Chronic obstructive pulmonary disease (COPD) is defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD)¹ as persistent, usually progressive airflow limitation associated with an enhanced inflammatory response, generally in response to noxious stimuli, such as cigarette smoking. COPD is one of the few major diseases with a rising burden; it is now the third leading cause of death in the United States.² Worldwide, an increasing prevalence of cigarette smoking, other exposures such as to biomass fuel, a reduction in other causes of early mortality, and an aging population are expected to lead to an increase in the global burden of COPD, and its rise from the fifth to the fourth most common cause of mortality (Fig. 97-1).³

COPD is a common comorbid condition in patients presenting for thoracic surgical evaluation, in large part due to shared risk factors of age and cigarette smoking. In addition, increasing evidence suggests that COPD itself may be an independent risk factor for lung cancer⁴ and cardiovascular disease.^5,6 COPD is commonly underdiagnosed.⁷ The presence of COPD has substantial impact on thoracic surgical outcomes.^8,9

This chapter reviews some of the diagnostic and management considerations of COPD related to thoracic surgery, specifically:

1. 
   

   Diagnosis and severity of COPD.

   
   
2. 
   

   Management of stable COPD, with the goal of identifying comorbidities and optimizing pulmonary function prior to surgery.

   
   
3. 
   

   Management of exacerbations.

Assessment of preoperative pulmonary risk is covered in Chapter 4. Surgical management of COPD is discussed in the ensuing Chapters 97 to 100.

The diagnosis of COPD should be considered in any patient who has persistent dyspnea, chronic cough or sputum, and/or a history of exposure to risk factors for disease (generally at least 10–20 pack-years of cigarette smoking).^1,10 The GOLD definition of COPD is deliberately simple: airflow obstruction is identified by a reduced forced expiratory volume in 1 second (FEV₁) together with a reduced FEV₁ to forced vital capacity (FEV₁/FVC) ratio <0.7, and thus can be diagnosed in the appropriate setting by spirometry and bronchodilator testing. The use of the fixed ratio of FEV₁/FVC is chosen for simplicity but may lead to underdiagnosis in young patients and more conspicuously, potential overdiagnosis in elderly patients,¹¹ because of the normal decline in FEV₁/FVC with age, as demonstrated in population-based studies of healthy normal controls. Of interest, older subjects potentially misclassified as having obstruction have been shown to have worse outcomes, suggesting that using a fixed ratio is acceptable.^12,13

Despite the simplicity of making a diagnosis of COPD based on spirometry and fixed-ratio definition of airflow obstruction, underdiagnosis is common because many patients with COPD are asymptomatic or minimally symptomatic.⁷ Conversely, a large fraction of patients who carry a diagnosis of COPD either do not have obstruction on spirometry or have never had spirometry.^14,15 Dyspnea together with a history of cigarette smoking is insufficient to establish a diagnosis of COPD: only a minority of long-term cigarette smokers develops airflow obstruction and COPD. Even in the presence of compatible spirometry, the differential diagnosis of airflow obstruction is broad, and many diseases can masquerade as COPD or be present in addition to COPD (e.g., asthma, congestive heart failure, bronchiectasis, tuberculosis, and bronchiolitis).¹

COPD is a complex disease that incorporates three other disease states: emphysema, small airways disease (respiratory bronchiolitis), and chronic bronchitis.¹⁶ Airflow obstruction in COPD results from emphysema and small airways disease. Emphysema is defined anatomically as parenchymal destruction due to abnormal and permanent enlargement of the airspaces distal to the terminal bronchioles without obvious fibrosis. Emphysema leads to airflow obstruction through loss of lung elastic recoil and flow limitation, although a substantial portion of subjects with emphysema by CT scan do not have airflow obstruction.¹⁷ Small airways disease is the major cause of airflow limitation in COPD, and detailed studies have demonstrated that narrowing and loss of these small airways precedes emphysematous destruction.¹⁸ Chronic bronchitis, the consequence of mucous gland hyperplasia and hypertrophy in larger, more central airways, is defined by symptoms of chronic cough productive of phlegm for at least 3 months out of the year for at least 2 years.¹⁹ While these symptoms frequently overlap with conditions causing airflow obstruction, a substantial fraction of patients with chronic bronchitis do not have chronic airflow obstruction.²⁰ Nonetheless, chronic mucous hypersecretion is an independent risk factor for postsurgical respiratory complications, including hypoxemia and pneumonia.²¹

