Chronic obstructive pulmonary disease (COPD), as defined by the World Health Organization (WHO), is a syndrome characterized by airflow obstruction that is not fully reversible with medical therapy.^1,2 Most COPD patients are comprised of the 16–18 million Americans with chronic bronchitis and emphysema (Fig. 85-1). COPD is also a common comorbid condition for patients who present for thoracic or cardiac surgical evaluation. Coronary heart disease and lung cancer share with COPD the common risk factor of cigarette smoking. Thus many patients who present for surgical treatment of these conditions have physiologically relevant irreversible airflow obstruction.^3,4 When evaluating patients with COPD for thoracic or cardiac surgery, it is important to assess the following:

1. Severity of obstructive lung disease, which is best done in the context of the current WHO staging guidelines^5,6

2. Pulmonary risk for surgery, which is a function of disease, degree of airflow limitation, functional status, extent of compromise in gas exchange, age, and the specific surgical procedure

3. Baseline medical therapy, with the goal of optimizing the patient's pulmonary function prior to surgery

4. Smoking status because smoking cessation reduces the risk of postoperative complications⁷

Assessment of pulmonary risk in the thoracic surgery patient is discussed in Chapter 4 and will not be covered here. This chapter concerns the current WHO classification of disease severity for patients with COPD, recommendations for medical therapy in patients with varying degrees of airflow obstruction, recommendations for use of oxygen therapy in patients with chronic respiratory failure, recommendations for use of pulmonary rehabilitation (PR), the approach to smoking cessation in the COPD patient, and current guidelines for management of COPD exacerbations in the outpatient and perioperative settings. The surgical management of COPD is described in the ensuing chapters of this section (see Chaps. 86, 87, 88, and 89).

WHO CLASSIFICATION OF COPD

The recent Global Initiative for Chronic Obstructive Lung Disease consensus statement divides COPD into five stages depending on the extent of airflow limitation.^5,6 Stage 0 disease refers to patients with risk factors for the development of COPD (most commonly a more than 20 pack-year smoking history) and symptoms of chronic cough and phlegm but no evidence of airflow obstruction (FEV₁ 80% predicted, FEV₁/FVC ratio > 70%). These patients are "at risk" for the development of COPD, and a fraction ultimately will develop clinically significant airflow obstruction. Stage 1 disease refers to patients with very mild obstructive lung disease (FEV₁ 80% predicted, FEV₁/FVC ratio < 70%), the majority of whom have little, if any, functional compromise. Most patients with stage 1 disease remain undiagnosed, and their pulmonary symptoms have minimal impact on their functional status. Stage 2 disease refers to patients with mild to moderate airflow obstruction (80% FEV₁ 50% predicted, FEV₁/FVC ratio < 70%). At this stage, functional capacity may be somewhat compromised, and patients may experience dyspnea with exertion. However, most patients with stage 2 COPD do not seek medical attention for pulmonary symptoms and may escape diagnosis until presentation for a distinct medical problem such as newly diagnosed cardiac disease or lung cancer. Stage 3 disease refers to patients with moderate to severe airflow obstruction (50% FEV₁ 30% predicted, FEV₁/FVC ratio < 70%), most of whom experience pulmonary symptoms and carry the medical diagnosis of COPD. Stage 4 disease refers to patients with severe to very severe airflow obstruction (30% > FEV₁ predicted, FEV₁/FVC ratio < 70%). These patients experience significant respiratory compromise and are at the greatest risk of pulmonary complications after cardiothoracic surgery.

MEDICAL THERAPY FOR STABLE COPD BASED ON DISEASE SEVERITY

Staging is useful not only for stratifying surgical risk but also for guiding medical therapy. Current WHO recommendations suggest a stepwise approach to medical management depending on the extent of airflow limitation. Therapeutic recommendations for patients with stage 0 disease focus on smoking cessation, prevention of serious infections (e.g., influenza and pneumococcus vaccine administration), and development of a monitoring plan to assess disease progression, which includes yearly evaluations of pulmonary function.⁶ Patients with stage 1 disease should be considered for "as needed" use of a short-acting bronchodilator in the form of either an inhaled beta agonist (e.g., albuterol, metaproterenol, or terbutaline) or anticholinergic (e.g., ipratropium or oxytropium) in addition to the management recommended for stage 0 patients. With disease progression to stages 2, 3, and 4, medical therapy also should include regular use of long-acting bronchodilators (e.g., salmeterol, formoterol, or tiotropium). Patients with advanced disease (stages 3 and 4) who experience one or more COPD exacerbations annually also should be considered for inhaled corticosteroid therapy, and individuals with respiratory failure (PaO₂ < 55 mm Hg or PaO₂ < 60 mm Hg with either cor pulmonale or hematocrit > 55) should receive oxygen therapy. PR can improve functional capacity and quality of life in patients with stage 2, 3, or 4 disease.

