Tara R. Whetsel and Nicole D. Verkleeren
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Describe the pathophysiology of chronic obstructive pulmonary disease (COPD).
2. Identify signs and symptoms of COPD.
3. List the treatment goals for a patient with COPD.
4. Design an appropriate COPD treatment regimen based on patient-specific data.
5. Develop a monitoring plan to assess effectiveness and adverse effects of pharmacotherapy for COPD.
6. Formulate an appropriate education plan for a patient with COPD.
KEY CONCEPTS
Inflammation plays a key role in the pathophysiology of chronic obstructive pulmonary disease (COPD), but it differs from that seen in asthma; therefore, the use of and response to anti-inflammatory medications are different.
An integrated approach of health maintenance (e.g., smoking cessation), drug therapy, and supplemental therapy (e.g., oxygen and pulmonary rehabilitation) should be used in a stepwise manner.
Smoking cessation slows the rate of decline in pulmonary function in patients with COPD.
Bronchodilators are the mainstay of treatment for symptomatic COPD. They reduce symptoms and improve exercise tolerance and quality of life. In patients with moderate to severe COPD, bronchodilators may reduce the rate of decline in pulmonary function.
In symptomatic patients with severe COPD and frequent exacerbations, regular treatment with inhaled corticosteroids decreases the number of exacerbations per year and improves health status. Corticosteroids may reduce the rate of decline in pulmonary function in patients with moderate to severe COPD.
Antibiotics should be used in patients with COPD exacerbations who: (a) have all three cardinal symptoms (increased dyspnea, increased sputum volume, and increased purulence); (b) have increased sputum purulence along with one other cardinal symptom; or (c) experience a severe exacerbation requiring mechanical ventilation.
INTRODUCTION
Chronic obstructive pulmonary disease (COPD) is a progressive disease characterized by airflow limitation that is not fully reversible. It is caused by exposure to noxious particles or gases, most commonly cigarette smoke. It is a major cause of morbidity and mortality and a leading cause of disability in the United States.
COPD includes chronic bronchitis and emphysema. Chronic bronchitis is defined clinically as a chronic productive cough for at least 3 months in each of two consecutive years in a patient in whom other causes have been excluded.1 Emphysema is defined pathologically as the presence of permanent enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of their walls without obvious fibrosis.1 The major risk factor for both conditions is cigarette smoking, and many patients share characteristics of each condition. Therefore, new consensus guidelines have moved away from using these subsets and instead focus on chronic airflow limitation.
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) is an expert panel of health professionals who have developed a consensus document with recommendations for the diagnosis and care of patients with COPD.2The online document is updated annually and is commonly referred to as the GOLD guidelines. The American Thoracic Society (ATS) and the European Respiratory Society (ERS) have jointly published standards for the diagnosis and treatment of patients with COPD.1 The ATS-ERS guidelines provide more specific recommendations on oxygen therapy, pulmonary rehabilitation, and other treatment issues than the broader GOLD guidelines.
EPIDEMIOLOGY AND ETIOLOGY
In 2006, 12.1 million U.S. adults 18 years of age and older reported having COPD.3 The true prevalence is larger; COPD is underdiagnosed because many patients have few or no symptoms in the early stages.
COPD is the fourth leading cause of death in the United States; in 2005,127,049 adults died from the disease.3 In 2007, COPD was estimated to cost the United States $42.6 billion, with direct medical costs accounting for $26.7 billion of the total.3 Morbidity, mortality, and costs are all expected to increase over the next decade; by 2020, it is expected to be the third leading cause of death worldwide.2
Exposures and host factors play a role in the development of COPD. Cigarette smoking is the leading cause of COPD and accounts for 80% to 90% of cases in developed countries.4 Environmental tobacco smoke (i.e., secondhand smoke) may increase the risk of COPD.2 Occupational exposure to dusts and chemicals (vapors, irritants, and fumes) also plays a role. Environmental air pollution has been implicated as an etiologic factor, but its exact role is unclear. Not all smokers develop clinically significant COPD, which suggests that genetic susceptibility plays a role. The best documented genetic factor is a rare hereditary deficiency of α1-antitrypsin (AAT). Severe deficiency of this enzyme results in premature and accelerated development of emphysema. Asthma and airway hyper-responsiveness have been identified as risk factors, but how they influence the development of COPD is unknown. Failure to reach maximal lung function, due to recurrent infections or exposure to tobacco smoke during childhood, may also increase the risk of COPD.
PATHOPHYSIOLOGY
COPD is characterized by pathologic changes in the central airways, peripheral airways, lung parenchyma, and pulmonary vasculature. Chronic inflammation in the lung from repeated exposure to noxious particles and gases is primarily responsible for these changes.2 An imbalance between proteinases and antiproteinases in the lung and oxidative stress are also thought to be important in the pathogenesis of COPD. These processes may be a result of ongoing inflammation or may arise from environmental (e.g., oxidants in cigarette smoke) or genetic (e.g., AAT deficiency) factors (Fig. 15–1).2 In addition to these destructive processes, chronic inflammation and exposure to noxious particles and gases disrupts or impairs the normal protective and repair mechanisms.
