continues in the area of recombinant products and inhalational therapy.

The safety of AAT replacement therapy has been evaluated in two large observational studies. In the most recent study, 174 patients (n = 747) reported 720 adverse events, classified as severe in 8.8% of cases and moderate in 72.4% of cases.133 Common complaints included headache, dizziness, nausea, dyspnea, and fever. The overall rate of adverse events was low (i.e., two events over 5 years).

TREATMENT

COPD Exacerbation

Desired Outcomes

Images The goals of therapy for patients experiencing exacerbations of COPD are (a) prevention of hospitalization or reduction in hospital stay, (b) prevention of acute respiratory failure and death, and (c) resolution of exacerbation symptoms and a return to baseline clinical status and quality of life.134 Acute exacerbations can range from mild to severe. Factors that influence the severity, and subsequently the level of care required, include the severity of airflow limitation, presence of comorbidities, and the history of previous exacerbations. Table 16-12 includes factors that warrant treatment in the hospital.

TABLE 16-12 Factors Favoring Hospitalization for Treatment of COPD Exacerbation

Images

Various therapeutic options for exacerbation management are summarized in Table 16-13. Pharmacotherapy consists of intensification of bronchodilator therapy and a short course of systemic corticosteroids. Antimicrobial therapy is indicated in the presence of selected symptoms. Since the frequency and severity of exacerbations are closely related to each patient’s overall health status, all patients should receive optimal chronic treatment, including smoking cessation, appropriate pharmacologic therapy, and preventative therapy such as vaccinations.

TABLE 16-13 Therapeutic Options for Acute Exacerbations of COPD

Images

Nonpharmacologic Therapy

Controlled Oxygen Therapy

Oxygen therapy should be considered for any patient with hypoxemia during an exacerbation. Caution must be used, however, because many patients with COPD rely on mild hypoxemia to trigger their drive to breathe. In normal, healthy individuals, the drive to breathe is triggered by carbon dioxide accumulation. For patients with COPD who retain carbon dioxide as a result of their disease progression, hypoxemia rather than hypercapnia becomes the main trigger for their respiratory drive. Overly aggressive administration of oxygen to patients with chronic hypercapnia may result in respiratory depression and respiratory failure. Oxygen therapy should be used to achieve a PaO2 of greater than 60 mm Hg or oxygen saturation of greater than 90%. However, an ABG should be obtained after oxygen initiation to monitor carbon dioxide retention owing to hypoventilation.

Noninvasive Mechanical Ventilation

Noninvasive positive-pressure ventilation (NPPV) provides ventilatory support with oxygen and pressurized airflow using a face or nasal mask with a tight seal but without endotracheal intubation. There have been numerous trials reporting the benefits of NPPV for patients with acute respiratory failure due to COPD exacerbations. In one meta-analysis of eight studies, NPPV was associated with lower mortality, lower intubation rates, shorter hospital stays, and greater improvements in serum pH in 1 hour compared with treatment with usual care alone.135 The benefits seen with NPPV generally can be attributed to a reduction in the complications that often arise with invasive mechanical ventilation. Not all patients with COPD exacerbations are appropriate candidates for NPPV. Patients with altered mental status may not be able to protect their airway and thus may be at increased risk for aspiration. Patients with severe acidosis (pH <7.25), respiratory arrest, or cardiovascular instability should be not considered for NPPV. Patients failing a trial of NPPV or those considered poor candidates might be considered for intubation and mechanical ventilation.

Pharmacologic Therapy

Bronchodilators

During exacerbations, intensification of bronchodilator regimens is used commonly. The doses and frequency of bronchodilators are increased to provide symptomatic relief. Short-acting β2-agonists are preferred owing to rapid onset of action. Anticholinergic agents may be added if symptoms persist despite increased doses of β2-agonists. In fact, combinations of these agents are employed often, although data are lacking about the benefit versus higher doses of one agent. Bronchodilators may be administered via MDIs or nebulization with equal efficacy. Nebulization may be considered for patients with severe dyspnea who are unable to hold their breath after actuation of an MDI. Clinical evidence supporting the use of theophylline during exacerbations is lacking, and thus theophylline generally should be avoided. However, addition of one of these agents may be considered for patients not responding to other therapies. The risk of adverse effects such as cardiac arrhythmias should be considered and serum levels monitored closely.

Corticosteroids

Until recently, the literature supporting the use of corticosteroids in acute exacerbations of COPD was sparse. However, since 1996, five studies have been performed that document the value of systemic corticosteroids in exacerbations of COPD.136140 The Systemic Corticosteroids in Chronic Obstructive Pulmonary Disease Exacerbations (SCCOPE) trial evaluated three groups of patients hospitalized for exacerbations of COPD.136 The first group received an 8-week course of corticosteroids given as methylprednisolone 125 mg IV every 6 hours for 72 hours, followed by once-daily oral prednisone (60 mg on days 4 to 7, 40 mg on days 8 to 11, 20 mg on days 12 to 43, 10 mg on days 44 to 50, and 5 mg on days 51 to 57). The second group received a 2-week course given as methylprednisolone 125 mg IV every 6 hours for 72 hours, followed by oral prednisone (60 mg on days 5 to 7, 40 mg on days 8 to 11, and 20 mg on days 12 to 15) and placebo on days 16 to 57. The third group received placebo for all 57 days of study. Rates of treatment failure and hospital stay were significantly higher in the placebo group than in either treatment group at 30 and 90 days. Groups randomized to corticosteroid treatment also had a significantly shorter length of hospital stay compared with the placebo group. The 8-week regimen was not found to be superior to the 2-week regimen. Significant treatment benefits were no longer evident at 6 months.

Davies et al.137 evaluated the oral use of corticosteroids in hospitalized patients with acute exacerbations of COPD. Patients received either 30 mg/day oral prednisolone or placebo for 14 days. Patients who were treated with corticosteroids had a significantly more rapid improvement in FEV1 and a shorter hospital stay than did patients who received placebo. There was no significant difference between groups at 6-week follow-up.

In total, results from these trials suggest that patients with acute exacerbations of COPD should receive a short course of IV or oral corticosteroids. However, because of the large variability in dosage ranges, the optimal dose and duration of corticosteroid treatment are not known. It appears that short courses (9 to 14 days) are as effective as longer courses and have a lower risk of associated adverse effects owing to less time of exposure. Several trials used high initial doses of steroids before tapering to a lower maintenance dose. Adverse effects such as hyperglycemia, insomnia, and hallucinations may occur at higher doses. Depending on the clinical status of the patient, treatment may be initiated at a lower dose or tapered more quickly if these effects occur. It appears that a regimen of prednisone 40 mg orally daily (or equivalent) for 10 to 14 days can be effective for most patients.141 If steroid treatment is continued for greater than 2 weeks, a tapering oral schedule should be employed to avoid hypothalamic–pituitary–adrenal (HPA) axis suppression.