Bronchodilators

Bronchodilator therapy is the mainstay of pharmacologic therapy for COPD patients. Although desensitization to the pharmacologic effects of inhaled bronchodilators has been described in vitro, regular use of either short- or long-acting beta agonists (LABAs) or anticholinergics for extended periods has not been associated with loss of effectiveness in clinical practice. Both types of bronchodilators have a favorable therapeutic index and long-term safety profile.⁸

Several recent studies have demonstrated that combination therapy with a beta agonist and anticholinergic produces greater therapeutic benefit than either agent alone. Combination therapy also has been shown to reduce dyspnea during exercise and reduce the incidence of COPD exacerbations compared with monotherapy.^9,10 Bronchodilator therapy with long-acting agents, while more expensive than regimens using short-acting agents, is more effective and more convenient. Salmeterol and formoterol, LABAs with pharmacologic effects that last more than 12 hours, are both safe and effective in patients with mild to severe COPD. LABAs can be combined safely with either short- or long-acting anticholinergics, and the combination improves forced expiratory capacity in 1 second (FEV₁) and symptom scores relative to monotherapy with LABAs alone. Combination therapy with ipratropium, a short-acting anticholinergic, and LABAs is also superior to ipratropium plus a short-acting beta agonist.¹¹ Tiotropium, a long-acting anticholinergic with a duration of action of greater than 24 hours, in combination with LABAs improves pulmonary function in moderate to severe COPD to a greater extent that monotherapy.^12,13 New ultra-long-acting beta agonists such as carmoterol, bambuterol, and indacaterol are currently in clinical trials and, when available, should allow once-daily combination therapy, further simplifying treatment and reducing the potential for breakthrough symptoms.⁸

Theophylline, a methylxanthine with nonspecific phosphodiesterase and adenosine receptor antagonist activity, has been used for decades in the treatment of COPD but has fallen out of favor in recent years because of its low therapeutic index and risk of interactions with other medications. It is a mild bronchodilator, less effective than either inhaled ipratropium or albuterol at therapeutic doses. Nevertheless, slow-release theophylline preparations produce physiologic and functional benefits when combined with inhaled bronchodilators in patients with moderate to severe disease. Therefore, it is reasonable to consider the addition of slow-release theophylline for outpatient management of COPD in carefully selected patients. In combination with either albuterol or ipratropium, theophylline has been shown to produce a greater bronchodilatory effect than monotherapy with either inhaled agent.^14–16 Similar benefits have been demonstrated by combining theophylline with an LABA.¹⁷ While controlled studies examining the benefits of triple bronchodilator therapy using combined beta agonists, anticholinergics, and theophylline have not been conducted, it is reasonable to consider the addition of theophylline to inhaled bronchodilator combinations in selected patients when symptoms persist.

Leukotriene antagonists, which have bronchodilatory effects in asthma, have been considered for treatment of COPD, and two drugs are currently in clinical trials. The lack of data supporting a pathophysiologic role for the cysteinyl leukotrienes in COPD would suggest limited benefit as a bronchodilator, but leukotriene receptor blockers and 5'-lipoxygenase inhibitors may have beneficial anti-inflammatory effects by decreasing levels of leukotriene B₄, a potent chemoattractant for neutrophils, one of the cell types thought to contribute to inflammation in COPD.¹⁸

In summary, bronchodilators are the mainstay of pharmacotherapy for outpatient management of COPD. They are effective in treating symptoms and improving exercise capacity. However, they do not alter disease progression. Dosing should be based on the severity of disease, as assessed by spirometry. Intermittent dosing with a short-acting, immediate-onset agent should be initiated for patients once mild airflow obstruction (stage 1 disease, FEV₁/FVC < 70%, FEV₁ 80% predicted) is diagnosed. Whether a beta agonist (e.g., albuterol), anticholinergic agent (e.g., ipratropium bromide), or combination drug (e.g., Combivent, Boeringer Ingleheim) is selected should be individualized based on therapeutic response, side-effect profile, and personal preference. Patients with more severe airflow limitation (stages 2–4 with moderate to very severe disease) are best managed with long-acting agents. Available data suggest that combination therapy with an anticholinergic plus a beta agonist is more effective than monotherapy. Addition of theophylline to inhaled bronchodilators may provide additional benefit in selected patients, but because of its low therapeutic index and potential for drug interactions, theophylline is not universally recommended for outpatient treatment of COPD, and clear therapeutic benefit should be demonstrated before committing to long-term use of theophylline.

