AUTHOR INFORMATION

Section 1 of 12

Authored by Sat Sharma, MD, FRCPC, FACP, FCCP, DABSM, Program Director, Associate Professor, Department of Internal Medicine, Divisions of Pulmonary and Critical Care Medicine, University of Manitoba; Site Director of Respiratory Medicine, St Boniface General Hospital

Sat Sharma, MD, FRCPC, FACP, FCCP, DABSM, is a member of the following medical societies: American Academy of Sleep Medicine, American College of Chest Physicians, American College of Physicians-American Society of Internal Medicine, American Thoracic Society, Canadian Medical Association, Royal College of Physicians and Surgeons of Canada, Royal Society of Medicine, Society of Critical Care Medicine, and World Medical Association

Edited by Laurie Robin Grier, MD, Medical Director of MICU, Associate Professor of Medicine, Section of Pulmonary and Critical Care Medicine, Louisiana State University Health Science Center at Shreveport; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Om Prakash Sharma, MD, Professor, Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Southern California; Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine; and Zab Mosenifar, MD, Professor of Medicine, University of California at Los Angeles School of Medicine; Director, Division of Pulmonary/Critical Care Medicine, Executive Vice Chair, Department of Medicine, Cedars-Sinai Medical Center

Author's Email:	Sat Sharma, MD, FRCPC, FACP, FCCP, DABSM
Editor's Email:	Laurie Robin Grier, MD

eMedicine Journal, February 12 2007, VOLUME 8, Number 2

INTRODUCTION

Section 2 of 12

Background: Chronic obstructive pulmonary disease (COPD) is a devastating disorder that causes exorbitant human suffering; currently, COPD is 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. 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 Foundation 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 were 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 is defined in terms of anatomic pathology.

Pathophysiology: 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 effectively counteracted 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.

Pathological changes in COPD occur in the large (central) airways, the small (peripheral) bronchioles, and the lung parenchyma.

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.

Chronic obstructive pulmonary disease

COPD is associated with both emphysematous destruction and small airway inflammation, which often is found in combination in an individual patient. 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:

• In the US: Approximately 14.2 million people have COPD—approximately 12.5 million cases are from chronic bronchitis and 1.7 million are from emphysema. Since 1982, the number of 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.

• Internationally: Worldwide data are sparse, but the rates likely are higher because more than 1.2 billion people 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 (in 1985) were 200 per 100,000 males and 80 per 100,000 females. Internationally, a marked variation in overall mortality rates from COPD is observed. The extremes are more than 400 deaths per 100,000 males aged 65-74 years in Romania and 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.

CLINICAL

Section 3 of 12

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 does not occur until the sixth decade of life. By the time forced expiratory volume in 1 second (FEV₁) has fallen to 30% of the predicted value, 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.

• 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 (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, total pack years, and current smoking status predict COPD mortality. Smokers 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


• • Alpha1-antitrypsin (AAT) deficiency is the only known genetic risk factor for developing COPD, and it 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 people who do not smoke and 40 years for people who do smoke.
  
  
  
  • PiMM phenotypes occur in 90% of people and produce normal serum levels. PiZZ is the most common deficient state and accounts for 95% of people in the severely deficient category.
  
  
  

DIFFERENTIALS

Section 4 of 12

Bronchiectasis
Bronchitis
Emphysema

Other Problems to be Considered:

• Congestive heart failure is differentiated by the presence of fine basal crackles, findings on chest radiograph, and nonobstructed pulmonary function tests (PFTs).
  
  
• 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 12

Lab Studies:

• Polycythemia 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 females 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.



• Sputum


• • In stable chronic bronchitis, sputum is mucoid, and macrophages are the predominant cell. With an exacerbation, sputum becomes purulent, with excessive neutrophils. A mixture of organisms 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.
  
  
  
• CT 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 show 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 liter per second, 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. The absence of bronchodilator response does not justify withholding therapy.
  
  
  

The two types of emphysema that commonly produce the symptoms of obstructive lung disease are centrilobular and panacinar emphysema. Centrilobular emphysema is much more common than panacinar emphysema and is rare in people who do not smoke.

Some people with the symptoms of chronic bronchitis may have no demonstrable histologic abnormality in their airways. However, people with chronic bronchitis show a strong tendency for the presence of mucous gland hyperplasia in the bronchial walls. This accounts for the increased sputum production because the bronchial wall glands produce approximately 98% of the total airway mucus production.

The mucous gland hyperplasia usually is measured and reported by 1 of 2 methods The older of these is the Reid index, which is the ratio of the thickness of the mucous glands to the thickness of the bronchial mucosa as measured from the basement membrane of the surface epithelium to the perichondrium. The other method is to measure the mucous gland area in a given area of mucosa.