Recent data suggest that ICs may be beneficial for treating COPD exacerbations, although this is not the standard of care. In one study, inhaled budesonide, alone or combined with formoterol, was as effective as oral corticosteroids in treating COPD exacerbations.142

Antimicrobial Therapy

Images It is thought that most acute exacerbations of COPD are caused by viral or bacterial infections. However, as many as 30% of exacerbations are caused by unknown factors.1 A meta-analysis of nine studies evaluating the effectiveness of antibiotics in treating exacerbations of COPD determined that patients receiving antibiotics had a greater improvement in peak expiratory flow rate than those who did not.143

This meta-analysis concluded that antibiotics are of most benefit and should be initiated if at least two of the following three symptoms are present: increased dyspnea, increased sputum volume, and increased sputum purulence. The utility of sputum Gram stain and culture is questionable because some patients have chronic bacterial colonization of the bronchial tree between exacerbations.

The emergence of drug-resistant organisms has mandated that antibiotic regimens be chosen judiciously. Selection of empirical antimicrobial therapy should be based on the most likely organism(s) thought to be responsible for the infection based on the individual patient profile. The most common organisms for any acute exacerbation of COPD are Haemophilus influenzaeMoraxella catarrhalisStreptococcus pneumoniae, and Haemophilus parainfluenzae. More virulent bacteria may be present for patients with more complicated acute exacerbations of COPD, including drug-resistant pneumococci, β-lactamase–producing H. influenzae and M. catarrhalis, and enteric gram-negative organisms, including Pseudomonas aeruginosaTable 16-14 summarizes recommended antimicrobial therapy for exacerbations of COPD and the most common organisms based on patient presentation.144

TABLE 16-14 Recommended Antimicrobial Therapy in Acute Exacerbations of COPD

Images

Therapy with antibiotics generally should be continued for at least 7 to 10 days. Studies evaluating shorter treatment courses (usually 5 days) with the fluoroquinolones, second- and third-generation cephalosporins, and macrolide antimicrobials have demonstrated comparable efficacy with the longer treatment regimens.145 If the patient deteriorates or does not improve as anticipated, hospitalization may be necessary, and more aggressive attempts should be made to identify potential pathogens responsible for the exacerbation.

COPD patients are at increased risk for pulmonary embolism during severe exacerbations requiring hospitalizations. An increased awareness of this risk and appropriate preventative measures are warranted.146

Complications

Cor Pulmonale

Cor pulmonale is right-sided heart failure secondary to pulmonary hypertension. Long-term oxygen therapy and diuretics have been the mainstays of therapy for cor pulmonale. Increasing the PaO2 above 60 mm Hg with supplemental oxygen therapy decreases pulmonary hypertension and thus decreases the force against which the right ventricle has to work. While diuretics may help decrease fluid overload, caution should be used because patients with significant right-sided heart failure are highly dependent on preload for cardiac output. Therefore, the decision to use diuretics must be based on a risk-to-benefit ratio. Digitalis glycosides have no role in the treatment of cor pulmonale.

Other pharmacologic agents that have been investigated to treat cor pulmonale include hydralazine, calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin II antagonists. However, there is insufficient evidence to offer guidelines for the role of these agents in COPD patients with cor pulmonale.

Polycythemia

Polycythemia secondary to chronic hypoxemia in COPD patients can be improved by either oxygen therapy or periodic phlebotomy if oxygen therapy alone is not sufficient. COT was shown by the Nocturnal Oxygen Therapy Trial Group to reduce hematocrit values in treated patients.31 Acute phlebotomy is indicated if the hematocrit is above 55% to 60% and the patient is experiencing CNS effects suggestive of sludging from high blood viscosity. Long-term oxygen then can be used to maintain a lower hematocrit.

Other Pharmacologic Considerations

A number of other treatments have been explored over the years. Among these therapies, either there is insufficient evidence to warrant recommending their use or they have been proven to not be beneficial in the management of COPD. A brief summary is provided because the clinician likely will encounter patients who are receiving or inquire about these treatments.

Suppressive Antimicrobial Agents

Because COPD patients often are colonized with bacteria and experience recurrent exacerbations of their condition, a common practice employed in the past has been the use of low-dose antimicrobial therapy as preventative or prophylaxis against these acute exacerbations. However, clinical studies over the past 40 years have failed to demonstrate any significant benefit from this practice.1

In certain pulmonary conditions such as cystic fibrosis and bronchiectasis, chronic therapy with macrolide antibiotics, specifically azithromycin, has shown clinical benefit based on its proposed antiinflammatory properties and is used in clinical practice. A recent study evaluated the effect of chronic azithromycin in patients with COPD. Patients were randomized to azithromycin (250 mg orally daily) or placebo in addition to maintenance therapy for COPD and were followed for 1 year.147 Chronic azithromycin was associated with a lower rate of exacerbations and improved quality-of-life scores; however, more patients in the azithromycin group reported hearing deficits (25% vs. 20% in the placebo group). Therapy with azithromycin was also associated with a higher rate of colonization with macrolide-resistant bacteria during the study period. Of note, patients were carefully screened for hearing impairment and risk factors for QT prolongation prior to entering the study and were excluded if either was present.

In May 2012, a retrospective, observational study reported an increase in cardiac events with short courses of azithromycin and the FDA has since updated the product labeling to include a precaution about QT prolongation.148Given the limited evidence for long-term treatment (beyond 1 year) with azithromycin, it would be prudent to wait for more long-term safety data before routinely recommending this therapy for patients with COPD who are at risk for exacerbations. Clinicians may choose to consider azithromycin for individual patients at high risk for exacerbations after weighing the risks and benefits of therapy.

Expectorants and Mucolytics

Adequate water intake generally is acceptable to maintain hydration and assist in the removal of airway sections. Beyond this, the regular use of mucolytics or expectorants for COPD patients has no proven benefit. This includes the use of saturated solutions of potassium iodide, ammonium chloride, acetylcysteine, and guaifenesin. In 2011, the FDA announced its intention to remove various unapproved cough and cold preparations (including several containing guaifenesin) from the market due to safety and efficacy concerns. Two formulations are currently approved by the FDA (Humibid and Mucinex); however, data are lacking on their benefit.

Narcotics

Systemic (oral and parenteral) opioids, especially morphine, can relieve dyspnea for patients with end-stage COPD. Nebulized therapy is sometimes used in clinical practice, although data about clinical benefit are lacking.149Opioids should be used carefully, if at all, to avoid adverse effects on ventilatory drive.