BRONCHODILATORS IN THE PERIOPERATIVE PERIOD

In COPD patients undergoing cardiothoracic surgery, inhaled bronchodilators should be continued throughout the perioperative period. Short-acting beta agonists, anticholinergics, and preformulated combinations of the two agents are available for use with standard nebulizers. These agents also can be continued using metered-dose inhalers (MDIs) together with a spacer system in-line with the mechanical ventilator circuit or attached to a facemask to facilitate assisted dosing until the patient is able to resume self-administration. Dosing adjustments that ensure adequate delivery of medication are required when using MDIs to deliver inhaled bronchodilators through a ventilator circuit.¹⁹

For COPD patients who have been clinically stable on theophylline preparations prior to surgery, continuation is recommended throughout the perioperative period. Theophylline can be continued as an IV infusion or as an elixir to allow nasogastric, gastric, or jejunal feeding tube administration until patients are able to resume oral intake. Theophylline can predispose to atrial tachyarrhythmias even when serum levels are within the therapeutic range. Therefore, dosing in the perioperative period should be individualized and should target levels that have been demonstrated to be safe and therapeutically effective for each patient preoperatively. Theophylline also can alter the metabolism of other drugs administered during periopertaive management and must be used with caution.

ANTI-INFLAMMATORY GLUCOCORTICOID THERAPY

Clinical responses to glucocorticoid therapy in COPD patients are substantially different from those in asthmatics, for whom steroids have proved to be effective in blunting inflammation and improving lung function in a majority of patients.²⁰ Steroid effects in COPD are more variable, and benefits are limited primarily to patients with stage 3 and 4 disease who experience frequent exacerbations. In such patients, inhaled steroids reduce the frequency of exacerbations and improve quality of life.²¹ Corticosteroids should be administered specifically as inhaled preparations for long-term maintenance therapy in COPD. Oral steroids are not recommended for this purpose because their use is associated with a high incidence of serious complications. Furthermore, an apparent short-term favorable response to high-dose oral steroids does not reliably identify patients who benefit from long-term inhaled corticosteroids. Thus "screening" for steroid responsiveness using a trial of oral steroids is not recommended.^22,23

There is convincing evidence showing that inhaled corticosteroids do not slow disease progression or alter mortality in patients with COPD.^24–26 Three large randomized clinical trials involving patients with mild to severe disease confirm that the beneficial effects of inhaled corticosteroids in COPD relate specifically to a decreased incidence of exacerbations in patients who experience at least one episode annually.

Studies that have examined combination therapy involving inhaled corticosteroids and LABAs suggest a possible synergistic effect between these two classes of drugs. Several single-center cohort studies have demonstrated that the combination of an inhaled steroid with salmeterol or formoterol improves spirometry compared with monotherapy with either LABA.^27,28 A meta-analysis of six studies that evaluated salmeterol-fluticasone and budesonide-formoterol combinations concluded that both were superior to placebo and to inhaled corticosteroid monotherapy with respect to FEV₁ improvement. Beta agonist-steroid combinations also were superior to placebo and beta agonist monotherapy with respect to frequency of exacerbations.²⁹

Results from the Toward a Revolution in COPD Health (TORCH) study, a 6100-patient multicenter prospective, randomized, blinded clinical trial sponsored by GlaxoSmithKline comparing fluticasone, salmeterol, and the combination to placebo, have shown a trend toward reduced mortality at 3 years in the combination therapy group versus placebo (17% reduction, p = 0.052). Combination therapy also was associated with a statistically significant reduction in COPD exacerbations (p < 0.001) and an improvement in health-related quality of life (p < 0.001) compared with placebo.^30–32

Extended use of inhaled corticosteroids has been well tolerated in patients with COPD. Side effects have included increased skin bruising and a slight decrease in bone density, although the clinical significance of these findings is unclear.