The increased thickness of the bronchial mucosa due to mucous gland hyperplasia and increased luminal mucin may contribute to airflow obstruction. However, with chronic bronchitis, frequent small airway abnormalities are present and this likely contributes to most of the obstructive component. The small airway abnormalities include fibrosis and an inflammatory cell infiltrate in the bronchiolar walls extending out into the surrounding tissues and goblet cell hyperplasia of the lining of the small airways. Goblet cell hyperplasia may increase small airway lumen mucin, contributing to obstruction. In addition, the bronchiolar wall inflammation and fibrosis result in decreasing the luminal diameter of the small airways. Bronchiolar constriction and instability, ie, the collapsing and sticking together of the walls of the bronchioles, also are possible mechanisms of airflow obstruction in chronic bronchitis.

TREATMENT

Section 6 of 12

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. Many patients with COPD have a history of smoking and continue to smoke. A smoking cessation plan is an essential part of a comprehensive management plan. The success rates are low because of the addictive potential 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 strategies include self-help, group, physician-delivered, workplace, and community programs.

Establishing a quit date may be helpful. Physicians and other healthcare providers should participate in setting the target date and follow up regarding 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 person who smokes requires his or her first cigarette within 30 minutes of waking up, they are most likely 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. Transdermal nicotine patches are readily available for replacement therapy. Long-term success rates are 22-42%, compared to 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. The usual drug-dosing schedule is the same for all 3 brands. Individuals who smoke more than 1 pack per day initially need a 21-mg patch, followed by 14-mg and 7-mg patches.

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 to ease the initial cravings for 2 weeks. Gradually reduce the amount chewed over the next 3 months.

The use of an antidepressant medication (eg, Zyban) also is effective for smoking cessation. Another antidepressant, bupropion, is a nonnicotine aid to smoking cessation that enhances central nervous nonadrenergic function. A recent study demonstrated that 23% of patients sustained cessation at 1 year, compared to 12% who sustained cessation with the placebo. Bupropion also is effective in patients who have 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 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 frequency of exacerbations and improved disease-specific and health-related quality of life.

Inhaled corticosteroids have fewer adverse effects than oral agents do. 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.

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.

Methylxanthines have decreased in popularity over the last decade because of the narrow therapeutic range and frequent toxicity. The mechanism of action 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 benefits. 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 improve symptoms and morning peak flows and may be useful when bronchodilators are used frequently. 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 is achieved. This medication has slower onset and a longer duration than a beta2 agonist and is less suitable for use as needed.

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)

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 (>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 to treat acute exacerbations with success. 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 individuals with stable COPD, researchers found that approximately 10% 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 S pneumoniae, H 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 and trimethoprim/sulfamethoxazole. Second-line antibiotic regimens are the more expensive antibiotics, including azithromycin 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 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.

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 for 15-19 hours per day.

Specialists recommend long-term oxygen therapy, therefore, for patients with 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 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.
  
  
  
  • Oxygen-conserving devices function by delivering all of the oxygen during early inhalation. These devices improve the portability of oxygen therapy and reduce overall costs. Three distinct oxygen-conserving devices exist—reservoir cannulas, demand pulse delivery devices, and transtracheal oxygen delivery.
  
  
  
  • 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 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 are useful.

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 12

Smoking cessation continues to be the most important therapeutic intervention. Many patients have a history of smoking and currently smoke. Nicotine replacement therapy works best when used in conjunction with a support program, such as counseling, group therapy, or behavioral therapy.

• Nicotine patches (ie, Habitrol, Nicoderm CQ, Nicotrol) are available. Individuals who smoke more than 1 pack per day initially need a 21-mg patch followed by 14-mg and 7-mg patches.

• Nicotine polacrilex (Nicorette) is another option. Nicotine is absorbed through oral mucosa. In this form, nicotine is absorbed quickly and closely approximates the time course of plasma nicotine levels observed after cigarette smoking.
  • Nicotine gum is available as 2-mg or 4-mg pieces in a box containing 96 pieces. Careful adherence to chewing instructions is important for effective use. The manufacturer recommends that the gum not be used longer than 6 months.

  • 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 for initial cravings for 2 weeks; then, gradually reduce the amount chewed over 3 months.

• Bupropion hydrochloride (Zyban) is an antidepressant used to help with smoking cessation. This drug is to be used in conjunction with a support group and/or behavioral counseling. It is administered at 150 mg PO qd for 3 days and then is increased to 150 mg PO bid with at least 8 hours between each dose for 7-12 weeks.

