AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Chronic obstructive pulmonary disease (COPD) is a devastating disorder that causes a huge degree of human suffering. COPD is currently the fourth leading cause of death in the United States.

In Western Europe, Badham (1808) and Laennec (1827) made the classic description of chronic bronchitis and emphysema in the early 19th century. A British medical textbook of the 1860s described the familiar clinical picture of chronic bronchitis as an advanced disease with repeated bronchial infections that ended in right heart failure. Overall, this malady caused more than 5% of all deaths in the Middle Ages and earlier. The condition was the most common among the poor; therefore, it was attributed to "bad" living.

Developments in the 20th century include the widespread use of spirometry, recognition of airflow obstruction as a key factor in determining disability, and the improvement of pathological methods to assess emphysema. Participants of the Ciba symposium of 1958 proposed definitions of chronic bronchitis and emphysema, incorporating the concept of airflow obstruction.

COPD is defined as a disease state characterized by the presence of airflow obstruction due to chronic bronchitis or emphysema. The airflow obstruction generally is progressive, may be accompanied by airway hyperreactivity, and may be partially reversible. Chronic bronchitis is defined clinically as the presence of a chronic productive cough for 3 months during each of 2 consecutive years (other causes of cough being excluded). Emphysema is defined as an abnormal, permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis. Chronic bronchitis is defined in clinical terms and emphysema in terms of anatomic pathology.

Pathophysiology

Pathological changes in COPD occur in the large (central) airways, the small (peripheral) bronchioles, and the lung parenchyma. The pathogenic mechanisms are not clear but most likely involve diverse mechanisms. The increased number of activated polymorphonuclear leukocytes and macrophages release elastases in a manner that cannot be counteracted effectively by antiproteases, resulting in lung destruction. The primary offender has been human leukocyte elastase, with a possible synergistic role suggested for proteinase 3 and macrophage-derived matrix proteinases, cysteine proteinases, and a plasminogen activator. Additionally, increased oxidative stress caused by free radicals in cigarette smoke, the oxidants released by phagocytes, and polymorphonuclear leukocytes all may lead to apoptosis or necrosis of exposed cells.

Chronic bronchitis

Mucous gland enlargement is the histologic hallmark of chronic bronchitis. The structural changes described in the airways include atrophy, focal squamous metaplasia, ciliary abnormalities, variable amounts of airway smooth muscle hyperplasia, inflammation, and bronchial wall thickening. Neutrophilia develops in the airway lumen, and neutrophilic infiltrates accumulate in the submucosa. The respiratory bronchioles display a mononuclear inflammatory process, lumen occlusion by mucous plugging, goblet cell metaplasia, smooth muscle hyperplasia, and distortion due to fibrosis. These changes, combined with loss of supporting alveolar attachments, cause airflow limitation by allowing airway walls to deform and narrow the airway lumen.

Emphysema

Emphysema has 3 morphologic patterns. The first type, centriacinar emphysema, is characterized by focal destruction limited to the respiratory bronchioles and the central portions of acinus. This form of emphysema is associated with cigarette smoking and is most severe in the upper lobes. The second type, panacinar emphysema, involves the entire alveolus distal to the terminal bronchiole. The panacinar type is most severe in the lower lung zones and generally develops in patients with homozygous alpha1-antitrypsin (AAT) deficiency. The third type, distal acinar emphysema or paraseptal emphysema, is the least common form and involves distal airway structures, alveolar ducts, and sacs. This form of emphysema is localized to fibrous septa or to the pleura and leads to formation of bullae. The apical bullae may cause pneumothorax. Paraseptal emphysema is not associated with airflow obstruction.

Chronic obstructive pulmonary disease

Both emphysematous destruction and small airway inflammation often are found in combination in individual patients. When emphysema is moderate or severe, loss of elastic recoil, rather than bronchiolar disease, is the mechanism of airflow limitation. By contrast, when emphysema is mild, bronchiolar abnormalities are most responsible for the deficit in lung function. Although airflow obstruction in emphysema is virtually irreversible, bronchoconstriction due to inflammation accounts for a limited amount of reversibility.

Role of inflammation in COPD

In contrast to the eosinophil, which is the most prominent inflammatory cell in asthma, the cellular composition of the airway inflammation in COPD is predominantly mediated by the neutrophils. Cigarette smoking induces macrophages to release neutrophil chemotactic factors and elastases, thus unleashing tissue destruction. Severity of airflow obstruction has correlated with greater induced sputum neutrophilia that is also more prevalent in patients with chronic cough and sputum production and is associated with an accelerated decline in lung function.