Respiratory Stimulants

There is no role for respiratory stimulants in the long-term management of COPD.1 Agents that have shown some utility in the acute setting include almitrine and doxapram. However, almitrine is available only in Europe, and its usefulness is limited by neurotoxicity. Doxapram is available for IV use only and may be no better than intermittent NPPV.

Secondary pulmonary hypertension is a feature of severe COPD. This has prompted interest about the potential role of agents used to treat primary pulmonary hypertension. However, the use of an endothelin receptor antagonist (bosentan) failed to improve exercise tolerance and worsened hypoxemia in one trial.150 Investigations with sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, have been conflicting in uncontrolled clinical trials. Due to concerns that PDE5 inhibitors may worsen gas exchange in patients with COPD, they are not recommended outside of clinical trials.

Surgical Intervention

Various surgical options have been employed in the management of COPD. These include bullectomy, lung volume reduction surgery (LVRS), and lung transplantation. Bullectomy has been performed for many years and may be useful when large bullae (>1 cm) are noted on computerized axial tomography (CT or CAT) scan. The presence of bullae may contribute to complaints of dyspnea, and their removal can improve lung function and reduce symptoms, although there is no evidence of a mortality benefit.

Because of the prevalence of COPD, it is the most frequent indication for lung transplantation. Transplantation is considered when predicted survival is less than 2 years, FEV1 is <25% predicted, and hypoxemia, hypercapnia, and pulmonary hypertension exist despite medical management.3 Experience to date shows 2-year survival of 65% to 90%, and 5-year survival of 41% to 53%.

Recent trials have evaluated the effect of bilateral LVRS for management of severe COPD. Short-term trials comparing the effects of pulmonary rehabilitation plus LVRS with pulmonary rehabilitation alone reported that the combination of treatments resulted in greater improvements in lung function, gas exchange, and quality of life at 3 months. Only recently have data evaluating the long-term effect of LVRS compared with pulmonary rehabilitation been published. The National Emphysema Treatment Trial (NETT), a prospective, randomized trial evaluating the long-term effects of LVRS plus pulmonary rehabilitation compared with pulmonary rehabilitation alone, followed 1,218 patients for 3 years.151 The primary end points for the study were mortality and maximal exercise capacity 2 years after randomization. Secondary end points included pulmonary function, distance walked in 6 minutes, and quality-of-life measurements. At an interim analysis, patients with an FEV1 of less than 20% of predicted or a carbon monoxide diffusing capacity of less than 20% of predicted were noted to be at high risk of death after surgery and subsequently were excluded from the study. Results of the study showed no mortality benefit with LVRS compared with pulmonary rehabilitation alone. Patients undergoing surgery had improved exercise capacity, lung function, and quality of life at 2 years, but these patients also had a higher risk of short-term morbidity and mortality associated with the surgery. A subgroup analysis of the study noted that patients with predominately upper-lobe emphysema and low exercise capacity undergoing surgery had lower mortality rates at 2 years compared with patients treated with medical therapy alone. Because of the costs and risks associated with LVRS, more studies are needed to better determine the ideal surgical candidates and identify subgroups of patients that would benefit most from surgery. The long-term benefits of LVRS are exhibited as improved oxygenation and decreased requirements for supplemental oxygen during treadmill walking as well as self-reported oxygen requirements for up to 24 months after the procedure.152

Dietary Supplements

There has been increasing interest in the role of antioxidants, including vitamins E and C and β-carotene, in reducing the frequency of exacerbations. It is postulated that they may be beneficial in COPD as a result of an imbalance between oxidants and antioxidants that has been considered in the pathogenesis of smoking-induced lung disease. However, there is no good evidence that antioxidant therapies improve COPD symptoms or slow disease progression. Nutritional supplements, including creatine, have not proven beneficial to improve the benefit of pulmonary rehabilitation programs.153

Investigational Therapies

Based on the knowledge about the importance of neutrophilic inflammation in COPD and potential therapeutic benefit of inhibition of neutrophil activity, a number of antiinflammatory compounds are being explored. Specifically, agents inhibiting LTB4, neutrophil elastase, and phosphodiesterases currently are being evaluated. To date, studies evaluating leukotriene-modifying therapies have been disappointing. Further studies are needed to evaluate the clinical benefit of such inhibitors for patients with COPD.

Neutrophil elastase is implicated in the induction of bronchial disease, causing structural changes in lungs, impairment of mucociliary clearance, and impairment of host defenses. Protease inhibitors, namely, inhibitors of neutrophil elastase, are being investigated currently for the treatment of COPD.

Results have been disappointing in evaluating the benefit of infliximab, a TNF-α-blocker, in treating COPD. A total of 234 patients with moderate-to-severe COPD received either infliximab 3 or 5 mg/kg or placebo at baseline, 2, 6, 12, 18, and 24 weeks. Subjects completed a quality-of-life questionnaire (CRQ) during treatment and out to 44 weeks. There were no differences on the CRQ or on any secondary end points including lung function, exercise capacity, or exacerbation rates. The discontinuation rate due to adverse events was high (20% to 27%) in the active treatment group.154

PHARMACOECONOMIC CONSIDERATIONS

The overall cost of therapy is an important consideration in contemporary medical practice. Meaningful cost analysis goes beyond the cost of the medication itself and incorporates the impact of a given therapeutic agent on overall healthcare cost. Because of the relative lack of benefit among objective outcome measures in COPD clinical trials, pharmacoeconomic studies can be useful in decision making about pharmacotherapy options. Pharmacoeconomic analyses in COPD, although limited, are available regarding antibiotic use in acute exacerbations and some therapies for management of chronic stable COPD.

The costs of managing an acute exacerbation of COPD in the ambulatory setting were evaluated in over 2,400 patients. Subjects were followed for 1 month following the diagnosis of the exacerbation. The overall relapse rate was 21%, with 31% and 16% of subjects requiring care in the emergency department and hospital, respectively. The overall costs for exacerbation treatment averaged $159, with 58% attributed to hospitalization.155 These authors concluded that a significant cost saving would result from improving the successful ambulatory management of acute exacerbations.

Grossman et al. conducted a trial investigating the use of aggressive antimicrobial therapy (ciprofloxacin) compared with usual antibiotic therapy (defined as any nonquinolone) in the treatment of acute exacerbations of COPD.156 Overall, the results indicated no preference for either treatment arm. However, for patients who were categorized as high risk (severe underlying lung disease, more than four exacerbations per year, duration of bronchitis greater than 10 years, elderly, significant comorbid illness), the use of aggressive antibiotic therapy was associated with improved clinical outcome, higher quality of life, and fewer costs. The results of this study are consistent with Table 16-14, which suggests that higher-risk patients are likely to have more resistant strains of organisms and thus require more aggressive antimicrobial treatment.