These components of COPD lead to several pathophysiologic consequences. The most typical finding in COPD is chronic airflow obstruction. During exhalation, airflow is determined by the balance of elastic recoil of the lungs and airway resistance, both of which are impaired in COPD. Hyperinflation is a consequence of airflow obstruction and reduced elastic recoil. It serves as a compensatory mechanism to increase lung volumes and expiratory flow rates. However, hyperinflation also leads to a disadvantageous position of the diaphragm and increased work of inspiration, increased sensation of dyspnea, decreased exercise capacity, and impaired cardiac function.²² Gas exchange abnormalities are largely a consequence of ventilation–perfusion mismatch,²³ although significant hypoxemia at rest may be absent even in patients with severe airflow obstruction and associated dyspnea. In the absence of respiratory depressant medications, hypercapnia develops in a minority of patients and only in the presence of severe airflow obstruction (FEV₁ less than approximately 1.5 L).²⁴

The major risk factor for COPD is cigarette smoking, and smoking cessation is the single most effective measure to reduce the risk of further decline in lung function. There is a dose-response curve with smoking, such that each pack-year increases the risk of COPD.²⁵ Ongoing smoking increases the rate of decline in lung function, and smoking cessation reduces the rate of lung function decline.²⁶ Exposures to noxious particles other than cigarette smoke, either through occupation²⁷ or in the home,²⁸ are also potential contributors to COPD. A substantial contribution of genetic factors has been identified in family based studies, although most of these factors have yet to be determined.²⁹ An exception is the small and under-recognized fraction of patients with COPD who have a specific genetic predisposition—alpha-1 antitrypsin deficiency. These patients are important to identify as they may benefit from genetic counseling and weekly infusions of purified alpha-1 antitrypsin protein (augmentation therapy).³⁰ Other risk factors include asthma and developmental or early lung disease. Asthma and COPD generally have different underlying causes of inflammation. However, long-standing asthma frequently leads to irreversible airflow obstruction³¹ and these two diseases can have substantial overlap, particularly in the setting of cigarette exposure. Airways hyperresponsiveness – bronchoconstriction in response to external triggers – in patients without a clinical diagnosis of asthma is also a risk factor for chronic airflow obstruction.³² Factors related to lung growth and development – and subsequent reduced maximally attained lung function – are also likely important. In epidemiologic studies, birth weight is associated with FEV₁.³³ More specifically, in prematurely born infants, bronchopulmonary dysplasia is associated with risk for emphysema and airways obstruction,³⁴ although the characteristics of bronchopulmonary dysplasia are changing.³⁵

The severity of COPD is most commonly characterized according to GOLD grade (formerly stage), which utilizes the degree of airflow obstruction based on postbronchodilator spirometry (Table 97-1). FEV₁ is a simple metric that has been associated with symptoms of dyspnea, other measures of disease severity (such as degree of emphysema³⁶ and exacerbations,³⁷) and importantly, overall survival.^38,39 However, other metrics such as the BODE index,⁴⁰ which combines body mass index (BMI), airflow obstruction (FEV₁), dyspnea (Medical Research Council Dyspnea Score), and exercise capacity (6-minute walk), have been demonstrated to provide better prediction of mortality than FEV₁ alone. Recent GOLD guidelines suggest a combined COPD assessment, based on GOLD spirometric classification and Modified British Medical Research Council dyspnea score or COPD Assessment Test (www.catestonline.org).^1,41 Biochemical markers are being sought that can further characterize COPD phenotypes and improve predictive models of COPD mortality.⁴²

COPD is a highly morbid disease, with predictably greater mortality at higher stages of airflow obstruction (Table 97-2). The decline in lung function in COPD is also generally progressive, with a mean decline of FEV₁ of approximately 30 to 40 mL per year,^43,44 but highly variable. A large-scale, 3-year, multi-center observational study of COPD, called “Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints” (ECLIPSE), found that approximately one-third of subjects had a decline of FEV₁ of <20 mL per year, while one-third of subjects had a decline of >40 mL per year. Rate of decline was inversely proportional to initial FEV₁. Risk factors for accelerated decline were current smoking, emphysema, and bronchodilator reversibility⁴⁴; the former two of these risk factors have been identified in multiple other studies.^26,45

