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Chronic obstructive
pulmonary disease is partially reversible airflow obstruction caused
by an inflammatory response to inhaled toxins, often cigarette smoke. α1-Antitrypsin
deficiency and various of occupational exposures are less common
causes in nonsmokers. Symptoms are productive cough and dyspnea
that develop over years; common signs include decreased breath sounds,
prolonged expiratory phase of respiration, and wheezing. Severe
cases may be complicated by weight loss, pneumothorax, right heart
failure, and respiratory failure. Diagnosis is based on history,
physical examination, chest x-ray, and pulmonary function tests.
Treatment is with bronchodilators, corticosteroids, and, when necessary,
O2 and antibiotics. About 50% of patients
die within 10 yr of diagnosis.
Chronic obstructive pulmonary disease (COPD) comprises chronic obstructive bronchitis (clinically defined) and emphysema (pathologically defined). Many patients have features of both.
Chronic
obstructive bronchitis is chronic bronchitis with airflow obstruction. Chronic bronchitis (also called chronic mucous hypersecretion syndrome) is defined as productive cough for at least 3 mo total duration in 2 successive years. Chronic bronchitis becomes chronic obstructive bronchitis if spirometric evidence of airflow obstruction develops. Chronic asthmatic bronchitis is a similar, overlapping condition characterized by chronic productive cough, wheezing, and partially reversible airflow obstruction; it occurs predominantly in smokers with a history of asthma. In some cases, the distinction between chronic obstructive bronchitis and chronic asthmatic bronchitis is unclear.
Emphysema is destruction of lung parenchyma leading to loss of elastic recoil and loss of alveolar septa and radial airway traction, which increases the tendency for airway collapse. Lung hyperinflation, airflow limitation, and air trapping follow. Airspaces enlarge and may eventually develop bullae.
Epidemiology
An estimated 24 million people in the US have airflow limitation, of whom about half have COPD. COPD is the 4th leading cause of death, resulting in 122,000 deaths in 2003—compared with 52,193 deaths in 1980. From 1980 to 2000, the COPD mortality rate increased 64% (from 40.7 to 66.9/100,000).
Prevalence, incidence, and mortality rates increase with age. Prevalence is higher in men, but total mortality is similar in both sexes. Incidence and mortality are generally higher in whites, blue-collar workers, and people with fewer years of formal education, probably because these groups have a higher prevalence of smoking. COPD seems to aggregate in families independent of α1-antitrypsin (α1-antiprotease inhibitor) deficiency (see Chronic Obstructive Pulmonary Disease (COPD): α1-Antitrypsin Deficiency).
COPD is increasing worldwide because of the increase in smoking in developing countries, the reduction in mortality due to infectious diseases, and the widespread use of biomass fuels. It caused an estimated 2.74 million deaths worldwide in 2000 and is projected to become one of the top 5 causes of disease burden globally by the year 2020.
Etiology
Cigarette
smoking is the primary risk factor in most countries, although only about 15% of smokers develop clinically apparent COPD; an exposure history of 40 or more pack-years is especially predictive. Smoke from burning biomass fuels for indoor cooking and heating is an important contributing factor in developing countries. Smokers with preexisting airway reactivity (defined by increased sensitivity to inhaled methacholine), even in the absence of clinical asthma, are at greater risk of developing COPD than are those without. Low body weight, childhood respiratory diseases, passive cigarette smoke exposure, air pollution, and occupational dust (eg, mineral dust, cotton dust) or chemical (eg, cadmium) exposure contribute to the risk of COPD but are of minor importance compared with cigarette smoking.
Genetic
factors also contribute. The best-defined genetic disorder is α1-antitrypsin deficiency (see Chronic Obstructive Pulmonary Disease (COPD): α1-Antitrypsin Deficiency), which is an important cause of emphysema in nonsmokers and influences susceptibility to disease in smokers. Polymorphisms in microsomal epoxide hydrolase, vitamin D–binding protein, IL-1β, IL-1 receptor antagonist, phospholipase A2, matrix metalloproteinase 9, and ADAM-33 genes are all associated with rapid decline in forced expiratory volume in 1 sec (FEV1) in selected populations.
Inhalational exposures trigger an inflammatory response in airways and alveoli that leads to disease in genetically susceptible people. The process is thought to be mediated by an increase in protease activity and a decrease in antiprotease activity (see Chronic Obstructive Pulmonary Disease (COPD): α1-Antitrypsin Deficiency). Lung proteases, such as neutrophil elastase, matrix metalloproteinases, and cathepsins, break down elastin and connective tissue in the normal process of tissue repair. Their activity is balanced by antiproteases, such as α1-antitrypsin, airway epithelium–derived secretory leukoproteinase inhibitor, elafin, and matrix metalloproteinase tissue inhibitor. In people with COPD, activated neutrophils and other inflammatory cells release proteases as part of the inflammatory process; protease activity exceeds antiprotease activity, and tissue destruction and mucus hypersecretion result. Neutrophil and macrophage activation also leads to accumulation of free radicals, superoxide anions, and hydrogen peroxide, which inhibit antiproteases and cause bronchoconstriction, mucosal edema, and mucous hypersecretion. Neutrophil-induced oxidative damage, release of profibrotic neuropeptides (eg, bombesin), and reduced levels of vascular endothelial growth factor may contribute to apoptotic destruction of lung parenchyma. Infection, in conjunction with cigarette smoking, may amplify progression of lung destruction. The inflammation in COPD increases with increasing disease severity, and, in severe (advanced) disease, inflammation may not resolve completely with smoking cessation. Neither does this inflammation appear responsive to corticosteroids.