• Varenicline (Chantix) is a partial agonist selective for alpha4, beta2 nicotinic acetylcholine receptors. It is used in conjunction with support groups and/or behavioral counseling. Gradually titrate dose upward within 1 wk before quit date to 1 mg PO bid pc. Decrease dose with severe renal impairment or end-stage renal disease.

Drug Category: Inhaled beta-agonists -- Bronchial smooth muscle relaxants. Reduce airflow obstruction and increase ventilation to lungs. These medications can be used by inhalational route or parenteral route for prompt effect, although they generally are not used orally.

Drug Name	Albuterol (Ventolin, Proventil) -- Beta-agonist for bronchospasm. Relaxes bronchial smooth muscle by action on beta2 receptors with little effect on cardiac muscle contractility. Initially are prescribed prn. Frequency may be increased. Institute regular schedule in patients on anticholinergic drugs who remain symptomatic. Available as liquid for nebulizer, MDI, and dry powder inhalers.
Adult Dose	MDI: 2 puffs q3-4h Nebulizer: 0.2-0.3 mL of 0.5% inhalation solution diluted to 2.5 mL with isotonic sodium chloride solution, use tid/qid
Pediatric Dose	Infants and children: Nebulizer: 0.01-0.02 mL of 0.5% inhalation solution diluted in 2-3 mL of isotonic sodium chloride solution, used q4-6h Adolescents: Administer as in adults
Contraindications	Documented hypersensitivity; cardiac arrhythmia associated with tachycardia
Interactions	Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilatation by albuterol; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hyperthyroidism, diabetes mellitus, seizures, pheochromocytoma, and cardiovascular disorders; adverse effects include muscle tremors, nervousness, occasional insomnia, transient hypoxemia, and tachycardia

Drug Name	Metaproterenol (Alupent) -- Beta agonist for bronchospasm. Relaxes bronchial smooth muscle by action on beta2 receptors with little effect on cardiac muscle contractility. Initially prescribed prn. Frequency may be increased. Institute regular schedule in patients on anticholinergic drugs who remain symptomatic.
Adult Dose	MDI: 2 puffs q3-4h Nebulizer: 0.2-0.3 mL of 0.5% inhalation solution diluted to 2.5 mL with isotonic sodium chloride solution, use tid/qid
Pediatric Dose	<12 years: Not recommended >12 years: Administer as in adults
Contraindications	Documented hypersensitivity; cardiac arrhythmia associated with tachycardia
Interactions	Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilatation by albuterol; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hyperthyroidism, diabetes mellitus, seizures, pheochromocytoma, and cardiovascular disorders; adverse effects include muscle tremors, nervousness, occasional insomnia, transient hypoxemia, and tachycardia

Drug Name	Formoterol (Foradil, Oxis) -- Currently not available in United States. Investigational beta-agonist with rapid onset and long duration of action. Can relieve bronchospasms by relaxing the smooth muscles of bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis. Effect may also facilitate expectoration. Shown to improve symptoms and morning peak flows. May be useful for patients in whom bronchodilators are used frequently. More studies are needed to establish role for these agents. When administered at high or more frequent doses than recommended, incidence of adverse effects is higher. The bronchodilating effect lasts >12 h. Used on a fixed schedule in addition to regular use of anticholinergic agents.
Adult Dose	12-25 mcg inhalations bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; angina; tachycardia; cardiac arrhythmias associated with tachycardia
Interactions	Concomitant use of beta-blockers may decrease bronchodilating and vasodilating effects of beta-agonists; concurrent administration with methyldopa may increase pressor response; coadministration with oxytocic drugs may result in severe hypotension; ECG changes and hypokalemia resulting from diuretics may worsen
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Not indicated to treat acute asthmatic symptoms; adverse effects include tremors, nervousness, and tachycardia

Drug Name	Salmeterol (Serevent) -- Can relieve bronchospasms by relaxing the smooth muscles of the bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis. Effect also may facilitate expectoration. The bronchodilating effect lasts for 12 h or more. Used as fixed schedule in addition to regular use of anticholinergic agents.
Adult Dose	2 inhalations (50 mcg) bid
Pediatric Dose	<4 years: Not established >4 years: 1 inhalation (50 mcg) bid at least 12h apart >12 years: Administer as in adults
Contraindications	Documented hypersensitivity; angina; tachycardia; cardiac arrhythmias associated with tachycardia
Interactions	Concomitant use of beta-blockers may decrease bronchodilating and vasodilating effects of beta agonists (eg, salmeterol); concurrent administration with methyldopa may increase pressor response; coadministration with oxytocic drugs may result in severe hypotension; ECG changes and hypokalemia resulting from diuretics may worsen when coadministered with salmeterol
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Not indicated to treat acute asthmatic symptoms; adverse effects include tremors, nervousness, and tachycardia

Drug Category: Inhaled corticosteroids -- Lesser role in the management of chronic bronchitis. Several studies demonstrate no benefit, although approximately half of patients who respond to oral steroids may benefit from inhaled agents.