COPD has been increasingly recognized as a systemic disease with multiple comorbidities. While the majority of these likely arise due to shared risk factors (e.g., age and cigarette smoking), there is increasing evidence that COPD itself may be an independent risk factor for the development of these comorbid conditions, through either shared inflammatory mechanisms⁴ or altered physiology.⁴⁷ Cardiovascular disease frequently coexists with COPD and is an important cause of mortality,⁴⁸ yet some evidence suggests that coronary artery disease⁴⁹ and heart failure⁵⁰ are underdiagnosed. Pulmonary hypertension is common, particularly in more severe COPD. A selected group of patients have pulmonary artery pressures disproportionate to the degree of airflow obstruction,⁵¹ and it is possible that some of these patients may be candidates for pulmonary vasodilator therapy in a very limited number of settings.⁵² Reduced BMI and osteoporosis are associated with COPD and in particular with the degree of emphysema.⁵³ Anxiety and depression are common in COPD and associated with a worse prognosis.^54,55 Other common comorbidities are anemia and diabetes.⁵⁶ In an analysis of the cause-specific mortality among patients with COPD followed in a 3-year clinical trial, 27% died of cardiovascular diseases and 21% died of cancer.⁴⁸

In summary, COPD is deliberately simple to diagnose, yet represents a complex syndrome, with varying contributions from different risk factors, pathophysiologic manifestations, and comorbidities. Testing to consider in the diagnosis and evaluation of the COPD patient is listed in Table 97-3.

Smoking Cessation

In patients who continue to smoke, smoking cessation is the intervention with the greatest capacity to affect outcome in COPD. Smoking cessation is associated with reduced rate of lung function decline in COPD²⁶ and is one of the few modalities that affects mortality from COPD.⁵⁹ Smoking is an important risk factor for postoperative complications in thoracic surgery.⁶⁰ In a series of randomized trials in a variety of surgical disciplines, smoking cessation decreased the overall rate of complications by 41%, including pulmonary and wound healing complications,^61,62 with longer periods of cessation resulting in an increase in effect. Nevertheless, success is challenging; nicotine addiction is a chronic disease, and relapse is common. Long-term quit rates are often less than 25%.^63,64

Aids to facilitate a patient’s smoking cessation efforts generally consist of two components: (1) counseling and (2) pharmacotherapy. Even brief periods of counseling can increase quit rates, and there is a dose–response relationship with repeated counseling.^65,66 A five-step intervention program (the 5 A’s: Ask about smoking; Advise smokers to quit; Assess willingness to attempt to quit; Assist with treatment and referrals; Arrange follow-up) can form a useful framework for intervention, and three types of counseling – practical, and social support both as a part of treatment and outside of treatment – can be effective.⁶⁷ Successful programs provide information about the health effects of smoking, the medical basis of nicotine addiction, and guidance for recognizing and addressing the risk factors for relapse.⁶⁸

Nicotine replacement products (gum, inhaler, spray, patch, or lozenge) form the basis for most pharmacotherapy, and they successfully increase abstinence rates. Patients should be educated about the proper use of the product. The patch is the easiest and most widely used form of replacement: patients smoking more than half a pack of cigarettes per day should use the 21-mg dose and taper over 6 to 8 weeks. Patients opting for the gum should be instructed to chew the gum intermittently, as continuous chewing results in enhanced absorption and subsequent nausea. Bupropion, a mildly stimulating medication thought to act through noradrenergic and dopaminergic release, can approximately double the rate of smoking cessation compared with placebo.⁶⁹ Bupropion can reduce the seizure threshold and therefore is contraindicated in persons with a history of seizures. Varenicline is a centrally acting partial nicotine receptor agonist that has also been demonstrated to be effective versus placebo (approximately 2.3-fold increase in relative risk of quitting) and more effective than bupropion (relative risk approximately 1.52).⁷⁰ Concerns have been raised about a possible association between neuropsychiatric side effects – and in particular, suicidal and self-injurious behavior – for both bupropion and varenicline. Patients should be monitored closely for adverse effects, and the drug should be discontinued with evidence of unusual behavior or mood symptoms. Varenicline has also been associated with a possible increase in cardiovascular events.^71,72 Although this effect appears to be small and likely outweighed by the long-term benefits of smoking cessation, these data may be important to consider when choosing smoking cessation modalities. Electronic cigarette-shaped devices (“e-cigarettes”) provide a vapor for inhalation and allow smokers to mimic the behavior of smoking tobacco. However, the complete biochemical contents of the inhaled vapor from e-cigarettes are uncertain and unregulated, and the long-term safety of these devices has not been proved.⁷³