Few data are available about the cost-effectiveness of educational programs for patients with COPD. In an outpatient clinic, patients attending one 4-hour group session, followed by one to two individual sessions with a clinician, reported improved outcomes, and costs were reduced in an evaluation 12 months later.157 Additional research is needed regarding the best model for education and also the specific self-management strategies to teach.

Friedman et al. conducted a post hoc pharmacoeconomic evaluation of two multicenter, randomized trials comparing the combination of ipratropium and albuterol with both drugs used as monotherapy.158Patients who received a combination of ipratropium and albuterol had lower rates of exacerbations, lower overall treatment costs, and improved cost-effectiveness compared with either drug used alone. With the introduction of new bronchodilator therapies and with no clearly consistent advantage of one class of agents over another, pharmacoeconomic analyses may be useful for clinicians in determining the most appropriate therapy for their patients.


Clinical Controversy…

In the United States, all products containing a LABA agent, either alone or in combination with ICs, include a black box warning about an increased risk of severe asthma attacks or death associated with their use. This caution applies to patients with asthma, and it is strongly recommended that LABAs use should always be in conjunction with another controller therapy (e.g., ICs) and that use should be limited in duration. This concern only applies to patients with asthma and is not relevant concerning the use of LABA therapy for COPD patients.

A combination product of a long-acting inhaled β-agonist (salmeterol) and an inhaled corticosteroid agent (fluticasone) is one of the most commonly prescribed medications for lung disease, including COPD. However, in expert guidelines, ICs are indicated only for patients with more severe disease who experience frequent exacerbations. Many patients now receiving therapy with the combination inhaler may be candidates for bronchodilator therapy alone, although the benefit of ICs continues to be a focus of clinical research, including the potential for a mortality benefit.

The role of systemic corticosteroids for acute exacerbations of COPD has been clarified in recent years. However, the appropriate dosage regimen is not well established. Regimens range from initial high doses (methylprednisolone 125 mg every 6 hours) to more conservative dosing (prednisone 40–60 mg/day). Consensus guidelines indicate that bronchodilator therapy is the focus of pharmacotherapy for COPD. However, there is no clear choice for the initial agent. For patients with daily but not persistent symptoms, either ipratropium or albuterol offers advantages as initial therapy. Both also have limitations if chosen as the initial therapy.

International guidelines recommend long-acting bronchodilator therapy for patients with moderate to very severe disease or when symptoms are not adequately managed with short-acting agents or as-needed therapy. When response to a single long-acting bronchodilator is not optimal, guidelines recommend the use of combinations. However, data are lacking presently about the therapeutic benefit of combinations of long-acting bronchodilators, and this approach is associated with substantial costs.

EVALUATION OF THERAPEUTIC OUTCOMES

To evaluate therapeutic outcomes of COPD effectively, the practitioner must first delineate between chronic stable COPD and acute exacerbations. In chronic stable COPD, pulmonary function tests should be assessed periodically and with any therapy addition, change in dose, or deletion of therapy. Because objective improvements often are minimal, subjective assessments are important. Other outcome parameters are commonly evaluated, including dyspnea score, quality-of-life assessments, and exacerbation rates, including visits to the emergency department or hospitalization. In acute exacerbations of COPD, white blood cell count, vital signs, chest x-ray, and changes in frequency of dyspnea, sputum volume, and sputum purulence should be assessed at the onset and throughout treatment of an exacerbation. In more severe exacerbations, ABGs and oxygen saturation also should be monitored. As with any drug therapy, patient adherence to therapeutic regimens, side effects, potential drug interactions, and subjective measures of quality of life also must be evaluated.

To date, there is no evidence that any of the available pharmacotherapies for COPD impact disease progression. Removal of the primary causative factor for COPD (e.g., cessation of cigarette smoking) does improve survival, as does supplemental oxygen therapy in a subset of patients with COPD. The most pertinent clinical outcomes that have emerged from clinical trials over the past decade are symptom improvement and reductions in exacerbation frequency. While it is important to continue to explore strategies to improve survival, consideration should be given to these two relevant and important outcome measures when initiating, continuing, and monitoring therapy. Because of the tremendous impact of exacerbations on disease progression, a reduction in exacerbation frequency may be predicted to show a benefit; however, this has not been proven.

END-OF-LIFE CARE

Based on the natural course of COPD, characterized by the progressive decline in lung function and development of complications, consideration should be given to end-of-life decisions and advanced directives.159 Factors associated with expected mortality within 1 year have been identified. These include older age, diagnosis of depression, declining overall health status, hypercapnia, an FEV1 of less than 30% predicted, ability to walk only a few steps without resting, more than one emergent hospitalization in the past year, and the presence of comorbidities, including congestive heart failure. An effective strategy to discuss end-of-life care involves the patient’s participation in identifying advanced directives. Patients should be assured that symptoms, including pain, will be managed and their dignity will be preserved. Specific issues that should be addressed include location and provider for terminal care, desires to use or withhold mechanical ventilation, and involvement of other family members in decisions on behalf of the patient.

ABBREVIATIONS

Images

REFERENCES

    1. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease (GOLD). 2013, http://www.goldcopd.com/.

    2. Centers for Disease Control and Prevention. Chronic obstructive pulmonary disease among adults—United States, 2011. MMWR 2012;61(46):938–943.

    3. Qaseem A, Wilt TJ, Weinberger SE, et al. Diagnosis and management of stable COPD: A clinical practice guideline update from the American College of Physicians, the American College of Chest Physicians, the American Thoracic Society, and the European Respiratory Society. Ann Intern Med 2011;155:179–191.

    4. National Institutes of Health. Specialized Centers of Clinically Oriented Research (SCCOR) in Chronic Obstructive Pulmonary Disease (COPD). RFA Number: REA-HL-05-008. Bethesda, MD: National Institutes of Health, August 2004.

    5. National Center for Health Statistics. National Health Interview Survey. Hyattsville, MD: U.S. Department of Health and Human Services, CDC, NCHS, 2001, www.cdc.gov/nchs/nhis.htm.

    6. Mannino DM, Homa DM, Akinbami LJ, Ford ES, Redd SC. Chronic obstructive pulmonary disease surveillance—United States, 1971–2000. MMWR Surveill Summ 2002;51:1–16.

    7. Wilt TJ, Niewoehner D, Kim C, et al. Use of Spirometry for Case Finding, Diagnosis, and Management of Chronic Obstructive Pulmonary Disease (COPD). Evidence Report #121. AHRQ Publication 05-E017–1. Rockville, MD: Agency for Healthcare Research and Quality, August 2005.

    8. Centers for Disease Control and Prevention. Deaths from chronic obstructive pulmonary disease—United States, 2000–2005. MMWR Morb Mortal Wkly Rep 2008;57: 1229–1232.