Drug Name	Budesonide (Pulmicort Turbuhaler) -- Has extremely potent vasoconstrictive and anti-inflammatory activity. Has weak hypothalamic-pituitary-adrenocortical axis inhibitory potency when applied topically. Effectiveness not established.
Adult Dose	Previous therapy: Bronchodilator alone: 200-400 mcg bid; may titrate to 400 mcg bid prn Inhaled corticosteroids: 200-400 mcg bid; may titrate to 800 mcg bid prn Oral steroids: 400-800 mcg bid; may titrate to 800 mcg bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; viral, fungal, and bacterial infections
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Adverse effects include oral thrush, hoarseness, adrenal suppression, glaucoma, skin bruising, and alteration in bone metabolism

Drug Name	Fluticasone (Flovent) -- Potent anti-inflammatory agent, but effectiveness in COPD is not established.
Adult Dose	250-500 mcg bid Previous therapy: Bronchodilator alone: 88 mcg bid, may titrate to 440 mcg bid prn Inhaled corticosteroids: 88-220 mcg bid, may titrate to 440 mcg bid prn Oral steroids: 880 mcg bid; not to exceed 880 mcg bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; viral, fungal, and bacterial infections
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Adverse effects include oral thrush, hoarseness, adrenal suppression, glaucoma, skin bruising, and alteration in bone metabolism

Drug Category: Anticholinergic agents -- Relax airway smooth muscles via anticholinergic pathway and are mainstay of treatment for patients with chronic bronchitis or COPD. Primarily a symptomatic therapy for disease and does not change outcome.

Drug Name	Tiotropium (Spiriva) -- 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. Helps COPD patients by dilating narrowed airways and keeping them open for 24 h.
Adult Dose	Inhale contents of 1 cap (18 mcg) via HandiHaler device qd
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Coadministration with other anticholinergic-containing drugs (eg, ipratropium) may increase toxicity risk
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	For maintenance treatment only; not effective for acute (rescue) therapy of bronchospasm; discontinue use and consider other treatments if immediate hypersensitivity reactions (including angioedema) or paradoxical bronchospasm occur; caution with narrow-angle glaucoma, prostatic hyperplasia, or bladder neck obstruction; commonly causes dry mouth; may cause constipation, increased heart rate, blurred vision, glaucoma, and urinary difficulty or retention; monitor patients with moderate-to-severe renal impairment

Drug Name	Ipratropium (Atrovent) -- Chemically related to atropine. Has antisecretory properties and, when applied locally, inhibits secretions from serous and seromucous glands lining the nasal mucosa. Used on a fixed 4- to 6-h schedule with beta agonist prn.
Adult Dose	Nebulizer: 250 mcg diluted with 2.5 mL isotonic sodium chloride solution, use q4-6h MDI: 2-4 puffs q4-6h; not to exceed 12 inhalations in 24 h
Pediatric Dose	Nebulizer: 250 mcg tid MDI: 1-2 puffs tid; not to exceed 6 inhalations in 24 h
Contraindications	Documented hypersensitivity
Interactions	Drugs with anticholinergic properties (eg, dronabinol) may increase toxicity; albuterol may increase effects
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Not indicated for acute episodes of bronchospasm; caution in narrow-angle glaucoma, prostatic hypertrophy, and bladder neck obstruction

Drug Category: Methylxanthines -- Fallen out of favor since more effective therapies have become available. These agents still are used in the long-term management of bronchitis.