Bronchodilators

Bronchodilators are the current mainstay of management for COPD. These medications can improve lung emptying, reduce dynamic hyperinflation, and improve exercise performance. Importantly, bronchodilator responsiveness in COPD is not predicted by a single spirometric measurement. In one study, using American Thoracic Society (ATS) criteria for defining bronchodilator responsiveness, over 50% of patients changed status (bronchodilator responsive vs. nonresponsive) between visits.⁷⁴ Furthermore, the extent of improvement in symptoms and functional capacity is not predicted from bronchodilator testing or changes in FEV₁.^1,75 Inhaled bronchodilators are generally preferred, although proper technique is critical for effectiveness. There are two major classes of bronchodilators, beta₂-agonist and anticholinergic, both of which are available in both short- and long-acting formulations (Table 97-4). Combination of different pharmacologic classes (e.g., beta₂-agonist and anticholinergic) may be more effective and decrease side effects compared with monotherapy.⁷⁶

Short-acting bronchodilators (e.g., beta₂-agonists such as albuterol or anticholinergics such as ipratropium) can be useful for acute relief of symptoms or rescue therapy, with some data suggesting a greater effectiveness for anticholinergics.⁷⁷ However, long-acting bronchodilators are more effective at improving FEV₁, dyspnea, quality of life, and exacerbation rate and should generally be used for all but the most minimally impaired patients (e.g., FEV₁ >80%). These medications are also more convenient, as they are available in both twice-daily (beta-agonists salmeterol, formoterol) and once-daily (beta-agonists indacaterol and vilanterol, anticholinergics tiotropium and umeclidinium) dosing. Large, randomized controlled trials have demonstrated effectiveness of both long-acting beta₂-agonists and long-acting anticholinergics.^43,78 Adverse effects of these medications are generally minimal. In patients with asthma, use of long-acting betaagonists (LABAs) alone (without an inhaled corticosteroid) has been associated with worse outcomes compared to placebo. However, similar concerns do not apply to COPD.⁷⁹ Tachycardia and cardiac rhythm disturbances can occur with both categories of bronchodilator medications, although relief of obstruction and dyspnea generally outweighs the negative effects.^77,80 Initial concern for possible adverse cardiovascular effects of tiotropium was not substantiated in a large, randomized, controlled clinical trial.^43,81 No clear data favor the choice of one long-acting bronchodilator over another.^1,10 In one study, tiotropium was superior to the LABA, salmeterol, in reducing exacerbations, although the difference was small,⁸² and tiotropium has the advantage of once-daily dosing. Indacaterol, a newer once-daily LABA, appears at least as effective as tiotropium in effecting sustained bronchodilation.^83,84

Theophylline is an oral methylxanthine with nonspecific phosphodiesterase and adenosine receptor antagonist activity. It produces a modest bronchodilator effect compared with placebo and in combination with inhaled bronchodilators.^85,86 Theophylline also has potential nonbronchodilator effects that may improve symptoms in COPD.⁸⁷ The use of theophylline has generally been limited, due to a low therapeutic index and risk of interactions with other medications through the cytochrome P450 system; toxicity can include nausea, vomiting, tremor, arrhythmia, and seizures. Thus, use of theophylline is generally relegated to a select group of patients who may be refractory to other therapies.

Anti-inflammatory Medication

In contrast to the success of inhaled and oral corticosteroids in controlling asthma, the response in COPD is substantially less dramatic. Nevertheless, in patients with moderately severe disease (FEV₁ <60% predicted),⁷⁸ inhaled corticosteroids can improve lung function, improve quality of life, and reduce the frequency of exacerbations. An effect on rate of decline in lung function is unclear with some studies finding a modest benefit, and others showing no difference.^78,88 Although generally well tolerated, adverse effects can include oral candidiasis, hoarseness, easy bruising, and a small but significantly increased risk of pneumonia.⁸⁹ While significant, this latter risk may be outweighed by the reduction in exacerbations.⁹⁰ Use of oral steroids for stable COPD is generally not recommended, given the substantial side effects from long-term use and lack of convincing evidence of benefit.⁹¹ In addition, no data support the value of the response to a short course of oral corticosteroids in predicting the subsequent response to inhaled steroids.