Inflammation is present in the lungs of all smokers. It is unclear why only 15% to 20% of smokers develop COPD, but susceptible individuals appear to have an exaggerated inflammatory response.5 The inflammation of COPD differs from that seen in asthma, so the use of anti-inflammatory medications and the response to those medications are different. The inflammation of asthma is mainly mediated through eosinophils and mast cells. In COPD, the primary inflammatory cells include neutrophils, macrophages, and CD8+ T lymphocytes. Eosinophils may be increased in some patients, particularly during exacerbations. Activated inflammatory cells release a variety of mediators, most notably leukotriene B4, interleukin-8, and tumor necrosis factor-α (TNF-α). Various proteinases, such as elastase, cathepsin G, and proteinase-3, are secreted by activated neutrophils. These mediators and proteinases are capable of sustaining inflammation and damaging lung structures.
FIGURE 15–1. Pathophysiology of COPD.
Proteinases and antiproteinases are part of the normal protective and repair mechanisms in the lungs. The imbalance of proteinase-antiproteinase activity in COPD is a result of either increased production or activity of destructive proteinases or inactivation or reduced production of protective antiproteinases. AAT (an antiproteinase) inhibits trypsin, elastase, and several other proteolytic enzymes. Deficiency of AAT results in unopposed proteinase activity, which promotes destruction of alveolar walls and lung parenchyma, leading to emphysema.
Markers of oxidative stress (e.g., hydrogen peroxide, nitric oxide, and isoprostane F2 α-III) have been found in the epithelial fluid, breath, and urine of cigarette smokers and patients with COPD.2 Increased oxidative stress contributes to COPD in a variety of ways. Oxidants (e.g., reactive oxygen species, superoxide, and nitric oxide) can react with and damage a variety of molecules leading to cell dysfunction and damage to the lung extracellular matrix. Oxidative stress promotes inflammation and contributes to the proteinase-antiproteinase imbalance by reducing antiproteinase activity. In addition, oxidants constrict airway smooth muscle, contributing to reversible airway narrowing.
In the central airways (the trachea, bronchi, and bronchioles greater than 2 to 4 mm in internal diameter), inflammatory cells and mediators stimulate mucus-secreting gland hyperplasia and mucus hypersecretion. Mucus hypersecretion and ciliary dysfunction lead to chronic cough and sputum production. The major site of airflow obstruction is the peripheral airways (small bronchi and bronchioles with an internal diameter less than 2 mm). Three mechanisms are postulated to be involved in the narrowing of these small airways.2 Airways may be blocked by inflammatory exudates and mucus hypersecretion. Loss of elasticity and destruction of alveolar attachments leads to loss of support and closure of small airways during expiration. Infiltration of inflammatory cells, increased smooth muscle tissue, and fibrosis cause thickening of airway walls. Of these mechanisms, the structural changes in the airway walls are the most important cause of fixed airflow obstruction.
As airflow obstruction worsens, the rate of lung emptying is slowed and the interval between inspirations does not allow expiration to the relaxation volume of the lungs. This leads to pulmonary hyperinflation, which initially only occurs during exercise, but later is also seen at rest. Hyperinflation contributes to the discomfort associated with airflow obstruction by flattening the diaphragm and placing it at a mechanical disadvantage.
In advanced COPD, airflow obstruction, damaged bronchioles and alveoli, and pulmonary vascular abnormalities lead to impaired gas exchange. This results in hypoxemia and eventually hypercapnia.Hypoxemia is initially present only during exercise but occurs at rest as the disease progresses. Inequality in the ventilation-to-perfusion ratio (VA/Q) is the major mechanism behind hypoxemia in COPD. As hypoxemia worsens, the body may compensate by increasing the production of erythrocytes in an attempt to increase oxygen delivery to tissues.
Pulmonary hypertension develops late in the course of COPD, usually after the development of severe hypoxemia. It is the most common cardiovascular complication of COPD and can result in cor pulmonale,or right-sided heart failure. Hypoxemia plays the primary role in the development of pulmonary hypertension by causing vasoconstriction of the pulmonary arteries and promoting vessel wall remodeling. Destruction of the pulmonary capillary bed by emphysema further contributes by increasing the pressure required to perfuse the pulmonary vascular bed. Cor pulmonale is associated with venous stasis and thrombosis that may result in pulmonary embolism. Another important systemic effect is the progressive loss of skeletal muscle mass, which contributes to exercise limitations and declining health status. These extrapulmonary effects may contribute to disease severity and should not be overlooked.
CLINICAL PRESENTATION AND DIAGNOSIS
Diagnosis
A suspected diagnosis of COPD should be based on the patient’s symptoms and/or history of exposure to risk factors. Spirometry is required to confirm the diagnosis. The presence of a postbronchodilator FEV1/FVC ratio less than 70% (the ratio of forced expiratory volume in 1 second [FEV1 to forced vital capacity [FVC]) confirms the presence of airflow limitation that is not fully reversible.1,2 Spirometry results can further be used to classify COPD severity (Table 15–1). Full pulmonary function tests (PFTs) with lung volumes and diffusion capacity and arterial blood gases (ABGs) are not necessary to establish the diagnosis or severity of COPD.