Drug Name	Theophylline (Theo-Dur, Slo-bid, Theo-24) -- Acts to increase collateral ventilation, respiratory muscle function, mucociliary clearance, and central respiratory drive. Partially acts by inhibiting phosphodiesterase, elevating cellular cyclic AMP levels, or antagonizing adenosine receptors in the bronchi, resulting in relaxation of smooth muscle. Potentiates exogenous catecholamines and stimulates endogenous catecholamine release and diaphragmatic muscular relaxation, which in turn stimulates bronchodilation. For bronchodilation, near toxic levels (ie, >20 mg/dL) usually are required. Clinical efficacy is controversial, especially in the acute setting. Target concentration is 10 mcg/mL. Dosing = (target concentration - current level) X 0.5 (ideal body weight). Alternatively, 1 mg/kg results in approximately 2-mcg/mL increase in serum levels.
Adult Dose	Initial: 10 mg/kg/d PO divided q8-12h, adjust dose in 25% increments to maintain serum theophylline level of 5-15 mcg/mL; maximum 800 mg/d Maintenance: 10 mg/kg/d PO qd or divided q12h, adjust dose in 25% increments to maintain serum theophylline level of 5-15 mcg/mL; maximum 800 mg/d
Pediatric Dose	Children: Initial dose: 10 mg/kg/d PO divided q8-12h, adjust dose in 25% increments to maintain serum theophylline level of 5-15 mcg/mL; not to exceed 16 mg/kg/d Maintenance: 10 mg/kg/d PO qd or divided q12h, adjust dose in 25% increments to maintain serum theophylline level of 5-15 mcg/mL; not to exceed 16 mg/kg/d Adolescents: Administer as in adults
Contraindications	Documented hypersensitivity; uncontrolled arrhythmia; peptic ulcers; hyperthyroidism; uncontrolled seizure disorders
Interactions	Aminoglutethimide, barbiturates, carbamazepine, ketoconazole, loop diuretics, charcoal, hydantoins, phenobarbital, phenytoin, rifampin, isoniazid, and sympathomimetics may decrease effects of theophylline; theophylline effects may increase with allopurinol, beta-blockers, ciprofloxacin, corticosteroids, disulfiram, quinolones, thyroid hormones, ephedrine, carbamazepine, cimetidine, erythromycin, macrolides, propranolol, and interferon
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in peptic ulcer disease, hypertension, tachyarrhythmias, hyperthyroidism, and compromised cardiac function; do not inject IV solution >25 mg/min; patients with pulmonary edema or liver dysfunction are at greater risk of toxicity due to reduced drug clearance

Drug Category: Oral corticosteroids -- Anti-inflammatory agent. Demonstrated to be beneficial in exacerbations, but limited efficacy in office management exists. Nonetheless, a patient on high doses of bronchodilators who is still symptomatic should be administered a steroid trial.

Drug Name	Prednisone (Deltasone, Orasone, Sterapred) -- Conduct steroid trial to identify responders. If FEV1 increases by 20% or more, taper dose to the minimum to maintain improvement. In nonresponders, drug is discontinued.
Adult Dose	0.5-1 mg/kg/d PO qd for 2-3 wk; gradually taper to 10-20 mg/d, dose that maintains improvement is continued long-term
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease
Interactions	Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Drug Category: Antibiotics -- Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of this clinical setting.

Drug Name	Trimethoprim and sulfamethoxazole (Bactrim, Bactrim DS, Septra, Septra DS) -- Inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid, resulting in the inhibition of bacterial growth. Antibacterial activity of TMP-SMZ includes common urinary tract pathogens except Pseudomonas aeruginosa. Demonstrated in vitro activity against B pertussis. Not useful in mycoplasmal infections.
Adult Dose	160 mg TMP/800 mg SMZ q12h for 10-14 d
Pediatric Dose	<2 months: Do not administer >2 months: 15-20 mg/kg/d, based on TMP, PO tid/qid for 14 d
Contraindications	Documented hypersensitivity; megaloblastic anemia due to folate deficiency
Interactions	May increase PT when used with warfarin (perform coagulation tests and adjust dose accordingly); coadministration with dapsone may increase blood levels of both drugs; coadministration of diuretics increases incidence of thrombocytopenia purpura in elderly people; phenytoin levels may increase with coadministration; may potentiate effects of methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of zidovudine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Avoid in infants due to the possibility of kernicterus; discontinue at first appearance of skin rash or sign of adverse reaction; obtain CBCs frequently; discontinue therapy if significant hematologic changes occur; goiter, diuresis, and hypoglycemia may occur with sulfonamides; prolonged IV infusions or high doses may cause bone marrow depression (if signs occur, administer 5-15 mg/d leucovorin); caution in folate deficiency (eg, people with chronic alcoholism, elderly people, those receiving anticonvulsant therapy, or those with malabsorption syndrome); hemolysis may occur in G-6-PD deficient individuals; AIDS patients may not tolerate or respond to TMP-SMZ; caution in renal or hepatic impairment (perform urinalyses and renal function tests during therapy); administer fluids to prevent crystalluria and stone formation