Macrophages also play an important role through macrophage-derived matrix metalloproteinases (MMPs). Cigarette smoke causes neutrophil influx and is required for the secretion of MMPs, therefore suggesting that both neutrophils and macrophages are required for the development of emphysema. Studies have also shown that T lymphocytes, particularly CD8+, in addition to the macrophages, play an important role in the pathogenesis of smoking-induced airflow limitation. To support the inflammation hypothesis further, a stepwise increase in alveolar inflammation occurs in surgical specimens from patients without COPD versus patients with mild or severe emphysema.

Frequency

United States

Approximately 14.2 million people have COPD, approximately 12.5 million have chronic bronchitis, and 1.7 million have emphysema. Since 1982, the patients diagnosed with COPD increased by 41.5%. Researchers estimate the prevalence of chronic airflow obstruction in the United States as 8-17% for men and 10-19% for women. The prevalence rates increased in women by 30% in the last decade.

International

Worldwide data are sparse, but the rates likely are higher because more than 1.2 billion humans are exposed to the ravages of smoking. A population-based epidemiologic study from Spain determined the prevalence of COPD in individuals aged 40-69 years at 9.1% (78% were men).

Based on pooled data from a number of studies, global prevalence of COPD was 7.5%, chronic bronchitis alone was 6.4%, and emphysema alone was 1.8%. The prevalence from 26 spirometric estimates was 8.9%. The most common spirometric definitions were those of the Global Initiative for Obstructive Lung Disease (GOLD). Thus, the prevalence of physiologically defined COPD in adults aged 40 years and older is approximately 9-10%.

Mortality/Morbidity

Absolute mortality rates for US patients aged 55-84 years (1985) were 200 per 100,000 males and 80 per 100,000 females. Internationally, a marked variation in overall mortality rates from COPD exists. The extremes are the more than 400 deaths per 100,000 males aged 65-74 years in Romania and the fewer than 100 deaths per 100,000 in Japan.

Sex

Researchers estimate that 4-6% of white male adults and 1-3% of white female adults have emphysema or COPD. Men have a higher mortality rate than women, but mortality due to COPD in women is expected to increase.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

Most patients with COPD have smoked at least 20 cigarettes per day for 20 or more years before the onset of the common symptoms of cough, sputum, and dyspnea. Presentation commonly occurs in the fifth decade of life.

• A productive cough or an acute chest illness is common. The cough usually is worse in the mornings and produces a small amount of colorless sputum.
• Breathlessness is the most significant symptom, but it usually does not occur until the sixth decade of life. By the time the forced expiratory volume in 1 second FEV₁ has fallen to 30% of predicted, the patient is breathless after minimal exertion.
• Wheezing may occur in some patients, particularly during exertion and exacerbations.
• With disease progression, intervals between acute exacerbations become shorter; cyanosis and right heart failure may occur. Anorexia and weight loss often develop and suggest a worse prognosis.

Physical

The sensitivity of a physical evaluation for detecting mild-to-moderate COPD is relatively poor; however, the physical signs are quite specific and sensitive for severe disease. Patients with severe disease experience tachypnea and respiratory distress with simple activities.

• The respiratory rate increases proportionally to disease severity. Use of accessory respiratory muscles and paradoxical indrawing of lower intercostal spaces is evident. In advanced disease, cyanosis, elevated jugular venous pulse (JVP), and peripheral edema are observed.
• Measurement of forced expiratory time (FET) maneuver is a simple bedside test; FET of more than 6 seconds indicates considerable expiratory flow obstruction (ie, FEV₁/forced vital capacity (FVC) <50%).
• Thoracic examination reveals hyperinflation (barrel chest), wheezing, diffusely decreased breath sounds, hyperresonance on percussion, and prolonged expiration. Coarse crackles beginning with inspiration may be heard, and wheezes frequently are heard on forced and unforced expiration.

Causes

• Cigarette smoking
• • The primary cause of COPD is exposure to tobacco smoke. Clinically significant COPD develops in 15% of cigarette smokers. Age of initiation of smoking, total pack-years, and current smoking status predict COPD mortality. People who smoke have a greater annual decline in FEV₁. Overall, tobacco smoking accounts for as much as 90% of the risk.
  • Secondhand smoke, or environmental tobacco smoke, increases the risk of respiratory infections, augments asthma symptoms, and causes a measurable reduction in pulmonary function.
• Air pollution
• • Although the role of air pollution in the etiology of COPD is unclear, the effect is small when compared to cigarette smoking.
  • The use of solid fuels for cooking and heating may result in high levels of indoor air pollution and the development of COPD.
• Airway hyperresponsiveness
• • Airway hyperresponsiveness (ie, Dutch hypothesis) stipulates that patients who have nonspecific airway hyperreactivity and who smoke are at increased risk of developing COPD with an accelerated decline in lung function. Nonspecific airway hyperreactivity is inversely related to FEV₁ and may predict a decline in lung function.
  • The possible role of airway hyperresponsiveness as a risk factor for the development of COPD in people who smoke is unclear. Moreover, bronchial hyperreactivity may result from airway inflammation observed with the development of smoking-related chronic bronchitis.
• Alpha1-antitrypsin deficiency
• • AAT deficiency is the only known genetic risk factor for developing COPD and accounts for less than 1% of all cases in the United States. AAT is a protease inhibitor produced by the liver that acts predominantly by inhibiting neutrophil elastase in the lungs.
  • Severe AAT deficiency leads to premature emphysema at the average age of 53 years for nonsmokers and 40 years for smokers.
  • PiMM phenotypes occur in 90% of people and produce serum levels within the reference range. PiZZ is the most common deficient state and accounts for 95% of people in the severely deficient category.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