Clinical Presentation and Diagnosis of COPD
General
• Patients with COPD are initially asymptomatic. The disease is usually not diagnosed until declining lung function leads to significant symptoms and prompts patients to seek medical care.
Symptoms
• The onset of symptoms is variable but often does not occur until the FEV1 has fallen to approximately 50% of predicted.2
• Initial symptoms include chronic cough (duration greater than 3 months), which may be intermittent at first, chronic sputum production, and dyspnea on exertion.
• As COPD progresses, dyspnea at rest develops and the ability to perform activities of daily living declines.
Signs
• Observation of the patient may reveal use of accessory muscles of respiration (manifested as paradoxical movements of the chest and abdomen, in a “seesaw”-type motion), pursed-lips breathing, and hyperinflation of the chest with increased anterior-posterior diameter (“barrel chest”).
• On auscultation of the lungs, patients may have distant breath sounds, wheezing, a prolonged expiratory phase of respiration, and rhonchi.
• In advanced COPD, signs of hypoxemia may include cyanosis and tachycardia.
• Signs of cor pulmonale include increased pulmonic component of the second heart sound, jugular venous distention (JVD), lower extremity edema, and hepatomegaly.
Laboratory Tests
• Hematocrit may be elevated and may exceed 55% (polycythemia).
• Arterial blood gases (ABGs) should be obtained in patients with an FEV1 less than 40% predicted or signs or symptoms suggestive of cor pulmonale or respiratory failure.2 COPD patients characteristically exhibit normal or increased arterial carbon dioxide tension (PaCO2) and decreased arterial oxygen tension (PaO2).
• An AAT level should be obtained in younger patients (less than 45 years old) presenting with COPD signs and symptoms, especially if there is a strong family history of emphysema.
Table 15–1 GOLD Classification of COPD Severitya
It is important to distinguish COPD from asthma because treatment and prognosis differ. Differentiating factors include age of onset, smoking history, triggers, occupational history, and degree of reversibility measured by pre-and postbronchodilator spirometry. In some patients, a clear distinction between asthma and COPD is not possible. Management of these patients should be similar to that of asthma. Bronchiectasis, cystic fibrosis, obliterative bronchiolitis, congestive heart failure, and tuberculosis are other possible differential diagnoses that are usually easier to distinguish from COPD. Chest radiography or high-resolution CT along with patient presentation help rule out these other lung diseases.
TREATMENT
Desired Outcomes
The goals of COPD management include: (a) smoking cessation; (b) reducing symptoms; (c) minimizing the rate of decline in lung function; (d) maintaining or improving the quality of life; (e) preventing and treating exacerbations; and (f) limiting complications.
General Approach to Treatment
An integrated approach of health maintenance (e.g., smoking cessation), drug therapy, and supplemental therapy (e.g., oxygen and pulmonary rehabilitation) should be used in a stepwise manner.Table 15–2 provides an overview of the management of stable COPD.
Patient Encounter, Part 1
A 49-year-old man with a medical history of hypertension presents to the clinic complaining of shortness of breath that began about 3 to 4 years ago. His symptoms have gradually gotten worse since then. He is now unable to walk 100 yards without having to stop and rest. He also has a daily cough that is usually productive of yellowish sputum. He smokes about one and a half packs of cigarettes a day and has done so for the last 30 years. He also drinks on average six to seven beers a day. He does not have any significant occupational exposures to dust, gases, or fumes.
What information is suggestive of COPD?
What risk factors does he have for COPD?
What additional information do you need to know before creating a treatment plan for this patient?
Nonpharmacologic Therapy
Smoking Cessation
Smoking cessation slows the rate of decline in pulmonary function in patients with COPD.6,7 Stopping smoking can also reduce cough and sputum production and decrease airway reactivity. Therefore, it is a critical part of any treatment plan for patients with COPD. Unfortunately, achieving and maintaining cessation is a major challenge. A clinical practice guideline from the U.S. Public Health Service recommends a specific action plan depending on the current smoking status and desire to quit (Fig. 15–2).8 Brief interventions are effective and can increase cessation rates significantly. The five As and the five Rs can be used to guide brief interventions (Table 15–3).
Table 15–2 Treatment Algorithm for Stable COPD
All tobacco users should be assessed for their readiness to quit and appropriate strategies implemented. Those who are ready to quit should be treated with a combination of counseling on behavioral and cognitive strategies and pharmacotherapy (nicotine replacement therapy, sustained-release bupropion, or varenicline; refer to Smoking Cessation in Chap. 36). In COPD patients, the likelihood of sustained abstinence is higher with nicotine replacement therapy than that with sustained-release bupropion.9
Pulmonary Rehabilitation
Pulmonary rehabilitation results in significant and clinically meaningful improvements in dyspnea, exercise capacity, β health status, and health care utilization.10 It should be considered for patients with COPD who have dyspnea or other respiratory symptoms, reduced exercise capacity, a restriction in activities because of their disease, or impaired health status.1 A comprehensive pulmonary rehabilitation program should include exercise training, nutrition counseling, and education. It should cover a range of nonpulmonary problems including exercise deconditioning, relative social isolation, altered mood states (especially depression), muscle wasting, and weight loss.
