Goals of Management of Stable Disease
Goals of management of stable COPD in the outpatient setting include slow disease progression, improvement of symptoms, particularly dyspnea and reduced exercise tolerance, prevent exacerbation, and reduce mortality. Smoking cessation and supplemental oxygen are the only interventions that have shown to reduce all-cause mortality. Current pharmacologic interventions neither reduce mortality nor influence the rate of decline of lung function. An overview of different therapies based on disease severity are shown in Fig. 83-8.
Overview of treatment for COPD by disease severity. (From GOLD. www.goldcopd.com)
Smoking cessation is difficult to achieve and more difficult to sustain in the general population. Physician-delivered smoking cessation interventions can significantly increase smoking abstinence rates. An empathetic, nonconfrontational interaction that maximizes patient participation is most effective. The essential elements of a smoking cessation program should include: (1) physician intervention (set a quit date) and appropriate follow-up; (2) group smoking cessation programs; and (3) pharmacologic therapy with nicotine replacement in highly dependent smokers. Such smokers can be identified as those who smoke a pack a day or more, require their first cigarette within 30 minutes of arising in the morning, and find it difficult refraining from smoking in places where it is forbidden. Therapy with the antidepressants, such as bupropion hydrochloride and nortryptiline, are effective and when used with nicotine replacement can yield quit rates that approach 35%. The LHS showed that despite intensive antismoking efforts, middle-aged smokers with COPD are not likely to quit and only 22% were sustained quitters at 5 years.
Smoking cessation rates are similar in the elderly compared to younger individuals. For instance, the Wisconsin Tobacco Quit Line program, which targeted older smokers by providing free nicotine patches and phone counseling, showed that 43% of the senior participants had successfully quit at 9 months. A recent survey among adult smokers older than 60 years was conducted by the Center of Social Gerontology and revealed that a key motivation to quit smoking was to improve health. There were varying levels of awareness of smoking cessation aids among these participants. The lack of information from physicians recommending or educating them about smoking cessation aids was an important barrier to try these interventions. These observations underscore the need to educate smokers about the health benefits and the various aids to quit smoking. Older adults fear that they will fail to quit smoking and therefore, the elderly patient must be reminded that the average smoker who successfully quits has done so after five to six attempts. The clinician's responsibility is to remember that tobacco addiction is a chronic disease and treatment should be offered at every visit. Several hotlines are offered by the American Cancer Society and the National Cancer Institute to help quit smoking.
The goal of pharmacologic management is to provide symptomatic relief, improve exercise capacity, and prevent exacerbations. A stepwise approach is provided in Figure 83-8. The average age of subjects recruited in most clinical trials for COPD is 65 years and few subjects older than 85 years are recruited in these studies. Therefore, the efficacy and side-effect profile of these medications in the very old remains unclear.
Short- and Long-Acting Beta Agonist
These agents act by relaxing airway smooth muscle by a direct action on the β2-adrenergic receptors on the cell surface. While oral agents are available, their side effect profile makes them less desirable than the inhaled agents. The short-acting β2 agonists achieve variable degrees of bronchodilatation, with a rapid onset of action of a few minutes, and last for 4 to 6 hours. Short-acting beta2 agonists are used for symptom control. In contrast, long-acting beta2 agonist last for 12 hours and are useful for maintenance therapy. Both improve shortness of breath, cough, and in most patients, improve exercise capacity. Short-acting beta2 agonists are usually prescribed as a metered dose inhaler (MDI) or with a compressor-driven nebulizer.
Despite minimal systemic absorption seen with these agents, slight tachycardia may be observed. This is presumably a result of vasodilatation from stimulation of β2 receptors in vascular smooth muscle. Tremor may also occur and is especially troublesome in the geriatric patient. It is thought to be caused by stimulation of β2 receptors in skeletal muscle. In general, however, when given three or four times a day, β2 agonists are safe and effective even in the elderly. Higher doses should be used cautiously because they may cause hypokalemia, especially when the patient is taking a diuretic.
