Bronchodilators, preferably inhaled, are recommended for all patients with chronic obstructive pulmonary disease; ipratropium, with a 6- to 8-hour duration of action, is effective maintenance therapy. Tiotropium is currently being reviewed by the FDA for release in the United States; its once-daily dosing schedule may facilitate adherence. Criteria for long-term oxygen therapy are severe hypoxemia (PaO2, 55 mm Hg or lower) or a PaO2 of 60 mm Hg or lower with signs of cor pulmonale or secondary polycythemia (hematocrit higher than 55%). When symptoms are disabling despite optimal medical management, referral for pulmonary rehabilitation is the next step. Patients with upper lobe-predominant emphysema and low exercise capacity may benefit most from lung volume reduction surgery. Consider transplantation if the patient has severe lung disease that is refractory to medical therapy and survival is expected to be less than 2 to 3 years.
The goals of therapy in chronic obstructive pulmonary disease (COPD) are to ameliorate symptoms, improve daily function, preserve lung function, identify and reduce exacerbations and, if possible, decrease mortality. A comprehensive approach that includes prevention, early identification, and pharmacotherapy-and oxygen therapy, pulmonary rehabilitation, and/or surgery when appropriate-can optimize patient outcomes.
Here we describe the latest developments in the management of COPD, including new, longer-acting bronchodilators and refined criteria for lung volume reduction surgery (LVRS) based on recent data. In Part 1 on page 21, we addressed prevention.
Comprehensive treatment guidelines for COPD were developed in a collaborative effort of the National Heart, Lung, and Blood Institute and the World Health Organization. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommendations are available on the GOLD Web site (www.goldcopd.com).1 We provide select highlights of the GOLD guidelines as well as those of the American Thoracic Society (ATS) in this article.
Bronchodilators. These agents are the mainstay of pharmacotherapy and should be used by all patients with COPD (Table 1). Bronchodilators effectively reduce symptoms and relieve dyspnea. Despite the amelioration of dyspnea, spirometric indices are often unchanged (in contrast to the improvement observed in patients with asthma).
Inhalation of a β2-agonist or anticholinergic through a metered-dose inhaler (MDI), nebulizer, or other aerosol delivery system is preferred. Reserve nebulization for patients who are severely short of breath and unable to use other inhalation methods. Oral agents play a minimal role; they are primarily for the few persons unable to take inhaled medications. Newer formulations of bronchodilators have been developed to be more specific, less toxic, and longer-acting to improve overall compliance and symptom control.
Anticholinergics. These agents have long been used to treat pulmonary symptoms. They interfere with acetylcholine receptors at parasympathetic cholinergic junctions, thereby decreasing bronchial smooth muscle tone.
Although the GOLD guidelines are not specific as to which bronchodilator should be started first,1 ipratropium, an inhaled anticholinergic agent, is recommended as the first-line bronchodilator by the ATS guidelines for the management of COPD.2 We generally follow the ATS guidelines and start ipratropium for our patients. It may be more effective than inhaled β2-agonists in patients with COPD and has a very good side-effect profile. Although ipratropium's onset of action (60 to 90 minutes) is longer than that of β2-agonists, its duration of action (6 to 8 hours) is longer, making it a good agent for maintenance therapy.
Newer, longer-acting anticholinergic agents are under investigation and may be available soon. Tiotropium is a once-daily inhaled anticholinergic approved for use in several countries and currently under review by the FDA for approval in the United States. In a 13-week clinical trial, it was shown to improve both spirometric and symptomatic measures to a greater extent than placebo.3 In a follow-up study comparing it to salmeterol, tiotropium demonstrated similar improvements in dyspnea and disease-specific health-related quality of life and slightly better spirometric measures after 6 months of continuous use.4 The once-daily dosing of tiotropium may facilitate adherence to long-term therapy.
β2-Agonists. Nonspecific β-adrenergic agonists cause rapid-onset bronchodilation via stimulation of the β2- receptor. Newer and preferred agents have less β1-agonist activity, which translates into fewer cardiovascular side effects, such as tachycardia and palpitations.