FIGURE 15–2. Algorithm for routine assessment of tobacco use status. (From Ref. 8.)
Rehabilitation programs may be conducted in the inpatient, outpatient (most common), or home setting. The minimum length of an effective program is 2 months; the longer the program, the more sustained the results.10 It is important for patients to continue with a home exercise program to maintain the benefits gained from the pulmonary rehabilitation program.
Table 15–3 Components of Brief Interventions for Tobacco Users
|
The 5 As for Brief Intervention |
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Ask: Identify and document tobacco-use status for every patient at every visit |
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Advise: Urge every tobacco user to quit |
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Assess: Is the tobacco user willing to make a quit attempt at this time? |
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Assist: Use counseling and pharmacotherapy to help patients willing to make a quit attempt |
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Arrange: Schedule follow-up contact, preferably within the first week after the quit date |
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The 5 Rs to Motivate Smokers Unwilling to Quit at Present |
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Relevance: Tailor advice and discussion to each smoker |
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Risks: Help the patient identify potential negative consequences of tobacco use |
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Rewards: Help the patient identify the potential benefits of quitting |
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Roadblocks: Help the patient identify barriers to quitting |
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Repetition: Repeat the motivational message at every visit |
Long-Term Oxygen Therapy
Long-term administration of oxygen (greater than 15 hours per day) to patients with chronic respiratory failure has been shown to reduce mortality and improve quality of life.1,2 Oxygen therapy should be initiated in stable patients with very severe COPD (GOLD stage IV) who are optimized on drug therapy and meet one of the following criteria: (a) A resting PaO2 at or below 55 mm Hg (7.32 kPa) or oxygen saturation (SaO2) at or below 88%; or (b) PaO2between 55 and 60 mm Hg (7.32 and 7.98 kPa) or SaO2 of 89% and evidence of pulmonary hypertension, peripheral edema suggesting congestive heart failure, or polycythemia.1,2
The dual-prong nasal cannula is the standard means of delivering continuous flow of oxygen. The goal of therapy is to increase the baseline oxygen saturation to at least 90% and/or PaO2 to at least 60 mm Hg (7.98 kPa), allowing adequate oxygenation of vital organs. The flow rate, expressed as liters per minute (L/min), must be increased during exercise and sleep and can be adjusted based on pulse oximetry. Hypoxemia also worsens during air travel; patients requiring oxygen should generally increase their flow rate by 2 L/min during flight.1
Oxygen therapy should be continued indefinitely if it was initiated while the patient was in a stable state (rather than during an acute episode). Withdrawal of oxygen because of improved PaO2 in such a patient may be detrimental.
Surgery
Bullectomy, lung volume reduction surgery, and lung transplantation are surgical options for very severe COPD. These procedures may result in improved spirometry, lung volumes, exercise capacity, dyspnea, health-related quality of life, and possibly survival. Patient selection is critical because not all patients benefit. Refer to the ATS/ERS COPD standards for a detailed discussion of appropriate selection of surgical candidates.1
Pharmacologic Therapy of Stable COPD
The medications available for COPD are effective for reducing or relieving symptoms, improving exercise tolerance, reducing the number and severity of exacerbations, and improving quality of life. Evidence showing that medications slow the rate of decline in pulmonary function are conflicting, with more recent studies showing a benefit.11
Bronchodilators
Bronchodilators are the mainstay of treatment for symptomatic COPD. They reduce symptoms and improve exercise tolerance and quality of life.2 They can be used as needed for symptoms or on a scheduled basis to prevent or reduce symptoms. Bronchodilator drugs commonly used in COPD include β2-agonists, anticholinergics, and theophylline. The choice depends on availability, individual response, and preferences. The inhaled route is preferred, but attention must be paid to proper inhaler technique training. Long-acting inhaled bronchodilators are more effective and convenient but more expensive than short-acting inhaled bronchodilators. Combination therapy improves efficacy and is preferred over increasing the dose of a single agent, especially since the dose-response relationship using FEV1 as the outcome is relatively flat for single-agent therapy.
β2--Agonists
β2-Agonists cause airway smooth muscle relaxation by stimulating adenyl cyclase to increase the formation of cyclic adenosine monophosphate (cAMP). Other nonbronchodilator effects have been observed, such as improvement in mucociliary transport, but their significance is uncertain.12 β2-Agonists are available in inhalation, oral, and parenteral dosage forms; the inhalation route is preferred because of fewer adverse effects.