Salmeterol and formoterol are two long-acting beta2 agonists. In the recent TORCH trial, salmeterol alone reduced exacerbations compared to placebo and the combination of salmeterol and fluticose provided additional benefit. A similar benefit was seen with salmeterol on health-related quality of life. There is no evidence of tachyphylaxis with these agents. Though beta receptor function diminishes with age, the short- and long-acting β2 agonists should be used because of their proven track record.
Ipratropium and tiotropium are two anticholinergic agents. These agents cause bronchodilatation and are capable of rapidly relieving symptoms. Muscarinic (M) receptors are present in the bronchial smooth muscles. M1 and M3 mediate bronchoconstriction, while M2 inhibits release of acetylcholine and thus results in feedback inhibition. Tiotropium has the advantage of prolonged action, lasting for 24 hours, and specifically inhibits M1 and M3 receptors, while it dissociates more quickly from M2 receptors. Ipratropium bromide has duration of action of 4 to 6 hours. Its onset of action is 30 minutes. This has made a single MDI of the combination of albuterol, a short-acting β2 agonist, and the anticholinergic, ipratropium bromide, very popular.
Tiotropium has a beneficial effect in reducing exacerbation rates compared to placebo or ipratropium bromide and improved health-related quality of life relative to placebo. An important beneficial effect of tiotropium is improvement in baseline FEV1. Therefore, tiotropium is preferred over ipratropium in patients with severe COPD.
As these agents are poorly absorbed, the side effects are generally mild. Occasionally, patients complain of a dry mouth or metallic taste. Worsening symptoms of prostrate enlargement and acute glaucoma are rare. Plasma concentrations are higher in individuals with moderate or severe renal failure, and therefore should be used cautiously. Ophthalmic complications may occur because of inadvertent spraying of eyes and can easily be avoided with proper inhalation techniques.
Theophylline is the most widely used drug in this class. It is given as a sustained-release preparation and has the advantage of being administered once a day. Small improvements in lung function are seen with chronic use and have been associated with improvement in symptoms and exercise capacity in COPD. Its use has diminished over the past decade because of safety concerns, especially in the elderly. While there is in general a steady decline in drug metabolism from early to late adulthood, theophylline clearance does not appear to be sufficiently altered in the elderly to recommend reducing the dose. The narrow therapeutic range of theophylline, frequency of concomitant illnesses that alter theophylline kinetics, and many drug interactions that affect the clearance of theophylline, make it important to closely monitor the blood theophylline level in older patients.
The clinical manifestations of theophylline toxicity have been correlated with blood levels of the drug. With high serum concentrations (>30 μg/mL), life-threatening events may occur. They include seizures and cardiac arrhythmias, such as atrial fibrillation, supraventricular tachycardia, ventricular ectopy, and ventricular tachycardia. The most common cause for theophylline toxicity is a self-administered increase in medication. There is a stepwise increase in the frequency of life-threatening events caused by theophylline toxicity with advancing age. At comparable theophylline blood levels, patients older than age 75 years have a 16-fold greater risk of life-threatening events or death than do patients younger than age 25 years. The risk of theophylline toxicity can be minimized with careful patient monitoring, including checking blood levels and patient education. A range of 8 to 15 μg/mL is generally considered therapeutic and gives a margin of error that helps avoid toxicity.
Long-term oral corticosteroid treatment is not recommended for COPD. Some have advocated giving a short course of oral corticosteroids for 2 weeks to identify patients with asthma and bronchitis, but such a short-term response is not an effective predictor. Complications include cataracts, osteoporosis, secondary infection, diabetes, skin damage, and steroid myopathy, which contribute to respiratory muscle weakness, poor exercise tolerance, and respiratory failure.