• Congestive heart failure is differentiated by the presence of fine basal crackles, by findings on chest radiograph, and nonobstructed pulmonary function test (PFT) results.
• In bronchiectasis, patients produce a large amount of purulent sputum, coarse crackles are present, and clubbing occurs; abnormalities appear on the chest radiograph.
• Bronchiolitis obliterans affects younger people with rheumatoid arthritis who do not smoke; CT scan may show areas of mosaic perfusion.
• Chronic asthma is difficult to distinguish in older patients; the important distinction is large bronchodilator response.

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Secondary polycythemia due to chronic hypoxemia may develop in severe COPD or in those patients who smoke excessively. A hematocrit of more than 52% in males and more than 47% in female indicates disease.
• Measure the AAT levels in all patients younger than 40 years or in those with a family history of emphysema at an early age. If the AAT level is low, then phenotyping should be obtained.
• Sputum
• • In stable chronic bronchitis, sputum is mucoid, and macrophages are the predominant cell. With an exacerbation, sputum becomes purulent due to the presence of neutrophils. A mixture of organisms often is visible using a Gram stain.
  • The pathogens most frequently cultured during exacerbation are Streptococcus pneumoniae and Haemophilus influenzae.

Imaging Studies

• Chest radiograph
• • Frontal and lateral chest radiographs reveal signs of hyperinflation, including a flattening of the diaphragm, increased retrosternal air space, and a long narrow heart shadow. Rapid tapering vascular shadows accompanied by hyperlucency of the lungs are signs of emphysema.
  • With complicating pulmonary hypertension, the hilar vascular shadows are prominent, with possible right ventricular enlargement and opacity in the lower retrosternal air space.
• Computed tomography scan
• • High-resolution CT (HRCT) scan is more sensitive than the standard chest radiograph.
  • HRCT scan is highly specific for diagnosing emphysema, and the outlined bullae are not always visible on a radiograph. This information does not alter therapy; therefore, a CT scan is not useful in the routine care of patients with COPD.

Other Tests

• Pulmonary function tests
• • These measurements are essential for the diagnosis and assessment of the severity of disease, and they are helpful in following its progress.
  • FEV₁ is a reproducible test and is the most common index of airflow obstruction. Lung volume measurements may document an increase in total lung capacity, functional residual capacity, and residual volume. The vital capacity decreases.
  • Carbon monoxide diffusing capacity is decreased in proportion to the severity of emphysema.
  • Arterial blood gases reveal mild-to-moderate hypoxemia without hypercapnia in the early stages. As the disease progresses, hypoxemia becomes more severe and hypercapnia supervenes. Hypercapnia commonly is observed as the FEV₁ falls below 1 L/s or 30% of the predicted value. The lung mechanics and gas exchange worsen during acute exacerbations.
  • As many as 30% of patients have an increase in FEV₁ by 15% or more after inhalation of a bronchodilator. However, the absence of bronchodilator response does not justify withholding therapy.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

The goal of management is to improve daily living and the quality of life by preventing symptoms and the recurrence of exacerbations by preserving optimal lung function. Once the diagnosis of COPD is established, educate the patient about the disease. Encourage the patient to participate actively in therapy.

Smoking cessation continues to be the most important therapeutic intervention. Most patients with COPD have a history of smoking or are currently smoking tobacco products. A smoking cessation plan is an essential part of a comprehensive management plan. The success rates are low because of the addictive power of nicotine, the conditioned response to smoking-associated stimuli, and psychological problems, including depression, poor education, and forceful promotional campaigns by the tobacco industry. The process of smoking cessation must involve multiple interventions.

Oral and inhaled medications are used for patients with stable disease to reduce dyspnea and improve exercise tolerance. Most of the medications employed are directed at 4 potentially reversible causes of airflow limitation in a disease state that has largely fixed obstruction. The following factors may be present: (1) bronchial smooth muscle contraction, (2) bronchial mucosal congestion and edema, (3) airway inflammation, and (4) increased airway secretion.