These drugs are also available in short-acting and long-acting formulations (Table 15–4). The short-actingβ2-agonists include albuterol (known as salbutamol outside the United States), levalbuterol (known as R-salbutamol outside the United States), pirbuterol, and terbutaline. They are used as “rescue” therapy for acute symptom relief. Most COPD patients need continuous bronchodilator therapy on a scheduled basis every day. For these patients, short-acting β2-agonists are inconvenient because of the need for frequent dosing. In addition, short-acting β2-agonists have been associated with a slight, but statistically significant, loss of effectiveness when used regularly for more than 3 months (tachyphylaxis).13
Long-acting β2-agonists include salmeterol, formoterol, and arformoterol. Salmeterol is a partial agonist with a slower onset of action than short-acting β2-agonists. Formoterol is a more complete agonist and has an onset of action similar to that of albuterol. Arformoterol is the (R, R)-isomer of formoterol; both are available for nebulization, providing an alternative for patients with poor inhaler technique. Full agonists (formoterol and arformoterol) produce greater response at full receptor capacity than partial agonists (salmeterol). Bronchodilator effects of long-acting β2-agonists last at least 12 hours, allowing for twice-daily dosing. Long-acting bronchodilators (LABDs) are superior to scheduled short-acting bronchodilators on important clinical outcomes, including frequency of exacerbations, degree of dyspnea, and health-related quality of life.12 For symptomatic patients, these are preferred over short-acting agents for maintenance therapy. In patients with moderate-to-severe COPD, salmeterol can reduce the rate of decline of FEV1.11 Patients should also have a short-acting β2-agonist such as albuterol available for as-needed use (“rescue” medication).
Adverse effects of both long-and short-acting β2-agonists are dose-related and include palpitations, tachycardia, hypokalemia, and tremor. Sleep disturbance may also occur and appears to be worse with higher doses of inhaled long-acting β2-agonists. Increasing doses beyond those clinically recommended is without benefit and could be associated with increased adverse effects.
Anticholinergics
Ipratropium and tiotropium are inhaled anticholinergic medications commonly used for COPD. They produce bronchodilation by competitively blocking muscarinic receptors in bronchial smooth muscle. They may also decrease mucus secretion, although this effect is variable. Tiotropium dissociates from receptors extremely slowly, resulting in a half-life longer than 36 hours, allowing for once-daily dosing. Ipratropium has an elimination half-life of about 2 hours, necessitating dosing every 6 to 8 hours.
Table 15–4 Maintenance Medications for COPD
Tiotropium provides the most consistent improvements on the widest range of outcomes among all the broncho-dilators. It has been shown to be superior to ipratropium and salmeterol in improving lung function and superior to ipratropium in relieving symptoms, reducing exacerbation frequency, and improving health status.14,15 Because of its superior efficacy, tiotropium is considered first-line therapy for all COPD patients with persistent symptoms (e.g., dyspnea, need for rescue medication more than twice a week, and night waking). The largest drawback to widespread use of tiotropium is the high cost of therapy. Patients using tiotropium as maintenance therapy should be prescribed albuterol as their rescue therapy. The combination of ipratropium and tiotropium is not recommended because of the risks of excessive anticholinergic effects.
Inhaled anticholinergics are well tolerated with the most common adverse effect being dry mouth. Occasional metallic taste has also been reported with ipratropium. Other anticholinergic adverse effects include constipation, tachycardia, blurred vision, and precipitation of narrow-angle glaucoma symptoms. Urinary retention could be a problem, especially for those with concurrent bladder outlet obstruction. Recent studies suggest that inhaled anticholinergics may increase the risk of myocardial infarction and cardiovascular death in patients with COPD.16,17 Further study is needed to clarify this risk. When initiating anticholinergic medications in patients with COPD, this potential risk should be weighed against the symptomatic benefits.
Methylxanthines
Theophylline is a nonspecific phospho-diesterase inhibitor that increases intracellular cAMP within airway smooth muscle resulting in bronchodilation. It has a modest bronchodilator effect in patients with COPD, and its use is limited due to a narrow therapeutic index, multiple drug interactions, and adverse effects. Theophylline should be reserved for patients who cannot use inhaled medications or who remain symptomatic despite appropriate use of inhaled bronchodilators.
Theophylline’s bronchodilatory effects are dependent upon achieving adequate serum concentrations, and therapeutic drug monitoring is needed to optimize therapy because of wide interpatient variability. If theophylline is used, serum concentrations in the range of 5 to 15 mcg/mL (28–83 μmol/L) provide adequate clinical response with a greater margin of safety than the traditionally recommended range of 10 to 20 mcg/mL (55–110 μmol/L). The most common adverse effects include heartburn, restlessness, insomnia, irritability, tachycardia, and tremor. Dose-related adverse effects include nausea and vomiting, seizures, and arrhythmias.
Tobacco smoke contains chemicals that induce the cytochrome P-450 isoenzymes 1A1, 1A2, and 2E1. Theophylline is metabolized by 1A2 and 2E1, and therefore smoking leads to increased clearance and subsequently decreased plasma levels of the drug.18 Because most patients with COPD are current or past smokers, it is important to assess current tobacco use and adjust the theophylline dose as required based on altered plasma theophylline levels if tobacco use changes.
Combinations of Bronchodilators
Patients with COPD often need maintenance treatment with two or three bronchodilators. Combining albuterol plus ipratropium, a long-acting β2-agonist plus theophylline, or a long-acting β2-agonist plus tiotropium, produces a greater change in spirometry than either drug alone.1,2,19,20 Administering a long-acting β2-agonist plus ipratropium leads to fewer exacerbations than either drug alone.21 A combination of all three bronchodilator classes (β2-agonist, anticholinergic, and theophylline) can be used if the response to a two-drug combination is inadequate. However, this approach has not been evaluated adequately in clinical trials.