Bacteria, especially Haemophilus
influenzae
, colonize the normally sterile lower airways of about 30% of patients with COPD. In more severely affected patients (eg, those with previous hospitalizations), Pseudomonas
aeruginosa colonization is common. Smoking and airflow obstruction may lead to impaired mucus clearance in lower airways, which predisposes to infection. Repeated bouts of infection increase the inflammatory burden that hastens disease progression. There is no evidence, however, that long-term use of antibiotics slows the progression of COPD in susceptible smokers.
Pathophysiology
In COPD, inflammatory mucous exudates accumulate in the lumens and walls of small airways. Alveolar attachments and alveolar septa are destroyed, contributing to loss of airway support and closure during expiration. Also, the lumens of small airways become blocked with mucous secretions.
Enlarged alveolar spaces sometimes consolidate into bullae, defined as airspaces Š1 cm in diameter. Bullae may be entirely empty or have strands of lung tissue traversing them in areas of locally severe emphysema; they occasionally occupy the entire hemithorax.
The cardinal pathophysiologic feature of COPD is airflow limitation caused by loss of elastic recoil as a result of emphysema, or airflow obstruction caused by mucus hypersecretion, mucus plugging, mucosal edema, bronchospasm, or all of these mechanisms. Increased airway resistance increases the work of respiration, as does lung hyperinflation. Increased work of breathing may lead to alveolar hypoventilation with hypoxia and hypercapnia, although hypoxia is also caused by ventilation/perfusion (V/Q) mismatch; increased caloric expenditure and weight loss may occur. Some patients with advanced disease develop chronic hypoxemia and hypercapnia. Chronic hypoxemia increases pulmonary vascular tone which, if diffuse, causes pulmonary hypertension (see Pulmonary Hypertension) and cor pulmonale (see Heart Failure: Cor Pulmonale).
Symptoms
and Signs
COPD takes years to develop and progress. Most patients have smoked ≥ 20 cigarettes/day for > 20 yr. Productive cough usually is the initial symptom, developing among smokers in their 40s and 50s. Dyspnea that is progressive, persistent, exertional, or worse during respiratory infection appears years later, by the time patients reach their late 50s or 60s. Symptoms usually progress quickly in patients who continue to smoke and who have higher lifetime tobacco exposure. Morning headache develops in more advanced disease and signals nocturnal hypercapnia or hypoxemia.
Acute exacerbations occur sporadically during the course of COPD and are heralded by increased symptom severity. The specific cause of any exacerbation is almost always impossible to determine, but exacerbations are often attributed to viral URIs or acute bacterial bronchitis. As COPD progresses, acute exacerbations tend to become more frequent, averaging about 3 episodes/yr. Those who suffer acute exacerbations are much more likely to have recurrent exacerbations.
Signs of COPD include wheezing, increased expiratory phase of breathing, lung hyperinflation manifested as decreased heart and lung sounds, and increased anteroposterior diameter of the thorax (barrel chest). Patients with advanced emphysema lose weight and experience muscle wasting that has been attributed to immobility, hypoxia, or release of systemic inflammatory mediators, such as tumor necrosis factor (TNF)-α. Signs of advanced disease include pursed-lip breathing, accessory muscle use paradoxical indrawing of the lower intercostal interspaces during inspiration (Hoover's sign), and cyanosis. Signs of cor pulmonale include neck vein distention; splitting of the 2nd heart sound with an accentuated pulmonic component, tricuspid insufficiency murmur, and peripheral edema. Right ventricular heaves are uncommon in COPD because the lungs are hyperinflated.
Spontaneous pneumothorax may occur as a result of rupture of bullae and should be suspected in any patient with COPD whose pulmonary status abruptly worsens.
Diagnosis
Diagnosis is suggested by history, physical examination, and chest imaging and is confirmed by pulmonary function tests. Differential diagnosis includes asthma, heart failure, and bronchiectasis. COPD and asthma are sometimes easily confused. Asthma (see also Asthma) and COPD are distinguished by factors described in Table 1: Chronic Obstructive Pulmonary Disease (COPD): Factors That May Help Differentiate Asthma and COPD . (See the workshop report of the Global Initiative for Chronic
Obstructive Pulmonary Disease for more information.)
Systemic disorders that may have a component of airflow limitation may suggest COPD; they include HIV infection, abuse of intravenous drugs (particularly cocaine and amphetamines), sarcoidosis, Sjögren's syndrome, bronchiolitis obliterans, lymphangioleiomyomatosis, and eosinophilic granuloma.