Smoking cessation, physical intervention

The transition from smoking to not smoking occurs in 5 stages: precontemplation, contemplation, preparation, action, and maintenance. Smoking intervention programs include self-help, group, physician-delivered, workplace, and community programs.

Setting a quit date may be helpful. Physicians and other healthcare providers should participate in setting the target date and follow-up with respect to maintenance.

Successful cessation programs usually employ the following resources and tools: patient education, a quit date, follow-up support, relapse prevention, advice for healthy lifestyle changes, social support systems, and adjuncts to treatment (eg, pharmacological agents).

Smoking cessation, pharmacologic intervention

Supervised use of pharmacologic agents is an important adjunct to self-help and group smoking cessation programs.

Nicotine is the ingredient in cigarettes primarily responsible for the addiction. Withdrawal from nicotine may cause unpleasant adverse effects, including anxiety, irritability, difficulty concentrating, anger, fatigue, drowsiness, depression, and sleep disruption. These effects usually occur during the first several weeks.

Nicotine replacement therapies after smoking cessation reduce withdrawal symptoms. If a smoker requires his or her first cigarette within 30 minutes of waking up, they most likely are highly addicted and would benefit from nicotine replacement therapy.

Several nicotine replacement therapies are available. Nicotine polacrilex is a chewing gum and has better quit rates than counseling alone. Nicotine replacement therapy chewing pieces are marketed in 2 strengths (ie, 2 mg, 4 mg). An individual who smokes 1 pack per day should use 4-mg pieces. The 2-mg pieces are to be used by individuals who smoke less than 1 pack per day. Instruct the patient to chew hourly and also to chew when needed for their initial cravings for 2 weeks. Gradually reduce the amount chewed over the next 3 months.

Transdermal nicotine patches are available readily for replacement therapy. Long-term success rates are 22-42%, compared with 2-25% with a placebo. These agents are well tolerated, and the adverse effects are limited to localized skin reaction. Nicotine replacement therapy patches are sold under the following trade names: Nicoderm, Nicotrol, and Habitrol. Each of these products is dosed with a scheduled graduated decrease in nicotine over 6-10 weeks.

The use of the antidepressant bupropion (Zyban) is also effective for smoking cessation. This nonnicotine aid to smoking cessation enhances central nervous nonadrenergic function. A recent study demonstrated that 23% of patients sustained cessation at 1 year, compared with 12% who sustained cessation with the placebo. Bupropion may also be effective in patients who not been able to quit smoking with nicotine replacement therapy.

The most recent drug to receive approval for smoking cessation is varenicline (Chantix). It is a partial agonist selective for alpha4, beta2 nicotinic acetylcholine receptors. Action is thought to result from activity at a nicotinic receptor subtype, where its binding produces agonist activity while simultaneously preventing nicotine binding. Agonistic activity is significantly lower than nicotine.

Anti-inflammatory agents, inhaled steroids

A minority of COPD patients who respond to oral corticosteroids can be maintained on long-term inhaled steroids.

Despite a lack of conclusive evidence to support the role of inhaled corticosteroids in the management of COPD, the use of these agents is widespread. Researchers completed 3 large placebo-controlled trials investigating the use of these agents in severe, mild, and very mild disease. Based on the rate of decline in FEV₁, results from these 3 trials suggest that inhaled corticosteroids did not slow the decline in lung function but decreased the frequency of exacerbations and improved disease-specific and health-related quality of life.

Inhaled corticosteroids have fewer adverse effects than oral agents. Although effective, these agents improve expiratory flows less effectively than oral preparations, even at high doses. These agents may be beneficial in slowing the rate of progression in a subset of patients with COPD who have rapid decline.

Bronchodilators

Inhaled beta2-agonist bronchodilators activate specific B2-adrenergic receptors on the surface of smooth muscle cells, which increases intracellular cyclic adenosine monophosphate (AMP) and smooth muscle relaxation. Patients, even those who have no measurable increase in expiratory flow, benefit from treatment using beta2 agonists.

The popularity of methylxanthines has decreased over last decade because of the narrow therapeutic range and frequent toxicity. The mechanism of actions may involve increased intracellular calcium transport, adenosine antagonism, and prostaglandin E2 inhibition. Additionally, methylxanthines may improve diaphragm muscle contractility.

In COPD, beta2 agonists produce less bronchodilatation compared to asthma. Furthermore, spirometric changes may be insignificant despite symptomatic benefit. Patients primarily use beta2 agonists for relief of symptoms of COPD. Inhaled beta2 agonists are the initial treatment of choice for acute exacerbations of COPD.