Corticosteroids
In symptomatic patients with severe COPD (FEV1less than 50% predicted) and frequent exacerbations, regular treatment with inhaled corticosteroids decreases the number of exacerbations per year and improves health status.2,22–26 Corticosteroids may reduce the rate of decline in pulmonary function in patients with moderate to severe COPD.11 They do not appear to improve mortality.27 A combination inhaler device is recommended when using a long-acting β2-agonist with an inhaled corticosteroid (e.g., Advair [fluticasone/salmeterol] and Symbicort [budesonide/formoterol]).
Patients should be reassessed 6 to 8 weeks after initiating inhaled corticosteroids to determine whether there has been a positive response. A positive response is indicated by an increase in FEV1 of 15% or more, improvement in symptoms, and/or improvement in 6-minute walking distance.28 Treatment should be discontinued if no substantial clinical or physiologic improvement is seen.1,28
Upon discontinuation of inhaled corticosteroids, some patients may experience deterioration in lung function and an increase in dyspnea and mild exacerbations; it is reasonable to reinstitute the medication in these patients.29
The most common adverse effects from inhaled corticosteroids include oropharyngeal candidiasis and hoarse voice. These can be minimized by rinsing the mouth after use and by using a spacer device with metered-dose inhalers (MDIs). Increased bruising, decreased bone density, and increased incidence of pneumonia have also been reported; the clinical importance of these effects remains uncertain.1,2,22,27
Long-term use of oral corticosteroids should be avoided due to an unfavorable risk-to-benefit ratio. The steroid myopathy that can result from long-term use of oral corticosteroids weakens muscles, further decreasing the respiratory drive in patients with advanced disease.
Immunizations
Serious illness and death in COPD patients can be reduced by about 50% with annual influenza vaccination. The optimal time for vaccination is usually from early October through mid-November. All patients with COPD should also receive a one-time vaccination with the pneumococcal polysaccharide vaccine, even though sufficient data supporting its use in COPD patients are lacking.1,2 Patients over 65 years of age should be revaccinated if it has been more than 5 years since initial vaccination and they were less than 65 years of age at the time.
α1-Antitrypsin Augmentation Therapy
The ATS and the ERS have published standards for the diagnosis and management of individuals with AAT deficiency.30 They recommend IV augmentation therapy for individuals with AAT deficiency and moderate airflow obstruction (FEV1 35–60% predicted). In these patients, augmentation therapy appears to reduce overall mortality and slow the decline in FEV1, although large randomized controlled trials have not been conducted.
Augmentation therapy consists of weekly transfusions of pooled human AAT with the goal of maintaining adequate plasma levels of the enzyme. The benefits of augmentation therapy are unclear in patients with severe (FEV1less than 35% predicted) or mild (FEV1 greater than 60% predicted) airflow obstruction. Augmentation therapy is not recommended for individuals with AAT deficiency who do not have lung disease.
Other Pharmacologic Therapies
Leukotriene modifiers (e.g., zafirlukast and montelukast) have not been adequately evaluated in COPD patients and are not recommended for routine use. Small, short-term studies showed improvement in pulmonary function, dyspnea, and quality of life when leukotriene modifiers were added to inhaled bronchodilator therapy.31,32 Additional long-term studies are needed to clarify their role.
Nedocromil, a mast cell stabilizer, has not been adequately tested in COPD patients and is not included in the GOLD recommendations.
N-acetylcysteine has antioxidant and mucolytic activity, which makes it a promising agent for COPD treatment, but clinical trials have produced conflicting results. One of the largest trials found N-acetylcysteine to be ineffective in reducing the decline in lung function and preventing exacerbations.33 Routine use cannot be recommended at this time.
Patient Encounter, Part 2: The Medical History, Physical Exam, and Diagnostic Tests
PMH: Hypertension for 6 years, currently controlled
SH: Patient works as an accountant; married with two children
FH: Father with emphysema and lung cancer. There is no family history of type 2 diabetes or heart disease
Meds: Lisinopril 40 mg orally once daily; hydrochloro-thiazide 25 mg orally once daily
ROS: (−) skin rash; (−) nasal congestion, drainage; (−) chest pain, paroxysmal nocturnal dyspnea, orthopnea; (+) shortness of breath, cough, intermittent wheezing; (−) hemoptysis; (−) heartburn, reflux symptoms, N/V/D, change in appetite, change in bowel habits; (−) joint pain or swelling; (−) pedal edema
PE:
VS: BP 134/82 mm Hg, P 80 bpm, RR 20/min, T 35.8°C (96.4°F), wt 60 kg (132 lb), ht 64 in. (163 cm), BMI 22.7 kg/m2 HEENT: EOMI; mucosal membranes are moist; no evidence of jugular venous distention; no palpably enlarged cervical lymph nodes
Lungs: Barrel-shaped chest; hyper-resonant on percussion bilaterally; lung sounds are distant, no rhonchi or crackles.
CV: RRR, normal S1 S2; no murmur, gallop, or rub
Abd: Soft, nontender, no hepatosplenomegaly
Ext: No cyanosis, edema, or finger clubbing; evidence of onychomycosis on all fingernails
Pulmonary Function Tests
Given this additional information, what is your assessment of the patient’s condition?