    9. Chronic Obstructive Pulmonary Disease: Data Fact Sheet. NIH Publication 03-5529. Bethesda, MD: U.S. Department of Health and Human Services, National Institutes of Health, NHLBI, March 2003.

   10. Holguin F, Folch E, Redd SC, Mannino DM. Comorbidity and mortality in COPD-related hospitalizations in the United States, 1979–2001. Chest 2005;128:2005–2011.

   11. Chronic Obstructive Pulmonary Disease (COPD) Fact Sheet. Washington, DC: American Lung Association, February 2010, www.lungusa.org/lung-disease/COPD/resources/fact-figures/COPD-Fact-Sheet.html.

   12. National Institutes of Health. NHLBI Morbidity & Mortality: 2004 Chart Book on Cardiovascular, Lung, and Blood Diseases. Washington, DC: U.S. Department of Health and Human Services, May 2004, http://www.nhlbi.nih.gov/resources/docs/cht-book.htm.

   13. Jansson SA, Andersson F, Borg S, Ericsson A, Jonsson E, Lundback B. Costs of COPD in Sweden according to disease severity. Chest 2002;122:1994–2002.

   14. U.S. Department of Health and Human Services. The Health Consequences of Smoking: A Report of the Surgeon General. Washington, DC: U.S. Department of Health and Human Services, 2004.

   15. Sandford AJ, Silverman EK. Chronic obstructive pulmonary disease. 1: Susceptibility factors for COPD the genotype–environment interaction. Thorax 2002;57:736–741.

   16. Carrel RW, Lomas DA. Alpha-1 antitrypsin deficiency: A model for conformational diseases. N Engl J Med 2002;346:45–53.

   17. Hunninghake GM, Cho MH, Tesfaigzi Y, et al. MMP12, lung function, and COPD in high-risk populations. N Engl J Med 2009;361:2599–2608.

   18. Barnes PJ. Chronic obstructive pulmonary disease. N Engl J Med 2000;343:269–280.

   19. Stockley RA. Neutrophils and the pathogenesis of COPD. Chest 2002;121:151S–155S.

   20. Hogg JC. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet 2004;364: 709–721.

   21. Hill AT, Bayley D, Stockely RA. The interrelationship of sputum inflammatory markers in patients with chronic bronchitis. Am J Respir Crit Care Med 1999;160:893–898.

   22. Ries AL. Impact of chronic obstructive pulmonary disease on quality of life: The role of dyspnea. Am J Med 2006;119:S12–S20.

   23. MacNee W. Pathophysiology of cor pulmonale in chronic obstructive pulmonary disease. Part 2. Am J Respir Crit Care Med 1994;150:1158–1168.

   24. Sin DD, Man SF. Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular disease? The potential role of systemic inflammation in chronic obstructive pulmonary disease. Circulation 2003;107:1514–1519.

   25. Casaburi R, ZuWallack R. Pulmonary rehabilitation for management of chronic obstructive pulmonary disease. N Engl J Med 2009;360:1329–1335.

   26. Rodriguez-Roisin R. Toward a consensus definition for COPD exacerbations. Chest 2000;117(Suppl 2):398S–401S.

   27. Ferris BG. Epidemiology standardization project (American Thoracic Society). Am Rev Respir Dis 1978;118:1–120.

   28. Jones PW, Harding G, Berry P, Wiklund L, Chen W-H, Kline Leidy N. Development and first validation of the COPD Assessment Test. Eur Respir J 2009;34:648–665.

   29. Anzueto A. Clinical course of chronic obstructive pulmonary disease: Review of therapeutic interventions. Am J Med 2006;119:S46–S53.

   30. Mannino DM, Doherty DE, Buist S. Global initiative on obstructive lung disease (GOLD) classification of lung disease and mortality: Findings from the atherosclerosis risk in communities (ARIC) study. Respir Med 2006;100: 115–122.

   31. Celli BR. The importance of spirometry in COPD and asthma. Chest 2000;117:15S–19S.

   32. Andersson F, Borg S, Janson S-A, et al. The costs of exacerbations in chronic obstructive pulmonary disease (COPD). Respir Med 2002;96:700–708.

   33. Anthonisen NR, Manfreda J, Warren CPW, et al. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 1987;106:196–204.

   34. Groenewegen KH, Schols AMW, Wouters EFM. Mortality and mortality-related factors after hospitalization for acute exacerbation of COPD. Chest 2003;124:459–467.

   35. Bach PB, Brown C, Gelfand SE, McCrory DC. Management of acute exacerbations of chronic obstructive pulmonary disease: A summary and appraisal of published evidence. Ann Intern Med 2001;134:600–620.

   36. Almagro P, Calbo E, Ochoa de Echaguen A, et al. Mortality after hospitalization for COPD. Chest 2002;121:1441–1448.

   37. Anzueto A. Impact of exacerbations on COPD. Eur Respir Rev 2010;19(116):113–118.

   38. Heffner JE, Fahy B, Hilling L, Barbieri C. Outcomes of advanced directive education of pulmonary rehabilitation patients. Am J Respir Crit Care Med 1997;155:1055–1059.

   39. Parrott S, Godfrey C, Raw M, et al. Guidance for commissioners on the cost-effectiveness of smoking cessation interventions. Health International Authority. Thorax 1998;53(Suppl 5):S1–S38.

   40. Anthonisen NR, Connett JE, Kiley JP, et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline in FEV1: The Lung Health Study. JAMA 1994;272: 1497–1505.

   41. Anthonisen NR, Skeans MA, Wise RA, Manfreda J, Kanner RE, Connett JE. The effects of a smoking cessation intervention on 14.5 year mortality: A randomized clinical trial. Ann Intern Med 2005;142:233–239.

   42. Fiore MC, Jaén CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Public Health Service. Rockville, MD: U.S. Department of Health and Human Services, May 2008, www.surgeongeneral.gov/tobacco.

   43. Jorenby DE, Leischow SJ, Nides MA, et al. A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med 1999;340:685–691.

   44. Tonstad S, Tonnesen P, Hajek P, et al. Effect of maintenance therapy with varenicline on smoking cessation: A randomized controlled trial. JAMA 2006;296:64–71.

   45. Celli BR, Halbert RJ, Nordyke RJ, Schan B. Airway obstruction in never smokers: Results from the Third National Health and Nutrition Examination Survey. Am J Med 2005;118:1364–1372.

   46. Oroczo-Levi M, Garcia-Aymerich J, Villar J, Ramirez-Samiento A, Anto JM, Gea J. Wood smoke exposure and risk of chronic obstructive pulmonary disease. Eur Respir J 2006;27:542–546.