In stable patients, beta2 agonists have an additive effect when used with an anticholinergic agent (eg, ipratropium bromide). Although oral preparations of beta2 agonists are available, the preferred route of administration is inhalation. Use a spacer if indicated to improve aerosol delivery and reduce adverse effects.

Two long-acting beta2 agonists (ie, formoterol, salmeterol) are available. They may be useful in patients who use short-acting bronchodilators frequently or for prevention of nocturnal symptoms. More studies should establish the best role for these agents.

Anticholinergic agents

Treatment with aerosolized anticholinergic agents (eg, ipratropium bromide) may be more effective than a beta2 agonist in patients with COPD. Ipratropium bromide has bronchodilatory activity with minimum adverse effects and is administered by a metered-dose inhaler.

Studies in patients with stable COPD have shown that ipratropium bromide has equivalent or superior activity when compared with a beta2 agonist. In combination with a beta2 agonist, an additional 20-40% bronchodilation occurs. This medication has slower onset and a longer duration than a beta2 agonist and is less suitable for use as on an as needed basis.

Inhaled anticholinergic bronchodilators do not influence the long-term decline of FEV₁. Initiate regular therapy with ipratropium at 2-4 puffs 4 times a day and add a beta2 agonist as needed.

Anticholinergic drugs compete with acetylcholine for postganglionic muscarinic receptors, thereby inhibiting cholinergically mediated bronchomotor tone, resulting in bronchodilatation. They block vagally mediated reflex arcs that cause bronchoconstriction. The onset of action is slower (eg, 30-60 min) than inhaled beta2 agonists.

Long-acting bronchodilators

In addition to its anti-inflammatory effects, theophylline improves respiratory muscle function, stimulates the respiratory center, and promotes bronchodilation. Adding theophylline to the combination of bronchodilators can result in further benefit in stable COPD. The response to theophylline therapy also may vary among patients with severe COPD. Patients metabolize theophylline primarily by the hepatic enzyme system, a process affected by age, the heart, and liver abnormalities. Monitor serum levels of theophylline during therapy because of the drug's potential for toxicity. Adverse effects include anxiety, tremors, insomnia, nausea, cardiac arrhythmia, and seizures.

Oral steroids

The use of corticosteroids requires a careful evaluation for individual patients on adequate bronchodilator therapy who do not improve sufficiently or who develop an exacerbation. Most studies suggest that 20-30% of patients with COPD improve if administered long-term oral steroid therapy. Carefully document the effectiveness of such therapy (ie, >20% improvement in FEV₁) before administering prolonged daily or alternate day treatment.

Researchers found a positive correlation between bronchial eosinophilia and bronchodilator response in patients who had mild-to-moderate airflow obstruction. Outpatients have used oral steroids with success to treat acute exacerbations. However, after stabilization, gradually wean patients off oral corticosteroids because of their potential adverse effects.

In a recent meta-analysis of 16 controlled trials in stable COPD, researchers found that approximately 10% of individuals respond to these drugs. Carefully identify recipients. An increase in FEV₁, by more than 20% has been used as a surrogate marker for steroid response. In acute exacerbation of COPD, use steroids routinely to improve symptoms and lung function.

Phosphodiesterase IV inhibitors

Cilomilast and roflumilast are systemically available, second-generation, selective phosphodiesterase-4 inhibitors. They cause a reduction of the inflammatory process (macrophages and CD8+ lymphocytes) in patients with COPD. Cilomilast is completely absorbed following oral administration and its elimination half-life is approximately 6.5 hours. A dose of 15 mg twice daily has been found to be clinically effective. Nausea, presumably of central origin, is the principal adverse reaction. The preliminary clinical studies suggest a favorable clinical effect in COPD.

Antibiotics

In patients with COPD, chronic infection or colonization of the lower airways is common from Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. The goal of antibiotic therapy in COPD is not to eliminate organisms but to treat acute exacerbations. Exacerbations are indicated by increased sputum purulence and volume and the development of dyspnea along with other features, including fever, leukocytosis, or infiltrate on a chest radiograph.

The first-line treatment choices include amoxicillin, cefaclor, or trimethoprim/sulfamethoxazole. Second-line antibiotic regimens are the more expensive antibiotics, including azithromycin, clarithromycin, and fluoroquinolones.

The use of antibiotics in patients with COPD is supported by the results of a meta-analysis showing that patients who received oral antibiotic therapy had a small, but clinically significant, improvement in peak expiratory flow rate and a more rapid resolution of symptoms. Patients who benefitted most were those whose exacerbations were characterized by at least 2 of the following: increases in dyspnea, sputum production, and sputum purulence (ie, Winnipeg criteria).

Mucolytic agents

These agents reduce sputum viscosity and improve secretion clearance. Viscous lung secretions in patients with COPD consist of mucous-derived glycoproteins and leukocyte-derived DNA.