In summary, inhaled corticosteroids have beneficial effects in a subset of patients with chronic stable COPD. They reduce the frequency of exacerbations in patients with advanced disease (FEV₁ < 50% predicted) who experience, on average, at least one exacerbation per year. In combination with LABAs, inhaled corticosteroids increase the extent of bronchodilation compared with LABA monotherapy, suggesting that the two types of drugs act synergistically. This combination has been shown to improve health-related quality of life compared with placebo treatment.

ANTI-INFLAMMATORY GLUCOCORTICOID THERAPY IN THE PERIOPERATIVE PERIOD

In COPD patients who have been maintained on high doses of inhaled steroids prior to surgery, the benefits of continued use in the perioperative period must be weighed against the potential risk of increased infection and poor wound healing that has been observed in patients on parenteral steroids.³³ While these risks generally are negligible in patients receiving inhaled formulations, systemic absorption and parenteral side effects can be substantial in some patients. Evidence of skin fragility, dermal ecchymoses, and cushingoid features on preoperative physical examination suggests clinically relevant systemic absorption of steroids. In such patients, tapering of steroids prior to surgery is reasonable to consider in stable patients. While this is expected to have no clinically significant detrimental effect on overall lung function in the short term, there are also no data demonstrating a clinical benefit of this approach with respect to improved wound healing; therefore, any such benefits are theoretical and should be based on prior history of COPD exacerbations and surgical complications associated with previous procedures. All COPD patients maintained on inhaled corticosteroids should receive stress-dose steroids in the immediate (24-hour) perioperative period. An extended taper is not necessary.

Liquid formulations of steroid preparations for nebulizer administration are not available for most formulations. Only budesonide suspension is currently available for use with a nebulizer. Dosing of inhaled steroids can be continued using MDIs with spacer devices in most patients. Perioperative substitution of parenteral for inhaled steroids in COPD patients whose respiratory status is stable is not recommended. There are no proven benefits to this approach, and even short courses of parenteral steroids can have undesirable effects on blood sugar, mental status, sleep-wake cycle, and electrolyte balance, as well as delaying wound healing and increasing infection risk.

TREATMENT OF ACUTE EXACERBATIONS IN THE OUTPATIENT AND POSTOPERATIVE SETTINGS

COPD exacerbations occur on average 1 to 3 times annually in patients with moderate to severe disease (stages 2, 3, and 4), and management recommendations are based on stage of disease and clinical presentation.³⁴Outpatient COPD exacerbations are thought to result from airway inflammation, the two most common causes of which are infection and exposure to inhaled pollutants.⁶

Patients with stage 1 and 2 disease who experience exacerbations generally can be managed as outpatients following physician assessment to ensure adequacy of gas exchange and ventilatory capacity and confirmation of this presumptive diagnosis. For the most of these patients, increased use of short-acting bronchodilators on an as-needed basis, combined with a short course of systemic corticosteroids and antibiotics, is sufficient therapy. Patients generally feel improvement within 1–2 days and return to baseline within 3–6 weeks. Although convincing evidence of bacterial infection is lacking in the majority of instances, Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis have been implicated as potential pathogens in COPD exacerbations involving patients with stage 1 and 2 disease. Therapy generally can be started empirically without microbiologic cultures using agents such as doxycycline, clarithromycin, azithromycin, ciprofloxacin, or levofloxacin that have activity against these pathogens (including beta-lactamase-producing strains). Antibiotic therapy has proved most beneficial for patients who present with increased sputum volume and purulence.³⁵ Prednisone should be prescribed at doses of 0.5 mg/kg/day (30–40 mg/day) for 10 days, without a subsequent taper. Higher doses have not proved to be more effective and are associated with an increased incidence of complications. Special precautions should be taken when initiating antibiotic therapy in patients receiving theophylline preparations because certain antibiotics (e.g., clarithromycin and ciprofloxacin) can raise serum levels of theophylline.

Management of COPD exacerbations in patients with advanced disease (stage 3 and 4 COPD) is similar to that in patients with mild to moderate disease. Patients should undergo an initial evaluation to confirm the presumptive diagnosis of COPD exacerbation. Myocardial ischemia, congestive heart failure, pneumonia, and pulmonary embolus can present with similar symptoms, especially in patients with more advanced disease, and must be considered in the differential diagnosis. Patients with stage 3 and 4 disease are best managed in the hospital given their limited reserve and the potential for respiratory failure. The sickest patients, including those with compromised gas exchange, signs of right-sided heart failure, altered mental status, and altered baseline breathing pattern with use of accessory muscles, should be admitted to an ICU because these signs and symptoms indicate substantial physiologic compromise and are associated with respiratory failure.