Advances in β2-therapy have focused on the development of long-acting agents, such as salmeterol. These agents can provide more than 12 hours of relief and can reduce dyspnea with a minimal increase in forced expiratory volume in 1 second (FEV1). They are particularly helpful in patients with nocturnal symptoms and in those who require frequent β2-agonist therapy. Long-acting β2-agonists can be used as sole maintenance therapy in patients with mild to moderate COPD. These medications should not be used as needed to relieve acute symptoms, because they have a delayed onset of action.
Combination bronchodilator therapy. The combination of an anticholinergic with a β2-agonist has been shown to be synergistic and to improve lung function more than either agent used alone.
Ipratropium and albuterol are delivered in an MDI that provides a fixed dose with each puff; this reduces the need for multiple inhalers and may improve compliance. The drawback of combination MDI delivery is the inability to change bronchodilator doses, particularly in relieving acute symptoms, and the need to use both agents when (typically) one agent might suffice. Despite these concerns, regular use of combined therapy is useful in some patients and is recommended for those with moderate to severe disease.
Corticosteroids. The benefit of inhaled or oral corticosteroids in asthma is well recognized. However, in COPD (primarily, emphysema and chronic bronchitis), the appropriate use of corticosteroids is controversial. Approximately 10% to 30% of patients with COPD (excluding patients with asthma) have a significant response to oral corticosteroid therapy.
Because of the many side effects, routine use of systemic corticosteroids in COPD should be avoided. Acute exacerbations may be treated with a short course of corticosteroids, such as 2 weeks or less of prednisone, 60 mg/d (or the equivalent) with a rapid taper; longer therapy may not provide any further benefit.5
Regular use of inhaled corticosteroids may be associated with clinical benefits, such as reduced exacerbations and hospitalizations, even without documented improvement in lung function.6 However, prolonged use of these agents-particularly at high doses-may produce systemic side effects (such as subcapsular cataracts and decreased bone mineral density).7,8 In addition, a recent meta-analysis of randomized controlled trials found that use of inhaled corticosteroids in patients with COPD followed for 24 to 52 months was not associated with a slower rate of decline in FEV1 when compared with placebo.9 This continues to be an area of controversy.10
Therefore, in view of the significant side effects of inhaled and oral corticosteroids and the fact that only a minority of patients will benefit from them, we advocate the GOLD recommendations of reserving long-term use of these agents for1:
Patients with a documented spirometric response to corticosteroids.
Those with an FEV1 of less than 50% of predicted and repeated exacerbations that require treatment with antibiotics and oral corticosteroids.
Oxygen therapy. Long-term oxygen therapy is one of the only treatments shown to improve overall survival in patients with COPD. Secondary advantages may include improvement in quality of life and neuropsychological function and stabilization of pulmonary hypertension-these are less well characterized in the literature.
Oxygen delivery has improved during the past 10 years, and newer oxygen conservation devices increase efficiency and prolong use. Some units provide pulse doses of oxygen, initiated by the patient's breath. Other facial and nasal reservoir devices allow oxygen to be stored before inhalation.
For maximal benefit, oxygen should be used more than 15 hours daily. Assess patient compliance regularly, because use is often suboptimal.
Criteria for long-term oxygen therapy are severe hypoxemia (PaO2, 55 mm Hg or lower) or a PaO2 of 60 mm Hg or lower with signs of cor pulmonale or secondary polycythemia (hematocrit higher than 55%). Measure the patient's oxygen level at rest and during exercise, because hypoxemia may worsen with physical activity.11
Leukotriene modifiers. Agents that interfere with the leukotriene pathway are useful in asthma therapy. They may be corticosteroid-sparing and are particularly helpful in aspirin-sensitive patients. In addition, neutrophilic airway inflammation is the hallmark of COPD, and leukotriene inhibitors have been shown to slow this process in vivo.12 However, no clinical end point data yet suggest that leukotriene modifiers have any role in the treatment of patients with COPD who do not have a significant asthma component. Therefore, use of these agents for COPD alone is not currently recommended.
Mucolytics. These agents decrease the viscosity of sputum, making it easier to cough up. Theoretically, the result is fewer respiratory exacerbations and improved airflow. A Cochrane review and meta-analysis showed a marginal reduction in exacerbations and disability days in patients with chronic bronchitis who already had a higher-than-average rate of annual exacerbations.13 These findings cannot be generalized to all patients with COPD.