The oral agent N-acetylcysteine has antioxidant and mucokinetic properties and is used to treat patients with COPD. However, the efficacy of mucolytic agents in the treatment of COPD is debatable.

Oxygen therapy

COPD commonly is associated with progressive hypoxemia. Oxygen administration reduces mortality rates in patients with advanced COPD because of the favorable effects on pulmonary hemodynamics.

Two landmark trials, The British Medical Research Counsel (MRC study) and the National Heart, Lung, Blood Institutes Nocturnal Oxygen Therapy Trial (NOTT), showed that long-term oxygen therapy improves survival 2-fold or more in hypoxemic patients with COPD. Hypoxemia is defined as PaO₂ of less than 55 mm Hg or oxygen saturation of less than 90%. Oxygen was used from 15-19 hours per day.

Specialists recommend long-term oxygen therapy, therefore, for patients with a PaO₂ of less than 55 mm Hg, a PaO₂ of less than 59 mm Hg with evidence of polycythemia, or cor pulmonale. Reevaluate these patients 1-3 months after initiating therapy because some patients may not require long-term oxygen.

Many patients with COPD who are not hypoxemic at rest worsen during exertion. Even though the studies designed to determine the long-term benefit of oxygen solely for exercise have not yet been conducted, home supplemental oxygen commonly is prescribed for these patients. Oxygen supplementation during exercise can prevent increases in pulmonary artery pressure, reduce dyspnea, and improve exercise tolerance.

Oxygen therapy generally is safe. Oxygen toxicity from high-inspired concentrations (ie, >60%) is well recognized. Little is known about the long-term effects of low-flow oxygen. The increased survival and quality of life benefits of long-term oxygen therapy outweigh the possible risks. PaCO₂ retention from depression of hypoxic drive has been overemphasized. PaCO₂ retention is more likely a consequence of ventilation/perfusion mismatching rather than respiratory center depression. While this complication is not common, it is best avoided by titration of oxygen delivery to maintain PaO₂ at 60-65 mm Hg.

The major physical hazards of oxygen therapy are fires or explosions. Patients, family, and other caregivers must be warned not to smoke. Overall, major accidents are rare and can be avoided by good patient and family training.

• Oxygen delivery systems
• • The continuous flow nasal cannula is the standard means of oxygen delivery for the stable hypoxemic patient. It is simple, reliable, and generally well tolerated. Each liter of oxygen flow adds 3-4% to the fraction of inspired oxygen (FiO₂). Nasal oxygen delivery also is beneficial for most mouth-breathing patients. Humidification generally is not beneficial when the patient receives oxygen by nasal cannula at flows of less than 5 L/min.
  • Oxygen conserving devices function by delivering all of the supplemental oxygen during early inhalation. These devices improve the portability of oxygen therapy and may reduce overall costs. Three distinct oxygen-conserving devices exist—reservoir cannulas, demand pulse delivery devices, and transtracheal oxygen delivery.
  • Transtracheal oxygen delivery involves the insertion of a catheter percutaneously between the second and third tracheal interspace. Transtracheal oxygen delivery is invasive and requires special training by the physician, the patient, and the caregiver. The procedure has risks as well as medical benefits but has limited application.
  • Pharmacologic treatment of COPD is targeted to symptom reduction. With the exception of smoking cessation and continuous long-term oxygen treatment, drug therapy does not modify the natural history of COPD. Recent long-term pharmacologic studies in COPD have evaluated prevention of exacerbations and/or hospitalization as the primary outcome. Tiotropium, a long-acting anticholinergic agent, reduces the frequency of exacerbations and the use of health care resources in patients with moderate-to-severe COPD. Inhaled steroids may also reduce the frequency and severity of exacerbations in patients with severe COPD. Whether the combination of inhaled steroids and long-acting bronchodilators has additive effects on lung function and/or exacerbations is still unclear.

Surgical Care

Over the past 50-75 years, researchers have described a variety of surgical approaches to improve symptoms and restore function in patients who have emphysema. Only giant bullectomy and, possibly, the lung volume reduction surgery (LVRS) are useful.