Assessment of gas exchange is a critical first step in determining the severity of an exacerbation and planning subsequent management. An arterial blood gas determination, rather than a peripheral saturation assessment, generally is required because it provides information regarding adequacy of both oxygenation and ventilation. In patients with altered mental status and either severe hypoxemia or marked acute hypercarbia, emergent intubation is indicated. Conversely, stabilization of awake, cooperative patients may be possible with oxygen supplementation alone or in combination with noninvasive (e.g., facemask) ventilation even when marked alterations in gas exchange are present. The goal of supplemental oxygen therapy is to maintain arterial oxygen saturation levels of approximately 90% (88–92%). In patients without a history of CO₂ retention, this can be accomplished in straightforward fashion by administration of either nasal prong or facemask oxygen. However, many patients with advanced COPD have hypercarbic respiratory insufficiency, which makes delivery of oxygen support more complicated. Administration of excess oxygen to such patients can suppress respiratory drive and precipitate worsening hypercarbia. Oxygen delivery therefore must be titrated carefully using either a Venturi mask system or nasal prongs with close observation.

Bronchodilator therapy remains a key component of the medical management of exacerbations in patients with advanced disease. Patients are often too dyspneic to use MDIs effectively, and inhaled bronchodilators must be administered using a nebulizer system. Current recommendations suggest using repeated doses (i.e., continuous nebulization) of a short-acting beta-2 agonist until a change in clinical status (i.e., improvement with stabilization or progression to respiratory failure necessitating ventilator support) or evidence of side effects is observed. Frequent administration of nebulized short-acting bronchodilators generally is required for several days, and the decision to taper dosing should be based on improvement in clinical status.

Steroid therapy is also an essential component of therapy. Recommended systemic dosing is 0.5 mg/kg/day for 10–14 days, similar to that of patients with less severe disease. Oral dosing is the preferred route of administration, although IV therapy may be required initially until patients are sufficiently stable to resume oral intake. Steroids have been shown to shorten recovery times, restore lung function to baseline more quickly, and reduce the risk of early relapse.^36,37 Higher doses and longer courses of steroids have not been shown to improve outcomes and are associated with a greater incidence of serious side effects. There are limited data addressing whether inhaled steroids are beneficial in this setting. One study suggests that nebulized budesonide may substitute for parenteral steroids in patients without evidence of respiratory failure.³⁸ The potential utility of combination therapy with systemic and parenteral steroids has not been examined.

The bacteriology of exacerbations in patients with severe disease differs from that of patients with mild to moderate disease. S. pneumoniae, H. influenzae, and M. catarrhalis remain important pathogens in patients with stage 3 and 4 COPD and appear to be associated with less severe exacerbations. However, in patients with severe exacerbations associated with respiratory failure, enteric gram-negative rods and Pseudomonas aeruginosahave been identified as potential pathogens.³⁹ Antibiotics with activity against these organisms, such as third-generation cephalosporins or fluoroquinolones, should be initiated in this setting pending culture results. Optimal duration of therapy has not been determined but has ranged from 3 to 10 days in clinical trials.

Between 10% and 30% of patients with COPD exacerbations will not respond to empirical therapy with bronchodilators, steroids, and antibiotics. If no clinical improvement is observed after 4 days of intensive treatment, medical reevaluation is indicated to ensure that the initial diagnosis was indeed correct or that a complicating condition (e.g., congestive heart failure, pulmonary embolus, or nosocomial pneumonia) has not developed subsequent to hospitalization.

Discharge can be considered once patients have been stable for 24 hours without episodes of acute shortness of breath, have resumed ambulation, and understand and are able to self-administer their medications. Follow-up visit should be scheduled for 4–6 weeks from the time of discharge.

Patients who are scheduled for elective or semielective surgery and then experience an intervening COPD exacerbation prior to their surgical date should have their procedure postponed until they have received appropriate therapy and their respiratory status has returned to baseline. Generally, 4–6 weeks is required for complete resolution.