Drug Name	Amoxicillin (Amoxil, Biomox) -- Interferes with synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria. Used in patients with exacerbation of chronic bronchitis who do not have risk factors for development of resistance to commonly used antibiotics. These patients have mild-to-moderate airflow obstruction and infrequent episodes of exacerbations.
Adult Dose	250-500 mg PO q8h
Pediatric Dose	20-50 mg/kg/d PO divided q8h
Contraindications	Documented hypersensitivity
Interactions	Reduces the efficacy of oral contraceptives; disulfiram and probenecid may increase levels; allopurinol has additive potential for amoxicillin rash
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in renal impairment; low incidence of cross-allergy with other beta-lactams and cephalosporins; adverse effects include fever, urticaria, rash, allergic reactions (eg, bronchospasm, serum sickness, angioedema); rarely ( <1%), seizures, nausea, vomiting, leukopenia, neutropenia, thrombocytopenia, jaundice, and interstitial nephritis may occur

Drug Name	Cefoxitin (Mefoxin) or cefditoren pivoxil (Spectracef) -- Cefoxitin: Second-generation cephalosporin indicated for gram-positive cocci and gram-negative rod infections. Infections caused by cephalosporin- or penicillin-resistant gram-negative bacteria may respond to cefoxitin. Cefditoren: Semisynthetic cephalosporin administered as prodrug. Hydrolyzed by esterases during absorption and distributed in circulating blood as active cefditoren. Bactericidal activity results from inhibition of cell wall synthesis via affinity for penicillin-binding proteins. No dose adjustment is necessary for mild renal impairment (CrCl 50-80 mgL/min/1.73 m2) or mild-to-moderate hepatic impairment. Indicated for the treatment of acute exacerbation of chronic bronchitis caused by susceptible strains of Streptococcus pyogenes.
Adult Dose	Cefoxitin: 2 g IV q6-8h Cefditoren: 400 mg PO with meals bid for 10 d Moderate renal impairment (CrCl 30-49 mL/min/1.73 m2): No more than 200 mg PO bid Severe renal impairment (CrCl <30 mL/min/1.73 m2): 200 mg PO qd
Pediatric Dose	Cefoxitin: 80-160 mg/kg/d IV in divided q4-6h Cefditoren: <12 years: Not established >12 years: Administer as in adults
Contraindications	Cefoxitin: Documented hypersensitivity Cefditoren: Documented hypersensitivity; hypersensitivity to penicillin, related compounds, or milk protein sodium caseinate; carnitine deficiency or inborn errors of metabolism that may result in clinically significant carnitine deficiency
Interactions	Cefoxitin: Probenecid may increase effects of cefoxitin; coadministration with aminoglycosides or furosemide may increase nephrotoxicity (closely monitor renal function) Cefditoren: Absorption reduced with H2 receptor antagonists and antacids of magnesium and aluminum hydroxides may reduce absorption; probenecid may increase plasma concentrations of cefditoren
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Cefoxitin: Bacterial or fungal overgrowth of nonsusceptible organisms may occur with prolonged use or repeated treatment; caution in patients with previously diagnosed colitis; administer half dose if creatinine clearance is 10-30 mL/min and one-quarter dose if <10 mL/min; fungal and microorganism overgrowth may occur with prolonged therapy Cefditoren: May cause diarrhea, nausea, and vaginal moniliasis (ie, yeast infection); pseudomembranous colitis may occur; clinical manifestations of carnitine deficiency may occur with prolonged use; prolonged use may result in emergence and overgrowth of resistant organisms; caution in breastfeeding

Drug Name	Azithromycin (Zithromax) -- Covers most potential etiologic agents, including Mycoplasma. The newer macrolides offer decreased GI upset and the potential for improved compliance through reduced dosing frequency. Improved action against Haemophilus influenzae compared with erythromycin.
Adult Dose	Day 1: 500 mg PO Days 2-5: 250 mg PO qd Alternatively, administer 500 mg IV qd
Pediatric Dose	Day 1: 10 mg/kg PO Days 2-5: 5 mg/kg PO qd
Contraindications	Documented hypersensitivity; hepatic impairment; do not administer with pimozide, sudden death may occur
Interactions	May increase toxicity of theophylline, warfarin, and digoxin; effects are reduced with coadministration of aluminum and/or magnesium antacids; nephrotoxicity and neurotoxicity may occur when coadministered with cyclosporine
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Site reactions can occur with IV route; bacterial or fungal overgrowth may result with prolonged antibiotic use; may increase hepatic enzymes and cholestatic jaundice; caution in patients with impaired hepatic function, prolonged QT intervals, or pneumonia; caution in hospitalized, geriatric, or debilitated patients