   47. American Thoracic Society/European Respiratory Society. Statement on pulmonary rehabilitation. Am J Respir Crit Care Med 2006;173:1390–1413.

   48. Nichol KL, Margolis KL, Wourenma J, Von Sternberg T. The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community. N Engl J Med 1994;331:778–784.

   49. Advisory Committee on Immunization Practices, Smith NM, Bresee JS, et al. Prevention and control of influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2006;55:1–42.

   50. Jackson LA, Neuzil KM, Yu O, et al. Effectiveness of pneumococcal polysaccharide vaccine in older adults. N Engl J Med 2003;348:1747–1755.

   51. Alfageme I, Vazquez R, Reyes N, et al. Clinical efficacy of anti-pneumococcal vaccination in patients with COPD. Thorax 2006;61:189–195.

   52. Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease. Ann Intern Med 1980;93:391–398.

   53. Medical Research Council Working Party. Long-term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Lancet 1981;1:681–685.

   54. O’Donohue WJ. Home oxygen therapy. Med Clin North Am 1996;80:611–622.

   55. Ferreira IM, Brooks D, Lacasse Y, et al. Nutritional support for individuals with COPD: A meta-analysis. Chest 2000;117:672–678.

   56. Celli BR, Thomas NE, Anderson JA, et al. Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: Results from the TORCH study. Am J Respir Crit Care Med 2008;178: 332–338.

   57. Dolovich MB, Ahrens RC, Hess DR, et al. Device selection and outcomes of aerosol therapy: Evidence-based guidelines. Chest 2005;127:335–371.

   58. Puhan MA, Bachmann LM, Kleijnen J, ter Riet G, Kessels AG. Inhaled drugs to reduce exacerbations in patients with chronic obstructive pulmonary disease: A network meta-analysis. BMC Med 2009;7:2.

   59. Truitt T, Witko J, Halpern M. Levalbuterol compared to racemic albuterol: Efficacy and outcomes in patients hospitalized with COPD or asthma. Chest 2003;123: 128–135.

   60. Asmus MJ, Hendeles L. Levalbuterol nebulizer solution: Is it worth five times the cost of albuterol? Pharmacotherapy 2000;20:123–129.

   61. Datta D, Vitale A, Lahiri B, ZuWallack R. An evaluation of nebulized levalbuterol in stable COPD. Chest 2003;124: 844–849.

   62. O’Donnel DE, Lam M, Webb KA. Measurement of symptoms, lung hyperinflation, and endurance during exercise in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;158:1557–1565.

   63. Friedman M. A multicenter study of nebulized bronchodilator solutions in chronic obstructive pulmonary disease. Am J Med 1996;100(Suppl 1A):30S–39S.

   64. Wiggins J. The role of anticholinergics in “stable” chronic obstructive pulmonary disease: Unanswered questions. Respiration 1994;61:303–304.

   65. Ikeda A, Nishimura K, Koyama H, et al. Dose–response study of ipratropium bromide aerosol on maximum exercise performance in stable patients with chronic obstructive pulmonary disease. Thorax 1996;51:48–53.

   66. Tsukino M, Nishimura K, Ikeda A, et al. Effects of theophylline and ipratropium bromide on exercise performance in patients with stable chronic obstructive pulmonary disease. Thorax 1998;53:269–273.

   67. Martin RJ, Bartelson BL, Smith P, et al. Effect of ipratropium bromide treatment on oxygen saturation and sleep quality in COPD. Chest 1999;115:1338–1345.

   68. Mahler DA, Donohue JF, Barbee RA, et al. Efficacy of salmeterol xinafoate in the treatment of COPD. Chest 1999;115:957–965.

   69. Rennard SI, Anderson W, ZuWallack R, et al. Use of a long-acting β2-agonist, salmeterol xinafoate, in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163:1087–1092.

   70. van Noord JA, Smeets JJ, Raaijmakers JA, Bommer AM, Maesen FP. Salmeterol versus formoterol in patients with moderately severe asthma: Onset and duration of action. Eur Respir J 1996;9:1684–1688.

   71. Dougherty JA, Didur BL, Aboussouan LS. Long-acting inhaled beta2 agonists for stable COPD. Ann Pharmacother 2003;37:1247–1255.

   72. Bouros D, Kottakis J, LeGros V, Overend T, Della Cioppa G, Siafakas N. Effects of formoterol and salmeterol on resting inspiratory capacity in COPD patients with poor FEV1 reversibility. Curr Med Res Opin 2004;20: 581–586.

   73. Rennard, SI, Anderson W, ZuWallack R, et al. Use of a long-acting inhaled beta2 adrenergic agonist, salmeterol xinafoate, in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163:1087–1092.

   74. Dahl R, Greefhorst LA, Nowak D, et al. Inhaled formoterol dry powder versus ipratropium bromide in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:778–784.

   75. Barnes PJ. The pharmacological properties of tiotropium. Chest 2000;117:63S–66S.

   76. Casaburi R, Mayler DA, Jones PW, et al. A long-term evaluation of once daily inhaled ipratropium in chronic obstructive pulmonary disease. Eur Respir J 2002;19: 217–224.

   77. Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax 2003;58:399–404.

   78. Vincken W, van Noord JA, Greefhorst AP, et al. Improved health outcomes in patients with COPD during one year treatment with tiotropium. Eur Respir J 2002;19: 209–216.

   79. Barr RG, Bourbeau J, Camargo CA Jr, Ram FSF. Tiotropium for stable chronic obstructive pulmonary disease: A meta-analysis. Thorax 2006;61:854–862.

   80. Anzueto A, Tashkin D, Menjoge S, Kesten S. One year analysis of longitudinal changes in spirometry in patients with COPD receiving tiotropium. Pulm Pharmacol Ther 2005;18:75–81.

   81. Donohue JF, van Noord JA, Bateman ED, et al. A 6-month placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol. Chest 2002;122:47–55.

   82. Tashkin DP, Celli B, Senn S, et al. A 4 year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008;359:1543–1554.

   83. Lee TA, Pickard S, Au DH, Bartle B, Weiss KB. Risk for death associated with medications for recently diagnosed chronic obstructive pulmonary disease. Ann Intern Med 2008;149:380–390.

   84. Lee TA, Wilke C, Joo M, et al. Outcomes associated with tiotropium use in patients with chronic obstructive pulmonary disease. Arch Intern Med 2009;169:1403–1410.

   85. Celli B, Decramer M, Leimer I, Vogel U, Kesten S, Tashkin DP. Cardiovascular safety of tiotropium in patients with COPD. Chest 2010;137:2–30.

   86. Fuhr R, Magnussen H, Sarem K, et al. Efficacy of aclidinium bromide 400 μg twice daily compared with placebo and tiotropium in patients with moderate to severe COPD. Chest 2012;141(3):745–752.