Inhaled corticosteroids reduce exacerbation frequency, health-related quality of life, exercise capacity, and improve FEV1. Although observational studies suggest that they may improve mortality, results of randomized clinical trials have failed to demonstrate improvement in all-cause mortality. Treatment with inhaled corticosteroids therefore has been recommended only for patients with moderate to advanced COPD. Two side effects, including bone loss and increased incidence of community-acquired pneumonia, can occur with chronic use, though the clinical relevance of pneumonia is uncertain. Different dosages of inhaled steroids have different potencies. In most clinical trials, 500 μg bid of fluticasone or 400 μg bid of budesonide has been used. Whether lower doses of inhaled corticosteroids can achieve similar efficacy is uncertain.
The combination of salmeterol and fluticasone has recently been shown to be better than individual medication in a randomized controlled trial of more than 6000 subjects. The average age of participants was 65 years. In this study, the combination of salmeterol and fluticasone reduced frequency of exacerbation, lung function decline, and improved health-related quality of life. Compared to placebo, the absolute reduction in all-cause mortality was 2.6% (relative reduction of 17.5%), but the results failed to reach statistical significance when adjusted for multiple interim analyses (adjusted p-value = 0.052 and unadjusted p-value = 0.04).
The inhaled route of therapy for COPD is preferred because it provides quicker action, fewer side effects, and greater bronchodilatation with smaller doses of medication. MDIs are the most commonly used methods for delivery of bronchodilators and corticosteroids. The great majority of the medication delivered by MDIs is deposited in the oropharynx, with only approximately 10% of the dose delivered to the lungs. Oropharyngeal deposition causes greater systemic absorption, more local irritation, and for corticosteroids, more likelihood of oropharyngeal candidiasis. Inadequate timing of actuation and inhalation is the most frequent error. Impaired mental function, weakened or deformed hands, and motor or musculoskeletal diseases are other reasons for inadequate MDI use. There are several solutions to this problem. One may deliver short-acting β agonists, ipratropium, and corticosteroid, budesonide, as aerosolized solutions by pressurized handheld nebulizers. Alternatively, there is a breath-actuated pressurized MDI that obviates the need to synchronize activation with inhalation. The use of spacer devices fitted to the mouthpiece of the MDI can overcome most of the drawbacks of MDI therapy. Spacers are cheap, easy to carry, reduce oropharyngeal deposition, and increase intrapulmonary deposition. Lastly, newer dry-powder delivery devices that deliver inhaled corticosteroids and long-acting β agonists provide simple, easy-to-use preparations that do not require coordination or muscle strength.
Mixed results have been reported for the use of mucolytic agents, such as N-acetyl cysteine, and expectorants, such as Guaifenesin, as chronic maintenance therapy for COPD. Symptoms may improve in some patients with COPD, especially those with viscous sputum. However, overall the benefits are small and their widespread use is not recommended. Randomized controlled trials suggest that they are ineffective at shortening the course or improving outcomes of patients with acute exacerbations of COPD.
Phosphodiesterase (PDE)-4 Inhibitors
PDE-4 is a major regulator of cyclic adenosine monophosphate metabolism in smooth muscle and immune cells. Since cyclic adenosine monophosphate downregulates the activity of these cells, the inhibition of PDE-4 is an attractive target for COPD drug development. Early studies with a PDE-4 inhibitor, Cilomilast, suggest that it causes bronchodilatation and may improve quality of life. Further studies are necessary before this class of drugs can be recommended for routine use.
Treatment with calcium and vitamin D supplementation should be considered in older COPD patients with osteoporosis. Depression and anxiety are common in COPD patients and treatment may improve quality of life. Although pneumococcal and influenza vaccination have limited efficacy in the elderly, routine use is recommended in COPD patients because vaccination is associated with few side effects and these organisms are an important cause of acute exacerbations or community-acquired pneumonia.
Several controlled studies have been done regarding the efficacy of long-term oxygen. These have been summarized by Crockett et al. In addition to smoking cessation, it is the only intervention to improve survival in advanced COPD. The beneficial effect is related to the duration of oxygen use. For example, patients who receive oxygen for 19 hours or more a day are likely to survive longer than those who use it 12 or 15 hours a day. Patients who use chronic oxygen therapy are likely to have a significant fall in their pulmonary artery pressures and an increase in cardiac output. Table 83-3 provides recommendations for long-term oxygen use in COPD. Long-term oxygen therapy does not improve survival in patients with moderate hypoxemia (PaO2, 56 to 65 mm Hg) or in patients with nocturnal hypoxemia alone.