Drug Name	Levofloxacin (Levaquin), Gemifloxacin (Factive) -- Fluoroquinolones should be used empirically in patients likely to develop exacerbation due to resistant organisms to other antibiotics. Rapidly becoming a popular choice in pneumonia. This is the L stereoisomer of the D/L parent compound ofloxacin, the D form being inactive. Good monotherapy with extended coverage against Pseudomonas species, as well as excellent activity against pneumococcus. Agent acts by inhibition of DNA gyrase activity. PO form has bioavailability that reportedly is 99%. Indicated for AECB caused by S pneumoniae, H influenzae, Haemophilus parainfluenzae, or M catarrhalis.
Adult Dose	Levofloxacin: 500 mg PO/IV qd Gemifloxacin: 320 mg PO qd for 5 d
Pediatric Dose	<18 years: Not recommended >18 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Levofloxacin: Increased risk of elevated INR and bleeding when coadministered with warfarin; antacids containing magnesium or aluminum decrease absorption; calcium containing preparations and iron supplements decrease bioavailability; not to be administered within 24 h of live typhoid vaccine (reduces vaccine effects) Gemifloxacin: Coadministration with antacids and divalent or trivalent cations (eg, aluminum, magnesium, iron) significantly reduces absorption (administer 3 h before or 2 h after gemifloxacin); sucralfate decreases absorption and should be administered 2 h following gemifloxacin; may increase QT interval prolongation risk if coadministered with class IA (eg, quinidine, procainamide) or class III antiarrhythmic agents (sotalol, amiodarone), or other drugs known to prolong QT interval (eg, erythromycin, antipsychotics, antidepressants)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy; may prolong QT interval

FOLLOW-UP

Section 8 of 12

Further Inpatient Care:

• Acute exacerbation of COPD


• • Acute exacerbations of COPD are one of the major reasons for hospital admission in the United States. Causes include upper respiratory infection, myocardial ischemia, congestive heart failure, thromboembolism, and recurrent aspiration.

  • 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. Initiate treatment 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 for lower dosages of beta agonists. The efficacy of theophylline or intravenous aminophylline is not definitely established, and theophylline and 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 meets 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 the 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 (pH <7.30), or the need for 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.

  • 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 as follows:
    1. To lessen air flow limitation

    2. To prevent and treat secondary medical complications (eg, hypoxemia, infection)

    3. To decrease respiratory symptoms and improve quality of life

Prognosis:

• The predictors of mortality are aging, continued smoking, accelerated decline in FEV₁, moderate-to-severe airflow obstruction, poor bronchodilator response, severe hypoxemia, the presence of hypercapnia, development of cor pulmonale, and overall poor functional capacity.



• The mortality rate is 24% in patients admitted to the ICU with an acute exacerbation; this doubles for patients 65 years or older. FEV₁ is a reliable predictor of mortality from COPD. The mortality rate for patients who have an FEV₁ of less than 0.75 L/s is 30% at 1 year and 95% at 10 years.



• The American Thoracic Society has recommended the staging of COPD severity according to lung function. Stage I is FEV₁ of equal or more than 50% predicted. Stage II is FEV₁ 35-49% predicted, and stage III is FEV₁ less than 35% predicted.

Patient Education:

• For excellent patient education resources, visit eMedicine’s Lung and Airway Center and Asthma Center. Also, see eMedicine’s patient education articles Chronic Obstructive Pulmonary Disease (COPD), Coughs, and Asthma.

MISCELLANEOUS

Section 9 of 12

Medical/Legal Pitfalls:

• Differentiating COPD from asthma is difficult because of overlap in the pathophysiology, clinical presentation, pulmonary function test results, and treatment. The approach to treatment and prognosis differ because of relative importance of anticholinergic versus beta2-agonist therapy and the use of corticosteroids or other inflammatory agents.



• Although exacerbations are an important event in the natural history of patients who have COPD, limited information is available on the frequency of exacerbations and their effect on the course of COPD. Many patients have subclinical exacerbations that should be treated aggressively to prevent complications.



• Controversy exists about which patients should receive a trial of systemic or inhaled corticosteroids. Although a small fraction improves markedly, no screening test identifies the responders and the characteristics that constitute improvement are unclear.



• AAT replacement therapy for those who are deficient is controversial, and researchers have not determined the optimal dose and dosing regimen.



• Noninvasive ventilation to provide intermittent respiratory muscle rest is beneficial in a select group of patients but is considered controversial and requires further clinical studies.



• More information is required to determine whether pulmonary rehabilitation, lung volume reduction surgery, and/or lung transplantation represent cost-effective interventions.



• Although preliminary studies show that inhaled corticosteroids may reduce progression of airflow obstruction, this should be confirmed with large prospective studies.

TEST QUESTIONS

Section 10 of 12

CME Question 1: A 65-year-old man is seen for evaluation of progressive dyspnea. He has a 40-year smoking history. A spirometry is requested. Which of the following spirometric values is diagnostic of chronic obstructive pulmonary disease (COPD)?