COPD Exacerbations Perioperatively

Management of COPD exacerbations following cardiothoracic surgery is similar to that of hospitalized patients in the nonoperative setting and includes the appropriate use of oxygen therapy, bronchodilators, steroids, and antibiotics. However, greater consideration must be given to alternative diagnoses such as myocardial ischemia, congestive heart failure, pulmonary embolus, nosocomial pneumonia/bronchitis, aspiration, and drug reaction. The exact incidence of COPD exacerbations following cardiothoracic surgery is unknown, but it is likely that the majority of episodes of worsening respiratory status that occur postoperatively are not the result of COPD exacerbations.

PULMONARY REHABILITATION

PR is a nonpharmacologic medical therapy that has been shown to increase exercise capacity, reduce breathlessness, improve health-related quality of life, and improve symptoms of anxiety and depression in patients with stable COPD. Most PR programs are hospital-based and are staffed by a multidisciplinary team that provides teaching and supervision in three separate areas: (1) exercise training, (2) nutrition counseling, and (3) disease education focusing on pathophysiology, risk factors, and management of exacerbations. Patients are evaluated at the beginning of participation to allow development of a customized, safe exercise program and on completion of PR to determine extent of improvement. Assessments of spirometry, respiratory muscle strength, exercise capacity, health-related quality of life, and dyspnea are performed. Programs vary in design across centers, but studies suggest that best results are achieved with programs of 6–10 weeks' duration that involve six to eight patients per class. Exercise on a stationary bike or treadmill is performed two to five times per week for 15–45 minutes at levels ranging from 50% to 75% of maximal oxygen consumption.

Studies suggest that rehabilitation programs benefit patients with all stages of COPD except for those who are homebound and suffer from rest symptoms.^40,41 Cohort studies indicate that patients with moderate disease improve their ability to exercise to a greater extent than patients with mild or severe disease. However, exercise capacity has been shown to improve in all groups.^40–42 Benefits appear to be maximal when patients are actively participating in PR, but some benefits have been shown to extend beyond the period of active participation. Specifically, reductions in dyspnea have been reported to persist as long as 9 months following completion of rehabilitation.⁴³ Home-based PR programs, which provide greater flexibility at reduced cost, have been compared recently with conventional hospital-based programs. Multiple studies have confirmed the benefits of home-based programs in selected patients.

There are no convincing data that either home- or hospital-based PR programs reduce health care costs, improve pulmonary function, slow disease progression, or reduce mortality in COPD. Several small cohort studies have suggested that PR patients may have fewer hospital visits and lower health care resource utilization than controls, although these trends generally have not reached statistical significance and were observed in poorly controlled observational trials. A large randomized, controlled trial to evaluate the effects of home-based PR on exercise capacity, health status, health-related quality of life, and health care resource utilization is presently under way in Canada and should address these issues in an unbiased way.⁴⁴

There are also no data to suggest that preoperative participation in PR programs substantially affects the incidence of perioperative complications in patients with COPD who undergo cardiothoracic surgery.^45,46Nevertheless, in patients with poor functional capacity and severe flow limitation who are being considered for elective or semielective procedures, participation in a preoperative PR program is reasonable and may be of therapeutic benefit. While PR has no effect on lung function, improvements in exercise capacity as a consequence of participation may facilitate early postoperative mobilization and thus may be helpful for selected patients in reducing complications associated with postoperative immobility, such as pneumonia, atelectasis, deep venous thrombosis, and pulmonary embolus.

OXYGEN THERAPY

The basic goal of oxygen therapy in patients with chronic stable COPD is to maintain peripheral arterial oxygen (PaO₂) values above 60 mm Hg at sea level.⁶ Therapy currently targets patients with clinically significant chronic respiratory failure, defined as a PaO₂ of 55 mm Hg or less or as a PaO₂ of 60 mm Hg or less and either cor pulmonale or hematocrit greater than 55%. Most of these patients have either stage 3 or stage 4 COPD.

Oxygen therapy for patients with chronic stable COPD generally is administered via nasal prongs at 1–6 L/min using one or more of the following approaches: (1) continuous use, (2) use with exercise, (3) use during sleep, (4) use during air travel, or (5) use as needed for symptoms of dyspnea independent of activity. Of these, only continuous administration (defined as therapy for more than 15 hours/day) has been shown to have beneficial effects on exercise capacity, mental capacity, cardiopulmonary hemodynamics, and survival in patients with chronic respiratory failure.^47,48 A recent meta-analysis that included the results of the two largest randomized, controlled trials of oxygen therapy for hypoxic COPD (Nocturnal Oxygen Therapy Trial and Medical Research Council Domiciliary Oxygen Therapy Trial) demonstrated that long-term oxygen therapy for 15 hours or more each day in patients with chronic respiratory failure reduces 5-year mortality substantially (relative risk of death with treatment = 0.45).^49,50 Patients treated with nocturnal oxygen alone and those with mild to moderate hypoxemia during exercise or sleep did not experience a reduction in mortality.