This patient’s COPD can be classified as what stage?
What are the treatment goals for this patient?
What nonpharmacologic and pharmacologic alternatives are feasible for this patient?
Develop a treatment plan for this patient.
Prophylactic, continuous use of antibiotics has no effect on the frequency of exacerbations; antibiotics should only be used for treating infectious exacerbations. Antitussives are contraindicated because cough has an important protective role. Opioids may be effective for dyspnea in advanced disease but may have serious adverse effects; they may be used to manage symptoms in terminal patients.
Therapy of COPD Exacerbations
An exacerbation is a sustained worsening of the patient’s symptoms from his or her usual stable state that is beyond normal day-to-day variations. It is acute in onset and sufficient to warrant a change in management. Commonly reported symptoms are worsening of dyspnea, increased sputum production, and change in sputum color. The most common causes of an exacerbation are respiratory infection and air pollution, but the cause cannot be identified in about one-third of severe exacerbations.2
Treatment depends on the symptoms and severity of the exacerbation. Mild exacerbations can often be treated at home with an increase in bronchodilator therapy with or without oral corticosteroids (Fig. 15–3). Antibiotics are indicated when there are specific signs of airway infection (e.g., change in color of sputum and/or increased sputum production or dyspnea) or when mechanical ventilation is needed. Moderate to severe exacerbations require management in the emergency department or hospital. Management should consist of controlled oxygen therapy, bronchodilators, oral or IV corticosteroids, antibiotics if indicated, and consideration of mechanical ventilation (noninvasive or invasive).
Bronchodilators
Albuterol is the preferred bronchodilator for treatment of acute exacerbations because of its rapid onset of action. Ipratropium can be added to allow for lower doses of albuterol, thus reducing dose-dependent adverse effects such as tachycardia and tremor. Delivery can be accomplished through MDI and spacer or nebulizer. The nebulizer route is preferred in patients with severe dyspnea and/or cough that would limit delivery of medication through an MDI with spacer. If response is inadequate, theophylline can be considered; however, clinical evidence supporting its use is lacking.
Oral Corticosteroids
Systemic corticosteroids shorten the recovery time, help to restore lung function more quickly, and may reduce the risk of early relapse.34 The GOLD guidelines recommend that corticosteroids be considered in addition to bronchodilators in all hospitalized patients and in outpatients with baseline FEV1 less than 50% predicted.2 Other authorities recommend corticosteroids for all patients experiencing a COPD exacerbation.1 Oral prednisone 30 to 40 mg/day for 10 to 14 days is recommended. Prolonged treatment does not result in greater efficacy and increases the risk of adverse effects. If inhaled corticosteroids are part of the patient’s usual treatment regimen, they should be continued during systemic therapy.
FIGURE 15–3. Algorithm for the management of an exacerbation of COPD at home. (From Ref. 2.)
Antibiotics
The role of antibiotic treatment in treating COPD exacerbation is evolving, and recent evidence suggests that subsets of patients may benefit from antibiotic treatment. Antibiotics should be used in patients with COPD exacerbations who: (a) have all three cardinal symptoms (increased dyspnea, increased sputum volume, and increased purulence); (b) have increased sputum purulence along with one other cardinal symptom; or (c) experience a severe exacerbation requiring mechanical ventilation.2
The predominant bacterial organisms in patients with mild exacerbations are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. In patients with more severe underlying COPD, other bacteria such as enteric Gram-negative bacilli (Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae) and Pseudomonas aeruginosa may be more common. Selection of empiric antibiotic therapy should be based on the most likely organism(s) thought to be responsible for the infection and on local resistance patterns. A risk stratification approach has been advocated to help guide antibiotic selection.1,2,35 This approach is based on risk factors found to be predictive of treatment failure or early relapse. Patients at risk for poor outcome are candidates for more aggressive initial antibiotic treatment. Table 15–5 provides recommended antibiotic treatment based on this risk stratification approach.2,35 Antibiotic treatment for most patients should be maintained for 3 to 7 days, until the patient has been afebrile for 3 consecutive days. Exacerbations due to certain infecting organisms (P. aeruginosa, E. cloacae, and methicillin-resistant Staphylococcus aureus), while not common, require more lengthy courses of therapy (21–42 days).
If there is worsening clinical status or inadequate clinical response in 48 to 72 hours, reevaluate the patient, consider sputum Gram stain and culture if not already obtained, and adjust antimicrobial therapy. If Gram stain and culture results are available, narrow the antibiotic therapy according to cultured organism(s) and sensitivities. If no cultures have been obtained, or cultures remain negative, consider additional antibiotics and/or change to antibiotics with a broader spectrum of activity.
Oxygen
The goal of oxygen therapy is to maintain PaO2 above 60 mm Hg (7.98 kPa) or SaO2 above 90% to prevent tissue hypoxia and preserve cellular oxygenation.1 Increasing the PaO2 much further confers little added benefit and may increase the risk of CO2 retention, which may lead to respiratory acidosis. ABGs should be obtained after 1 to 2 hours to assess for hypercapnia.