A: Forced vital capacity (FVC) 120% of predicted, forced expiratory volume in 1 second (FEV₁) 110% of predicted, and FEV₁/FVC 73%
B: FVC 90% of predicted, FEV₁ 85% of predicted, and FEV₁/FVC 80%
C: FVC 75% of predicted, FEV₁/FVC 90%
D: FVC 85% of predicted, FEV₁/FVC 52%
E: FEV₁/FVC is 60% of predicted, improves to 75% post bronchodilator therapy

The correct answer is D: An obstructive spirometric pattern that does not normalize following bronchodilator administration is diagnostic of COPD (irreversible airflow obstruction).

CME Question 2: An elderly patient has severe chronic obstructive pulmonary disease (COPD) and is on the maximum dose of an ipratropium inhaler, salbutamol inhaler, and theophylline. A steroid trial with prednisone is prescribed. Which of the following reflects benefit of steroid therapy?

A: Improved breathlessness
B: Resolution of cough
C: Improved well being
D: A 10% improvement in forced expiratory volume in 1 second (FEV₁)
E: A 20% improvement in FEV₁

The correct answer is E: In a patient with severely symptomatic COPD, steroid trial is recommended. An objective improvement (ie, FEV₁ improved by 20%) is the required prerequisite for long-term steroid administration.

Pearl Question 1 (T/F): Patients who have severe chronic obstructive pulmonary disease (COPD) and are current smokers do not benefit from smoking cessation.

The correct answer is False: Even in patients with severe COPD smoking cessation slows the decline in lung function.

Pearl Question 2 (T/F): Home oxygen therapy in a patient with hypoxemic chronic obstructive pulmonary disease (COPD) prolongs survival.

The correct answer is True: Smoking cessation and oxygen therapy are the only interventions known to prolong survival in COPD.

Pearl Question 3 (T/F): Replacement of alpha1-antitrypsin (AAT) in patients with AAT deficiency and emphysema is a proven therapy.

The correct answer is False: Replacement of AAT is not beneficial; however, large controlled studies are lacking.

Pearl Question 4 (T/F): A comprehensive pulmonary rehabilitation program improves lung function and survival in patients with chronic obstructive pulmonary disease (COPD).

The correct answer is False: A comprehensive pulmonary rehabilitation improves quality of life and walking distance but not lung function or survival.

PICTURES

Section 11 of 12

Caption: Picture 1. Chronic bronchitis. Forced expiratory volume in 1 second (FEV1) can be used to evaluate the prognosis in patients with emphysema. The benefit of smoking cessation is shown here because the deterioration in lung function parallels that of a nonsmoker, even in late stages of the disease.
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Caption: Picture 2. Chronic bronchitis. Gross pathology of advanced emphysema. Large bullae present on the surface of the lung.
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Caption: Picture 3. Although chronic bronchitis is defined clinically, morphologically it is defined as hyperplasia and hypertrophy of submucosal glands. A normal bronchus (left) is compared with one with chronic bronchitis (right).
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Caption: Picture 4. Chronic bronchitis mostly occurs in heavy smokers. A photomicrograph of a bronchus shows chronic inflammatory cells.
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Caption: Picture 5. Chronic bronchitis. At high magnification, in emphysema, loss of alveolar walls and dilatation of airspaces occurs.
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Caption: Picture 6. Histopathology of chronic bronchitis showing hyperplasia of mucous glands and infiltration of the airway wall with inflammatory cells.
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Caption: Picture 7. Histopathology of chronic bronchitis showing hyperplasia of mucous glands and infiltration of the airway wall with inflammatory cells.
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Caption: Picture 8. Histopathology of chronic bronchitis showing hyperplasia of mucous glands and infiltration of the airway wall with inflammatory cells.
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Caption: Picture 9. Chronic bronchitis. Posteroanterior (PA) and lateral chest radiograph in a patient with severe chronic obstructive pulmonary disease (COPD). Hyperinflation, depressed diaphragms, increased retrosternal space, and hypovascularity of lung parenchyma is demonstrated.
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Caption: Picture 10. Chronic bronchitis. A CT scan shows hyperlucency due to hypovascularity and bullae formation diffusely, predominantly in upper lobes.
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Caption: Picture 11. Chronic bronchitis. Flow volume curve of lungs in emphysema shows marked decrease in expiratory flows, hyperinflation, and air trapping (patient B) compared to a patient with restrictive lung disease, who has reduced lung volumes, preserved flows (patient A).
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Caption: Picture 12. Chronic bronchitis. Gross pathology of a patient with emphysema showing bullae on the surface.
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BIBLIOGRAPHY

Section 12 of 12

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