Subsequent studies have examined expanded applications for oxygen therapy in COPD patients; however, results to date have failed to clearly identify other COPD cohorts that benefit from this therapy. The potential utility of continuous oxygen therapy has been examined in patients with severe COPD who did not have signs of chronic respiratory failure. Long-term use of continuous oxygen (>15 hours/day) therapy had no beneficial effect on health-related quality of life for these patients after 3 months.^49–51 The use of supplemental oxygen in combination with vigorous exercise training also has been assessed. In a small single-center study, supplemental oxygen was administered to COPD patients without respiratory failure in an attempt to augment the benefits of exercise training by allowing more vigorous activity. Results failed to demonstrate a benefit from supplemental oxygen therapy administration during exercise training, however.⁵² Several cohort studies have demonstrated that in COPD patients with chronic respiratory failure, long-term oxygen therapy (>15 hours/day for more than 3 months) improves performance on neuropsychological testing.⁵³ Patients shown to benefit in these studies were those with very severe COPD and chronic respiratory failure, the same group that experiences a mortality benefit from therapy.

In summary, oxygen therapy benefits patients with severe and very severe COPD who also have chronic respiratory failure. Long-term oxygen therapy for greater than 15 hours per day confers a mortality benefit and improves exercise capacity and cognitive function. Patients with only mild intermittent hypoxemia but without chronic respiratory failure as defined by the WHO do not benefit from long-term oxygen therapy. Use of oxygen therapy only at night or with symptoms does not appear to confer any benefits.

SMOKING CESSATION

Cigarette smoking is the primary risk factor for COPD in industrialized countries. Although it is commonly stated that only 15% of smokers go on to develop COPD, recent data suggest that this is an underestimate of the true incidence of smoking-related disease because most smokers with early-stage disease go undiagnosed. There is convincing evidence showing that smoking cessation slows progression of COPD in susceptible individuals. Smokers lose lung function at two to three times the rate of nonsmokers (60–90 mL/year versus 20–30 mL/year decrease in FEV₁), and on cessation of smoking, the rate of lung function loss returns to normal.⁵⁴ However, there are some data to suggest that patients with far-advanced disease lose lung function at an accelerated rate in the absence of active smoking.⁵⁵

Smoking cessation programs generally involve two components: (1) counseling and (2) pharmacotherapy. Even a brief period of physician-initiated counseling is effective in promoting smoking cessation in 5–10% of patients and is more effective than simply providing reading materials that encourage discontinuation.^56–58 There is evidence showing that quit rates are proportional to the intensity of counseling, with sophisticated multisession programs achieving sustained quit rates of 20–35%. Successful programs provide information regarding the effects of cigarette smoking on the lung, symptoms of COPD, the medical basis for nicotine addiction, guidance for recognizing risk factors for relapse, and suggested approaches for dealing with stressful situations that can lead to relapse.^56–59

Pharmacotherapy includes nicotine replacement, bupropion, clonidine, and newer agents, including Chantix (Pfizer, Inc., Mission, KS). Nicotine has been and remains the cornerstone of smoking-cessation pharmacotherapy for most patients and is available in four different forms: (1) a transdermal patch, (2) gum, (3) inhaler, and (4) nasal spray. The patch is the most widely used form of nicotine replacement because it is the easiest to use. Patients who smoke more than a half a pack of cigarettes a day generally are advised to start at the highest dose of transdermal nicotine (21 mg) and to taper to lower doses over 6–8 weeks. Equivalent therapy using nicotine-containing gum requires some level of training. Patients must be instructed to chew the gum and then allow it to rest against the buccal mucosa to facilitate absorption. Continuous chewing results in the majority of the nicotine dose being washed into the esophagus and stomach, where it can cause cramps and nausea. Bupropion (Zyban, GlaxoSmithKline, Philadelphia, PA), a mildly stimulating slow serotonin reuptake inhibitor, has been shown to significantly increase long-term quit rates. At 1 year, therapy with bupropion alone was shown to be nearly as effective as the combination of bupropion and nicotine in promoting cessation.⁶⁰