   87. Combivent Inhalation Aerosol Study Group. In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone. Chest 1994;105:1411–1419.

   88. D’Urzo AD, De Salvo MC, Ramirez-Rivera A, et al. In patients with COPD, treatment with a combination of formoterol and ipratropium is more effective than a combination of salbutamol and ipratropium. Chest 2001;119:1347–1356.

   89. Karner C, Cates CJ. Long-acting beta2-agonist in addition to tiotropium versus either tiotropium alone or long-acting beta2-agonist alone for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2012; 4:CD008989.

   90. Barnes PJ. Theophylline in chronic obstructive pulmonary disease: New horizons. Proc Am Thorac Soc 2005;2: 334–339.

   91. Barnes PJ. Theophylline: New perspectives for an old drug. Am J Respir Crit Care Med 2003;167:813–818.

   92. Man GC, Chapman KR, Ali SH, Darke AC. Sleep quality and nocturnal respiratory function with once-daily theophylline (Uniphyl) and inhaled salbutamol in patients with COPD. Chest 1996;110:648–653.

   93. Nishimura K, Koyama H, Ikeda A, et al. The additive effect of theophylline on a high-dose combination of inhaled salbutamol and ipratropium bromide in stable COPD. Chest 1995;107:718–723.

   94. Karpel JP, Kotch A, Zinny M, et al. A comparison of inhaled ipratropium, oral theophylline plus inhaled beta agonist, and the combination of all three in patients with COPD. Chest 1994;105:1089–1094.

   95. ZuWallack RL, Mahler DA, Reilly D, et al. Salmeterol plus theophylline combination therapy in the treatment of COPD. Chest 2001;119:1661–1670.

   96. Callahan CM, Dittus RS, Katz BP. Oral corticosteroid therapy for patients with stable chronic obstructive pulmonary disease: A meta-analysis. Ann Intern Med 1991;114:216–223.

   97. Pizzichini E, Pizzichini MM, Gibson P, et al. Sputum eosinophilia predicts benefit from prednisone in smokers with chronic obstructive bronchitis. Am J Respir Crit Care Med 1998;158:1511–1517.

   98. Senderovitz T, Vestbo J, Frandsen J, et al. Steroid reversibility test followed by inhaled budesonide or placebo in outpatients with stable chronic obstructive pulmonary disease. The Danish Society of Respiratory Medicine. Respir Med 1999;93:715–718.

   99. Pauwels RA, Claes-Goran L, Latinen LA, et al. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. N Engl J Med 1999;340:1948–1953.

  100. Vestbo J, Sorenson T, Lange P, et al. Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: A randomized, controlled trial. Lancet 1999;353:1819–1823.

  101. Burge PS, Calverley PM, Jones PW, et al. Randomised, double-blind, placebo-controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: The ISOLDE trial. Br Med J 2000;320:1297–1303.

  102. Nishimura K, Koyama H, Ikeda A, et al. The effect of high-dose inhaled beclomethasone dipropionate in patients with stable COPD. Chest 1999;115:31–37.

  103. Weir DC, Bale GA, Bright P, Sherwood Burge P. A double-blind placebo-controlled study of the effect of inhaled beclomethasone dipropionate for 2 years in patients with nonasthmatic chronic obstructive pulmonary disease. Clin Exp Allergy 1999;29(Suppl 2):125–128.

  104. Paggiaro PL, Dahle R, Bakran I, et al. Multicentre, randomized, placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. International COPD Study Group. Lancet 1998;351:773–780.

  105. The Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med 2000;343:1902–1909.

  106. Sutherland ER, Allmers H, Ayas NT, Venn AJ, Martin RJ. Inhaled corticosteroids reduce the progression of airflow limitation in chronic obstructive pulmonary disease: A meta-analysis. Thorax 2003;58:937–941.

  107. Gartlehner G, Hansen RA, Carson SS, Lohr KN. Efficacy and safety of inhaled corticosteroids in patients with COPD: A systematic review and meta-analysis of health outcomes. Ann Fam Med 2006;4:253–262.

  108. Macie C, Wooldrage K, Manfreda J, Anthonisen NR. Inhaled corticosteroids and mortality in COPD. Chest 2006;130: 640–646.

  109. Sin DD, Wu L, Anderson JA, et al. Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease. Thorax 2005;60:992–997.

  110. Mapel DW, Hurley JS, Roblin D, et al. Survival of COPD patients using inhaled corticosteroids and long-acting beta agonists. Respir Med 2006;100:595–609.

  111. Calverley PMA, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775–789.

  112. Drummond MB, Dasenbrook EC, Pitz MW, Murphy DJ, Fan E. Inhaled corticosteroids in patients with stable chronic obstructive pulmonary disease: A systematic review and meta-analysis. JAMA 2008;300:2407–2416.

  113. Singh S, Amin AV, Loke YK. Long-term use of inhaled corticosteroids and the risk of pneumonia in chronic obstructive pulmonary disease: A meta-analysis. Arch Intern Med 2009;169:219–229.

  114. Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: A systematic review and meta-analysis. Arch Intern Med 1999;159:941–955.

  115. van Grunsven PM, van Schayck CP, Derenne JP, et al. Long-term effects of inhaled corticosteroids in chronic obstructive pulmonary disease: A meta-analysis. Thorax 1999;54:7–14.

  116. Hubbard R, Tatterfield A, Smith C, et al. Use of inhaled corticosteroids and the risk of fracture. Chest 2006;130:1082–1088.

  117. Jones A, Fay JK, Burr M, Stone M, Hood K, Roberts G. Inhaled corticosteroid effects on bone metabolism in asthma and mild chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2002;(1):CD003537.

  118. Decramer M, Ferguson G. Clinical safety of long acting beta2 agonists and inhaled corticosteroid combination therapy in COPD. COPD 2006;3:163–171.

  119. Calverly P, Pauwels R, Vestbo J, et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: A randomized, controlled trial. Lancet 2003;361:449–456.

  120. Szafranski W, Cukier A, Ramirez A, et al. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur Respir J 2003;21:74–81.

  121. Mahler DA, Wire P, Horstman D, et al. Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;166:1084–1091.

  122. Hanania NA, Darken P, Horstman D, et al. Efficacy and safety of fluticasone propionate (250 mcg) and salmeterol (50 mcg) combined in the Diskus inhaler for the treatment of COPD. Chest 2003;124:834–843.

  123. Calverley PM, Boonsawat W, Cseke Z, Zhong N, Peterson S, Olsson H. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J 2003;22:912–919.

  124. Kardos P, Wencker M, Glaab T, Vogelmeier C. Impact of salmeterol/fluticasone propionate versus salmeterol on exacerbations in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;175:144–149.