Genetically engineered deoxyribonuclease (dornase) breaks up DNA in mucus, can dramatically decrease secretions, and has been shown to play a role in the treatment of select cystic fibrosis patients. Such data do not exist for COPD, and results so far have been disappointing. Therefore, until further research is done, this agent is not recommended for patients who have COPD.
This multidisciplinary program for patients with chronic lung disease is individually tailored to optimize autonomy as well as physical and social performance. The clinical effectiveness and scientific validity of pulmonary rehabilitation have been well established in recent years through randomized, controlled clinical trials. Two reviews have summarized the results of these studies and provide important guidelines about the referral and management of these patients.14,15
Programs vary and can be adapted to an inpatient, outpatient, or home setting. Supervised sessions are typically offered several times weekly for 6 to 12 weeks while patients learn to perform their daily home-care program. Program components include exercise training, education, and psychosocial/behavioral interventions. The interdisciplinary team includes nurses; exercise specialists; and respiratory, physical, and occupational therapists.
Pulmonary rehabilitation is for patients with chronic lung disease who, despite optimal standard medical management, continue to have dyspnea, reduced exercise tolerance, restricted activity, and/or reduced quality of life (Table 2).15 Pulmonary rehabilitation reduces dyspnea, increases functional ability, and improves quality of life for persons with COPD, even in the face of irreversible abnormalities in lung architecture. Some studies have shown a reduction in COPD exacerbations as well as fewer hospital days and admissions. There is a trend toward decreased long-term mortality, but studies are not conclusive. In this age of managed care, pulmonary rehabilitation is proving itself to be cost-effective and is covered by many insurance plans.
LUNG VOLUME REDUCTION SURGERY
In the 1950s, LVRS was first used to treat emphysema by removing areas of hyperinflated lung. Although the condition of some patients improved, high rates of mortality and morbidity discouraged widespread use. In the 1990s, better surgical techniques facilitated the resurrection of this procedure.16 LVRS currently involves a bilateral resection of emphysematous lung via a stapling technique through either a median sternotomy or via thoracoscopy.
The primary goal of LVRS in patients with emphysema is to reduce hyperexpansion of the lungs by removing less functional emphysematous/bullous lung tissue. This relieves the compression of the remaining healthy lung and allows the diaphragm to regain a more efficient position in the thoracic cavity. Expansion of the healthy lung may increase its elastic recoil, helping to maintain patent airways and increasing expiratory flow rates. These combined effects can lead to reduced dyspnea, greater exercise tolerance, and diminished need for supplemental oxygen.
Early studies of LVRS with short-term follow-up in series of select patients suggest that about 50% to 80% of patients have a significant improvement in FEV1 postoperatively at 3 to 6 months.16 Several years ago, the procedure started to become more widely used despite the absence of adequate long-term data on the relative benefits, risks, and costs of surgery as compared with usual treatment.
To that end, a nationwide, multicenter, randomized controlled trial to examine the safety and efficacy of LVRS in the treatment of emphysema was recently completed. The National Emphysema Treatment Trial (NETT) was cosponsored by the Centers for Medicare and Medicaid Services (Medicare), the National Heart Lung and Blood Institute, and the Agency for Healthcare Research and Quality.17 In NETT, all patients received maxi-mal medical therapy, including pulmonary rehabilitation, before random assignment to either surgical or medical therapy.
In NETT, overall results indicated that after 24 months, exercise capacity and quality of life were significantly improved and symptoms were significantly diminished in patients who underwent surgery compared with those who received medication. There was no difference in mortality. Additional subgroup analyses suggested that patients with both upper lobe-predominant emphysema and low exercise capacity had the best results with surgery, evidenced by significantly better survival, exercise tolerance, symptom relief, and quality of life. In contrast, patients with non-upper lobe-predominant disease with high exercise tolerance had better survival without surgery and had no functional or symptomatic benefits. Table 3 outlines selection criteria for LVRS based on the NETT results.