Varnecline (Chantix) is a newly released central acting ₄,₂ nicotinic receptor agonist being marketed by Pfizer as a smoking-cessation aid. Results from six clinical trials involving over 3000 patients show that in combination with counseling, Chantix was more effective than Zyban and than counseling alone in promoting smoking cessation (44% versus 30% versus 17% quit rates) at 12 weeks. The most common side effects of therapy were nausea, vomiting, and sleep disturbances, with symptoms severe enough to cause drug discontinuation in 3% of study patients.^61,62

Smoking has been identified as an important risk factor for postoperative complications in patients undergoing cardiothoracic surgery.^63,64 It has been associated with an increased risk of pulmonary complications as well as poor wound healing in patients undergoing lobectomy and pneumonectomy. Based on these data, it is reasonable to encourage all patients being evaluated for elective cardiothoracic surgery to participate in a smoking-cessation program. There are data to suggest that cessation of smoking at least 8 weeks prior to planned cardiothoracic surgery reduces the incidence of postoperative complications. It is likely that cessation at any time prior to surgery is of some benefit, although data supporting this premise are lacking.

In patients who smoke one or more packs of cigarettes a day, cessation of smoking at the time of admission for surgery can be associated with symptoms of nicotine withdrawal. Nicotine replacement therapy in the form of a patch in combination with clonidine may be beneficial in preventing withdrawal symptoms in appropriately selected patients.

SUMMARY

Current medical therapy for COPD in the outpatient setting is directed primarily at relieving symptoms, improving exercise capacity, and decreasing the frequency of exacerbations. Only two simple interventions, smoking cessation and oxygen therapy for chronic hypoxemia, alter the natural history of COPD by changing the rate of lung function decline and reducing mortality. WHO recommendations suggest a stepwise approach to medical therapy. Patients with mild disease can be managed with as-needed bronchodilators. Patients with more severe disease should be prescribed long-acting bronchodilators on a regulator basis. The majority of data support the use of combination therapy with both an inhaled beta agonist and an anticholinergic agent. Long-acting preparations are easy to take and are associated with fewer exacerbations, although they are expensive. Oral theophylline can be added to combination inhaled therapy in patients with persistent symptoms, although this drug has a low therapeutic index and interacts with many other drugs. Inhaled steroids reduce the frequency of COPD exacerbations in patients who experience at least one exacerbation per year. Oxygen therapy is clearly of benefit in patients with advanced COPD and chronic respiratory failure but must be used continuously (>15 h/day) to produce clinical benefit. Use of oxygen therapy only with sleep and use of therapy by patients with only mild hypoxemia is of no clinical benefit. PR is beneficial for COPD patients with all stages of disease. It improves exercise capacity, reduces symptoms, and improves quality of life but does not alter disease progression or affect mortality. Smokers at all stages of COPD should be encouraged to participate in a smoking-cessation program. Counseling in combination with newer pharmacotherapy has increased the success rates for participation in smoking-cessation programs substantially.

Management of COPD exacerbations requires an initial evaluation to exclude other potential causes of respiratory compromise and an assessment of severity. Patients with advanced disease (stages 3 and 4) at baseline are best managed as inpatients, whereas those with mild to moderate disease without evidence of altered mental status, breathing pattern, or gas exchange can be managed as outpatients. Therapy consists of intensified bronchodilator therapy and a 10- to 14-day course of systemic corticosteroids. In patients with increased sputum production or purulence, a 7- to 10-day course of antibiotics is recommended. In patients with stage 1 and 2 COPD, antibiotic coverage for S. pneumoniae, H. influenzae, and M. catarrhalis is indicated. Patients with stage 3 and 4 disease should receive broader coverage with antibiotics active against enteric gram-negative rods andP. aeruginosa.

EDITOR'S COMMENT

Clinically relevant disease classifications should ideally provide both an explanation of the mechanism of disease as well as a prediction of the clinical course and response to therapy. An important result of the experience with lung volume reduction surgery is that the best predictor of surgical response—namely, apical predominant emphysema—is not incorporated into most current classification schemes. This observation suggests we need to actively integrate anatomic, spirometric and symptomatic data into our clinical assessments of emphysema patients—at least until more comprehensive classifications are developed.

–SJM

REFERENCES