• Bullectomy
• • Removal of giant bullae has been a standard approach in selected patients for many years.
  • The bullae in patients with emphysema generally range in size from 1-4 cm in diameter; however, on occasion, bullae can occupy more than 33% of the hemithorax (eg, giant bullae).
  • Giant bullae may compress adjacent lung tissue, thereby reducing the blood flow and ventilation to the healthy tissue. Removal of these bullae may result in the expansion of compressed lungs and improved function.
  • Patients who are symptomatic and have an FEV₁ of less than 50% of the predicted value have a better outcome after bullectomy. This surgery is performed through midline sternotomy, a lateral incision, or by video-assisted thoracoscopy. Postoperative bronchopleural air leak is the major potential complication.
  • Giant bullectomy can produce subjective and objective improvement in selected patients—in those who have bullae that occupy at least 30%, and preferably 50%, of the hemithorax and compress adjacent lung, who have FEV₁ of less than 50% of the predicted value, and who otherwise have relatively preserved lung function.
• Lung volume reduction surgery
• • Nearly 40 years ago, Brantigan et al first reported resectional surgery for diffuse emphysema in 33 patients. They resected 20-30% of each lung that appeared most diseased. Brantigan hypothesized that removal of a portion of the emphysematous lung increased the radial traction on the airways in the remaining lung, improving expiratory airflow and mechanical function of the respiratory system, thereby reducing symptoms.
  • Recently, the LVRS gained considerable momentum after researchers documented a marked improvement in the FEV₁ (ie, +82%), the FVC (ie, +27%), and the 6-minute walk distance and quality of life indices. Currently, large prospective studies are underway in the United States and Canada to evaluate the effectiveness and the long-term outcome and benefits of LVRS.
  • The indications and patient selection criteria for LVRS are not rigorously defined. Generally, the candidates for LVRS have symptoms secondary to severe emphysema, marked hyperinflation (ie, elevated residual volume [RV]/total lung capacity [TLC] ratio), and CT scan evidence of heterogeneous emphysema. The study excluded patients who are hypercapnic or have pulmonary hypertension or other cardiac risk factors.
  • The surgical approach uses a midline sternotomy with stapling of the lung margins. Surgeons generally resect 20-30% of each lung from the upper zones. The LVRS procedure has a mortality rate of 0-18%. Several complications, including pneumonia and prolonged air leaks, have been observed.
• Lung transplantation
• • Lung transplantation is a relatively new therapy for advanced lung disease. Patients with COPD are the largest single category of patients who undergo the process. The timing of transplant is difficult, but patients selected to receive a transplant should have a life expectancy of 2 years or less due to COPD.
  • With lung transplantation, the profound dyspnea and limited lifestyle is exchanged for an improved quality of life but at the risk of worsening survival.

Diet

Inadequate nutritional status associated with low body weight in patients with COPD is associated with impaired pulmonary status, reduced diaphragmatic mass, lower exercise capacity, and higher mortality rates. Nutritional support is an important part of their comprehensive care.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Bronchodilators

These agents act to decrease muscle tone in both small and large airways in the lungs, thereby increasing ventilation. Category includes subcutaneous medications, beta-andrenergics, methylxanthines, and anticholinergics.

Tiotropium (Spiriva), a bronchodilator similar to ipratropium, has recently been approved by the US Food and Drug Administration. Tiotropium is a quaternary ammonium compound. Elicits anticholinergic/antimuscarinic effects with inhibitory effects on M₃ receptors on airway smooth muscles, leading to bronchodilation. Available as a capsule dosage form containing a dry powder for oral inhalation via the HandiHaler inhalation device. For adults, the contents of one capsule (18 mcg) are inhaled every day via the HandiHaler device. Contraindications, drug interactions, and adverse effects are similar to those of ipratropium.

Drug Category: Corticosteroids

A recent meta-analysis of 16 controlled trials in stable COPD found that approximately 10% of patients respond to these drugs. The responders should be identified carefully. An increase in FEV₁ >20% is used as surrogate marker for steroid response. In acute exacerbation, steroids improve symptoms and lung functions. Inhaled steroids have fewer adverse effects compared to oral agents. Although effective, these agents improve expiratory flows less effectively than oral preparations, even at high doses. These agents may be beneficial in slowing rate of progression in a subset of patients with COPD who have rapid decline.

Drug Category: Smoking cessation therapies

Works best when used in conjunction with a support program, such as counseling, group therapy, or behavioral therapy. Nicotine replacements may be used to decrease physical withdrawal symptoms.

Antidepressants (eg, bupropion) are used as a nonnicotine aid to smoking cessation. A recent study demonstrated 23% sustained cessation with bupropion tablets at 1 y, compared to a 12% sustained cessation with placebo. Bupropion also may be effective in patients for whom nicotine replacement therapy is ineffective.

The most recent drug to receive approval for smoking cessation is varenicline (Chantix), a partial agonist selective for alpha4, beta2 nicotinic acetylcholine receptors.

Drug Category: Beta-adrenergic agonist and anticholinergic agent combinations

Combine the benefits of the rapid onset of a beta-adrenergic agonist with the prolonged action of an anticholinergic agent.