  125. Wedzicha JA, Calverley PM, Seemungal TA, et al. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med 2008;177:19–26.

  126. Baloria VA, Vialrino PC. Bronchodilator efficacy of combined salmeterol and tiotropium in patients with chronic obstructive pulmonary disease. Arch Bronchopneumol 2005;41:130–134.

  127. Aaron SD, Vandemheen KL, Fergusson D, et al. Tiotropium in combination with placebo, salmeterol or fluticasone–salmeterol for treatment of chronic obstructive pulmonary disease. Ann Intern Med 2007;146:545–555.

  128. Perng DW, Wu CC, Su KC, Lee YC, Perng RP, Tao CW. Additive benefits of tiotropium in COPD patients treated with long-acting beta2 agonists and corticosteroids. Respirology 2006;11:598–602.

  129. Juvelekian GS, Stoller JK. Augmentation therapy for alpha1 antitrypsin deficiency. Drugs 2004;64:1743–1756.

  130. Alpha-1-Antitrypsin Deficiency Registry Study Group. Survival and FEV1 decline in individuals with severe deficiency of alpha-1-antitrypsin. Am J Respir Crit Care Med 1998;158:49–59.

  131. Dirksen A, Dijkman JH, Madsen F, et al. A randomized clinical trial of alpha-1-antitrypsin augmentation therapy. Am J Respir Crit Care Med 1999;160:1468–1472.

  132. Gildea TR, Shermock KM, Singer ME, et al. Cost-effectiveness analysis of augmentation therapy for severe alpha1 antitrypsin deficiency. Am J Respir Crit Care Med 2003;167:1387–1392.

  133. Stoller JK, Fallat R, Schluchter MD, et al. Augmentation therapy with alpha1 antitrypsin: Patterns of use and adverse events. Chest 2003;123:1425–1434.

  134. Quon BS, Gan WQ, Sin DD. Contemporary management of acute exacerbations of COPD: A systematic review and metaanalysis Chest 2008;133:756–766.

  135. Lightowler JV, Wedzicha JA, Elliott MW, et al. Noninvasive positive pressure ventilation to treat respiratory failure resulting from exacerbations of chronic obstructive pulmonary disease: Cochrane systemic review and meta-analysis. Br Med J 2003;326:185–189.

  136. Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group. N Engl J Med 1999;340:1941–1947.

  137. Davies L, Angus RM, Calverley PMA. Oral corticosteroids in patients admitted to hospital with exacerbations of chronic obstructive pulmonary disease: A prospective, randomised, controlled trial. Lancet 1999;354:456–460.

  138. Thompson WH, Nielson CP, Carvalho P, et al. Controlled trial of oral prednisone in outpatients with acute COPD exacerbation. Am J Respir Crit Care Med 1996;154:407–412.

  139. Sayiner A, Aytemur ZA, Cirit M, et al. Systemic glucocorticoids in severe exacerbations of COPD. Chest 2001;119:726–730.

  140. Aaron SD, Vandemheen KL, Hebert P, et al. Outpatient oral prednisone after emergency treatment of chronic obstructive pulmonary disease. N Engl J Med 2003;348:2618–2625.

  141. Vondracek SF, Hemstreet BA. Is there an optimal corticosteroid regimen for the management of an acute exacerbation of chronic obstructive pulmonary disease? Pharmacotherapy 2006;26:522–532.

  142. Stallberg B, Selroos O, Vogelmeier C, Andersson E, Ekstrom T, Larsson K. Budesonide/formoterol as effective as prednisolone plus formoterol in acute exacerbations of COPD: A double blind, randomized, non-inferiority, parallel group, multicenter study. Respir Res 2009;10:11.

  143. Saint S, Bent S, Vittinghoff E, Grady D. Antibiotics in chronic obstructive pulmonary disease exacerbations: A meta-analysis. JAMA 1995;273:957–960.

  144. Niederman MS. Antibiotic therapy for exacerbations of chronic bronchitis. Semin Respir Infect 2000;15:59–70.

  145. Chodosh S, DeAbate C, Haverstock D, Aneiro L, Church D. Short-course moxifloxacin therapy for treatment of acute bacterial exacerbations of chronic bronchitis. Respir Med 2000;94:18–27.

  146. Rizkallah J, Man SF, Sin DD. Prevalence of pulmonary embolism in acute exacerbations of COPD: A systematic review and metaanalysis. Chest 2009;135:786–793.

  147. Albert RK, Connett J, Bailey WD, et al. Azithromycin for prevention of exacerbation in COPD. N Engl J Med 2011;365:689–698.

  148. Ray WA, Murray KT, Hall K, et al. Azithromycin and the risk of cardiovascular death. N Engl J Med 2012;366: 1881–1890.

  149. Jenning AL, Davies AN, Higgins JP, Gibbs JS, Broadley KE. A systematic review of the use of opioids in the management of dyspnea. Thorax 2002;57:939–944.

  150. Stolz D, Linka A, Di Valentino M, Meyer A, Brutsche M, Tamm M. A randomized, controlled trial of bosentan in severe COPD. Eur Respir J 2008;32:619–628.

  151. Fishman A, Martinez F, Naunheim K, et al. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 2003;348:2059–2073.

  152. Snyder ML, Goss CH, Neradilek B, et al. National Emphysema Treatment Trial Research Group. Changes in arterial oxygenation and self-reported oxygen use after lung volume reduction surgery. Am J Respir Crit Care Med 2008;178:339–345.

  153. Deacon SJ, Vincent EE, Greenhaff PL, et al. Randomized controlled trial of dietary creatine as an adjunct therapy to physical training in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008;178:233–239.

  154. Rennard SI, Fogarty C, Kelsen S, et al. The safety and efficacy of infliximab in moderate to severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;175:926–934.

  155. Miravitlles M, Murio C, Guerrero T, Gisbert R. Pharmacoeconomic evaluation of acute exacerbations of chronic bronchitis and COPD. Chest 2002;121:1449–1455.

  156. Grossman RF, Mukerjee J, Vaughan D, et al. A one-year community-based health economic study of ciprofloxacin versus usual antibiotic treatment in acute exacerbations of chronic bronchitis. Chest 1998;113:131–141.

  157. Gallefoss F. The effects of patient education in COPD in a 1-year follow-up randomized, controlled trial. Patient Educ Couns 2004;52:259–266.

  158. Friedman M, Serby CW, Menjoge SS, et al. Pharmacoeconomic evaluation of a combination of ipratropium plus albuterol compared with ipratropium alone and albuterol alone in COPD. Chest 1999;115: 635–641.

  159. Hansen-Flashen J. Chronic obstructive pulmonary disease: The last year of life. Respir Care 2004;49:90–97.