Table 15–5 Recommended Antibiotic Therapy in Acute Exacerbations of COPD
In advanced COPD, caution should be used because overly aggressive administration of oxygen to patients with chronic hypercapnia may result in respiratory depression and respiratory failure. In these patients, mild hypoxemia, rather than CO2 accumulation, triggers their drive to breathe.
Assisted Ventilation
Mechanical ventilation can be administered as follows: (a) invasive (conventional) mechanical ventilation through an endotracheal tube; and (b) noninvasive mechanical ventilation using either negative (e.g., iron lung—not recommended) or positive pressure devices. Noninvasive positive pressure ventilation (NPPV) is preferred whenever possible. It improves signs and symptoms, decreases the length of hospital stay, and most importantly, reduces mortality.36 Appropriate patients to consider for NPPV include those with the following characteristics: (a) moderate-to-severe dyspnea with use of accessory muscles and paradoxical abdominal motion; (b) moderate-to-severe acidosis (pH between 7.25 and 7.35) and hypercapnia (PaCO2 between 45 and 60 mm Hg [6–8 kPa]); and (c) respiratory rate between 25 and 35 breaths/min.2 Invasive mechanical ventilation should be used in patients with more severe symptoms and in those failing NPPV.
OUTCOME EVALUATION
• Monitor the patient for improvement in symptoms (dyspnea, cough, sputum production, and fatigue).
• Changes in FEV1 should not be the main outcome assessed. FEV1 changes are weakly related to symptoms, exacerbations, and health-related quality of life (outcomes that are important to patients).
• The Medical Research Council dyspnea scale can be used to monitor physical limitation due to breathlessness (Table 15–6). The scale is simple to administer and correlates well with scores of health status.37
• The BODE index is a validated predictor of mortality and a better predictor than FEV1 alone.38 It is a composite score derived from body mass index or BMI (B), FEVj or degree of airflow obstruction (O), modified Medical Research Council (MMRC) dyspnea scale (D), and 6-minute walking distance (E, exercise capacity). All of these variables predict important outcomes such as health-related quality of life, the rate of exacerbations, and the risk of death. The composite score is based on a 10-point scale in which higher scores indicate a higher risk of death (Table 15–7). The BODE index can be used clinically to monitor disease progression. Its usefulness in measuring outcomes of drug therapy, pulmonary rehabilitation, and the degree of health care resource utilization needs further study.
• Assess quality of life using the St. George’s Respiratory Questionnaire, which has been validated and is specific for COPD patients.39
• Monitor theophylline levels with goal serum concentrations in the range of 5 to 15 mcg/mL (28–83 μmol/L). Trough levels should be obtained 1 to 2 weeks after initiation of treatment and after any dosage adjustment. Routine levels are not necessary unless toxicity is suspected or disease has worsened.
Table 15–6 Medical Research Council Dyspnea Scale
Table 15–7 The BODE Index
Patient Care and Monitoring
1. Assess the patient’s symptoms and history of exposure to risk factors. For new patients, obtain a detailed medical history including:
• Medical conditions, especially history of respiratory disorders
• Immunization status (pneumococcal and influenza)
• Family history of COPD or other chronic respiratory disease
• History of exacerbations or previous hospitalizations for respiratory disorders
• Impact of disease on the patient’s life, including limitation of activity, missed work, and feelings of depression or anxiety
2. Obtain spirometry measurements to assess airflow limitation and aid in severity classification and treatment decisions. Measure arterial blood gases if FEV1 is less than 40% predicted or if the patient has clinical signs suggestive of respiratory failure or right heart failure.
3. Obtain a thorough history of prescription, nonprescription, and dietary supplement use. Assess inhaler technique and adherence to the medication regimen. Ask the patient about effectiveness of medications at controlling symptoms and adverse effects.
4. Ask current tobacco users about daily quantity, past quit attempts, and current readiness to quit.
5. Design a therapeutic plan including lifestyle modifications (e.g., smoking cessation) and optimal drug therapy. Consider need for pulmonary rehabilitation, oxygen therapy, and/or surgery.
6. Provide patient education about the disease state and therapeutic plan:
• What COPD is, and what its natural course is like
• Smoking cessation counseling
• Role of regular exercise and healthy eating
• How and when to take medications; importance of adherence to the medication plan; adverse effects and how to minimize them
• Signs and symptoms of an exacerbation and what to do if one occurs
• Advanced directives and end-of-life issues for patients with more severe disease
7. Determine the follow-up period based on patient status and needs (typically 3–6 months).
8. Follow-up visits should include:
• Assessment of tobacco use and/or quit attempts
• Assessment of change in symptoms. Obtain spirometry if there is a substantial increase in symptoms or a complication
• Review of drug therapy (dosages, adherence, inhaler technique, effectiveness, adverse effects, and drug interactions)
• Evaluation of exacerbation frequency, severity, and likely causes
9. Perform spirometry at least annually to assess disease progression.
10. Provide annual influenza vaccination.
11. Assess inhaler technique at every visit. Have the patient demonstrate proper use of each device using a placebo inhaler or personal inhaler. Proper use of these devices is critical for therapeutic success.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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