Table 83-3 Criteria for Home Oxygen in COPD ||Download (.pdf)
Table 83-3 Criteria for Home Oxygen in COPD
Arterial partial pressure of oxygen (PaO2) less than or equal to 55 mm Hg or arterial oxygen saturation (SaO2) less than or equal to 88%
PaO2 levels between 56 and 59 or SaO2 89% in the presence of pulmonary hypertension, cor pulmonale, edema secondary to right heart failure, or erythrocytosis with hematocrit greater than 55%
Following exercise (supplemental oxygen to be used during exercise only)
Patients who desaturate to an SaO2 less than or equal to 88% during exercise and who demonstrate improvement in both the hypoxia and dyspnea and/or exercise capacity when using oxygen
Pulmonary rehabilitation is a multidisciplinary program for patients with moderate to advanced COPD, especially those who have suffered deconditioning, significant weight loss, depression, and social isolation. The goals of a rehabilitation program are to improve exercise capacity, return the patient to more normal activities of daily living, and improve motivation, psychological well-being, and overall quality of life. With the use of lower-extremity exercise training and upper-extremity strength and endurance training, pulmonary rehabilitation improves dyspnea, endurance, and quality-of-life scores. Its effects on exacerbation are less clear and it does not influence survival. The benefits of pulmonary rehabilitation are short-lived and wane once the program is completed. Continuation of these exercises at home may have additional benefit. However, the benefit of repeat rehabilitation is less clear.
Weight Loss and Malnutrition
Weight loss, particularly skeletal muscle mass loss, is associated with a systemic inflammatory response in COPD. Resting energy expenditure is elevated and contributes to the negative energy balance. Nutritional supplements alone do not reverse the loss; results with anabolic steroids, growth hormone, and the progestational agent, megestrol acetate, show some effect on appetite and body weight. However, improved exercise tolerance and respiratory muscle function does not always follow, and side effects are often limiting.
Noninvasive Positive Pressure Ventilation
The chronic nocturnal use of noninvasive ventilation for COPD is controversial. There are theoretical advantages. Resting chronically fatigued muscles at night might improve daytime function. COPD patients have a high prevalence of nocturnal hypoxemia but the incidence of sleep apnea is similar. They have less rapid eye movement (REM) sleep and shorter sleep duration. Trials have examined the role of nocturnal noninvasive ventilation in COPD patients. These studies were small and have shown conflicting results. In general, nocturnal NIPPV for at least 3 months in hypercapnic patients with stable COPD had no consistent effect on lung function, gas exchange, respiratory muscle strength, sleep efficiency, or exercise tolerance.
Lung volume reduction surgery (LVRS) has emerged as a treatment for far advanced COPD caused by emphysema. It involves resection of functionless areas of emphysematous lung in order to improve lung elastic recoil and lung and chest wall hyperinflation.
The National Emphysema Treatment Trial Research Group examined the role of LVRS in over 1200 subjects. The average age of participants in this study was 65 years. Overall mortality with the procedure ranges between 0% and 6% within 30 days of surgery and between 0% and 8% at 6-months although in patients with very severe degrees of airflow obstruction and/or hypercarbia, the rates are higher. The range of FEV1 improvement pre- and postsurgery is approximately 250 to 350 mL and dyspnea scores and distance walked on the 6-minute walk test show improvement. Often patients no longer require oxygen following surgery. LVRS did not confer a survival advantage over medical therapy. It does yield a survival advantage for patients with both predominantly upper-lobe emphysema and low baseline exercise capacity. Currently, it is a modality that is being used in specialized centers for selected patients.
Resection of large bullae is occasionally necessary. The best results occur when the bullae occupy more than one-third of the hemithorax. Lung transplantation can be lifesaving in advanced cases, but is not offered to those of advanced age.