Drug Category: Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Acute exacerbation of COPD
• • Acute exacerbation of COPD is one of the major reasons for hospital admission in the United States.
  • Because of the lack of clinical studies, the general consensus supports the need for hospitalization of patients who develop severe respiratory dysfunction, disease progression, and other comorbid conditions (eg, pneumonia, poor response to outpatient management).
  • The purpose of hospitalization is to manage the patient's acute decompensation and to prevent further deterioration.
• Pharmacotherapy of COPD exacerbations
• • Physicians recommend a stepwise approach to drug therapy that takes into consideration the causes and complications related to the exacerbation, the degree of reversible bronchospasm, recent drug use, and contraindications to treatment. Sedation and pain management must be provided, despite a potential for respiratory depression, to ensure patient comfort and safety.
  • Patients with exacerbations respond to inhaled beta2 agonists and anticholinergic aerosols. Treatment is initiated with an inhaled beta2 agonist delivered via a spacer or nebulizer; inhaled ipratropium bromide usually is added. The combination therapy may act synergistically and may allow using lower dosages of beta agonists. The efficacy of theophylline or intravenous aminophylline is not definitely established, and theophylline and intravenous aminophylline may cause toxicity.
  • Corticosteroids generally are recommended and may be used intravenously for a short period. When response occurs, lower the dosage. Careful observation and spirometric evaluation are needed to prove the continuing benefit of steroids after a course of 1-2 weeks.
• Antibiotic therapy
• • When the patient has 2 or more Winnipeg criteria, prescribe an antibiotic.
  • The risk stratification scheme for antibiotic selection is recommended as follows: treat low-risk patients with amoxicillin, trimethoprim/sulfamethoxazole, or doxycycline. Treat high-risk patients, those who had multiple exacerbations in the past, and/or those with underlying cardiopulmonary dysfunction with a new generation macrolide, a second-generation cephalosporin, or a fluoroquinolone.
• Intensive care admission: Indications for intensive care admission are confusion, lethargy, respiratory muscle fatigue, worsening hypoxemia, respiratory acidosis (ie, pH <7.30), or when a patient requires invasive or noninvasive mechanical ventilation.
• Assisted ventilation
• • Progressive airflow obstruction may impair oxygenation and/or ventilation to the degree that the patient requires assisted ventilation.
  • The general guidelines for determining the ideal time to initiate ventilatory support are (1) patients who have experienced progressive worsening of respiratory acidosis and/or altered mental status and (2) clinically significant hypoxemia despite supplemental oxygen.
  • Patients may be treated with noninvasive mask ventilation or translaryngeal intubation and mechanical ventilation. Following noninvasive ventilation, provide adequate patient supervision and ensure patient's mental alertness and tolerance of appliances. Hemodynamic instability, difficulty with clearing of secretions, and copious secretions are contraindications to noninvasive assisted ventilation.
  • The main goal of assisted positive pressure ventilation in acute respiratory failure complicating COPD is to rest the ventilatory muscles and restore gas exchange. Major risks are ventilator-associated pneumonia, barotrauma, and laryngotracheal complications associated with intubation.

Further Outpatient Care

• Pulmonary rehabilitation
  • Many patients with COPD are unable to enjoy life to the fullest because of shortness of breath, physical limitations, and inactivity.
  • Pulmonary rehabilitation encompasses an array of therapeutic modalities designed to improve the patient's quality of life by decreasing airflow limitation, preventing secondary medical complications, and alleviating respiratory symptoms.
  • The 3 major goals of the comprehensive management of COPD are the following:
    1. Lessen airflow limitation
    2. Prevent and treat secondary medical complications (eg, hypoxemia, infection)
    3. Decrease respiratory symptoms and improve quality of life
• Pulmonary rehabilitation, a multidisciplinary team approach
• • Successful implementation of a pulmonary rehabilitation program usually requires a team approach, with individual components provided by health care professionals who have experience in managing COPD (eg, physician, dietitian, nurse, respiratory therapist, exercise physiologist, physical therapist, occupational therapist, recreational therapist, cardiorespiratory technician, pharmacist, psychosocial professionals).
  • This multidisciplinary approach emphasizes patient and family education, smoking cessation, medical management (eg, oxygen, immunization), respiratory and chest physiotherapy, physical therapy with bronchopulmonary hygiene, exercise, vocational rehabilitation, and psychosocial support.
• Benefits of pulmonary rehabilitation: As a result of rehabilitation, improvements occur in the objective measures of quality of life, well being, and health status, including a reduction in respiratory symptoms and an increase in exercise tolerance and functional activities (eg, walking, less anxiety and depression, increased feelings of control, self-esteem). Pulmonary rehabilitation also results in substantial savings in healthcare costs by reducing use of hospital and medical resources.
• Components of pulmonary rehabilitation
• • Pulmonary rehabilitation programs usually are conducted in an outpatient setting. A rehabilitation program may include a number of components and should be tailored to the needs of the individual patient. Provide all patients who c