COPD is the most common indication for single-lung transplantation. The benefits of lung transplantation can include the resumption of normal activities of daily living, normalization of lung function and hemodynamic parameters, and elimination of the need for supplemental oxygen.
Improved surgical techniques, better patient selection, and new immunosuppressive therapies for lung transplantation have improved outcomes. Patients with COPD have 1- and 3-year survival rates of 81% and 64%, respectively, after lung transplantation. Five-year survival at one US hospital has been recently reported to be as high as 59%,18 although the Registry of the International Society for Heart and Lung Transplantation reports a worldwide 5-year survival rate that approaches 50%.19 Unfortunately, progress in lung transplantation has not paralleled that for other organs; for example, in kidney transplantation, the 5-year survival rate is greater than 70%. The major factors limiting long-term survival of lung transplant recipients remain infection and chronic rejection.
Therefore, carefully consider transplantation when there is severe clinical and physiologic lung disease, medical therapy is no longer effective, and survival is expected to be less than 2 to 3 years (Table 4). A 1- to 2-year waiting period is typically expected. The survival benefit for patients with COPD has not been demonstrated clearly and is difficult to estimate, because many patients with severe COPD can live for years.20
1. Pauwels RA, Buist AS, Calverley PM, et al, for the GOLD Scientific Committee. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/ WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med. 2001;163:1256-1276.
2. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1995;152:S77-S121.
3. Casaburi R, Briggs DD Jr, Donohue JF, et al. The spirometric efficacy of once-daily dosing with tiotropium in stable COPD: a 13-week multicenter trial. The US Tiotropium Study Group. Chest. 2000; 118:1294-1302.
4. 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.
5. 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.
6. Alsaeedi A, Sin DD, McAlister FA. The effects of inhaled corticosteroids in chronic obstructive pulmonary disease: a systematic review of randomized placebo-controlled trials. Am J Med. 2002;113:59-65.
7. 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.
8. Pauwels RA, Lofdahl CG, Laitinen LA, et al. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. European Respiratory Society Study on Chronic Obstructive Pulmonary Disease. N Engl J Med. 1999;340:1948-1953.
9. Highland KB, Strange C, Heffner JE. Long-term effects of inhaled corticosteroids on FEV1 in patients with chronic obstructive pulmonary disease. A meta-analysis. Ann Intern Med. 2003;138:969-973.
10. Calverly PMA, Barnes PJ. Are inhaled steroids beneficial in COPD? A pro/con debate. Am J Respir Crit Care Med. 2000;161:341-344.
11. Anthonisen NR. Long-term oxygen therapy in moderate hypoxaemia. Thorax. 1997;52:667-668.
12. Kilfeather S. 5-Lipoxygenase inhibitors for the treatment of COPD. Chest. 2002;121:S197-S200.
13. Poole PJ, Black PN. Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2003:CD001287.
14. ACCP/AACVPR Pulmonary Rehabilitation Guidelines Panel. Pulmonary rehabilitation: joint ACCP/AACVPR evidence-based guidelines. Chest. 1997;112:1363-1396.
15. American Thoracic Society. Pulmonary rehabilitation: 1999. Am J Respir Crit Care Med. 1999;159: 1666-1682.
16. Fessler HE, Wise RA. Lung volume reduction surgery: is less really more? Am J Respir Crit Care Med. 1999;159:1031-1035.
17. Fishman A, Martinez F, Naunheim K, et al, for the National Emphysema Treatment Trial Research Group. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med. 2003;348:2059-2073.
18. Cassivi SD, Meyers BF, Battafarano RJ, et al. Thirteen-year experience in lung transplantation for emphysema. Ann Thorac Surg. 2002;74:1663-1670.
19. Trulock EP, Edwards LB, Taylor DO, et al. The Registry of the International Society for Heart and Lung Transplantation: Twentieth Official adult lung and heart-lung transplant report-2003. JHeart Lung Transplant. 2003;22:625-635.
20. International guidelines for the selection of lung transplant candidates. The American Society for Transplant Physicians (ASTP)/American Thoracic Society (ATS)/European Respiratory Society (ERS)/International Society for Heart and Lung Transplantation (ISHLT). Am J Respir Crit Care Med. 1998;158:335-339.