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Fig. 1
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Changes in lung function (percentage of predicted FEV1) in patients who quit smoking compared with those who continue.
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During the first year, lung function improved in patients who quit smoking and declined in those who continued. Subsequently, the rate of decline in those who continued was twice that of those who quit. Function declined in those who relapsed and improved in those who quit regardless of when the change occurred. Based on data from Scanlon PD et al: Smoking cessation and lung function in mild-to-moderate chronic obstructive pulmonary disease; the Lung Health Study. American Journal of Respiratory and Critical Care Medicine 161:381–390, 2000.
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Table 1
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Factors That May Help Differentiate
Asthma and COPD
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Factor
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Asthma
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COPD
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Age of onset
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Typically < 30 yr
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Typically > 40 yr
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Atopy
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Usual
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Uncommon
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Response to bronchodilators
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Nearly complete
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Partial
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Body habitus
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Variable, often obese
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BMI usually low in patients with emphysema
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Chest auscultation
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Wheezing during exacerbations
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Decreased breath sounds, particularly during exacerbations
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Cough
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Nonproductive with cold air or exercise or at night
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Morning, productive
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Diffusing capacity
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Normal or increased
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Normal or decreased
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Dyspnea
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Episodic
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Persistent, predictable
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Family history
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Common
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Uncommon
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Nocturnal symptoms
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Common
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Uncommon
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Progression
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Usually nonprogressive
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Progressive if smoking
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Purulent sputum
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Uncommon
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Typical
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Smoking history
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20–30% prevalence, usually < 20 pack yr
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90–95% prevalence, usually > 20 pack yr
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Response to corticosteroids
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Very responsive
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Poorly responsive
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BMI = Body mass index.
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Data from O'Donnell DE, Arron S, Bourbeau J, et al. Executive Summary: Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease—2003. Canadian Respiratory Journal 10(Supplement A):11A-33A, 2003; Executive Summary: Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. 2005 update.
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Pulmonary function tests:
Patients suspected of having COPD should undergo complete pulmonary function testing (see also Tests of Pulmonary Function (PFT)) to confirm airway obstruction, to quantify its severity and reversibility, and to distinguish COPD from other diseases. Pulmonary function testing is also useful for following disease progression and monitoring response to treatment. The primary diagnostic tests are FEV1, which is the volume of air forcefully expired during the first second after a full breath; forced vital capacity (FVC), which is the total volume of air expired with maximal force; and flow-volume loops, which are simultaneous spirometric recording of airflow and volume during forced maximal expiration and inspiration.
Reductions of FEV1, FVC, and the ratio of FEV1/FVC are the hallmark of airway obstruction. Flow-volume loops show a concave pattern in the expiratory tracing (see Fig. 3: Tests of Pulmonary Function (PFT): Flow-volume loops. ). FEV1 declines up to 60 mL/yr in smokers, compared with a less steep decline of 25 to 30 mL/yr in nonsmokers, beginning at about age 30. In middle-aged smokers who already have a low FEV1, the decline occurs more rapidly. When the FEV1 falls below about 1 L, patients develop dyspnea with activities of daily living (although dyspnea is more closely related to the degree of air trapping than to the degree of airflow limitation); when the FEV1 falls below about 0.8 L, they are at risk of hypoxemia, hypercapnia, and cor pulmonale. FEV1 and FVC are easily measured with office spirometry and define severity of disease (see Table 2: Chronic Obstructive Pulmonary Disease (COPD): Stages and Treatment of COPD) because they correlate with symptoms and mortality. Normal reference values are determined by patient age, sex, and height.
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Table 2
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Stages and Treatment of
COPD
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Stage
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Characteristics
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Recommended Treatment
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All
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Avoidance of risk factors (eg, smoking)
Influenza vaccine annually
Pneumococcal polysaccharide vaccine
Treatment of complications
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1: Mild COPD
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FEV1/FVC < 70%
FEV1 ≥ 80% predicted
With or without symptoms
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Short-acting bronchodilator when needed
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2: Moderate COPD
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FEV1/FVC < 70%
50% ≤ FEV1 < 80% predicted
With or without symptoms
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Regular treatment with one or more bronchodilators
Rehabilitation
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3: Severe COPD
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FEV1/FVC < 70% 30% ≤ FEV1 < 50% predicted
With or without symptoms
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Regular treatment with one or more bronchodilators
Inhaled corticosteroids for patients with repeated exacerbations or persistent symptoms despite bronchodilator therapy
Rehabilitation
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4: Very severe COPD
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FEV1/FVC < 70%
FEV1 < 30% predicted or < 50% predicted plus presence of chronic respiratory failure (Pao2 < 60 mm Hg while breathing room air at sea level)
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Regular treatment with one or more bronchodilators
Inhaled corticosteroids if symptoms persist despite bronchodilator therapy
Rehabilitation
Long-term O2 therapy if respiratory failure
Consider surgical treatments
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FEV1 = Forced expiratory volume in 1 sec; FVC = forced vital capacity; Pao2= arterial partial pressure of oxygen.
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Modified from 2004 Update: Executive Summary, Global Strategy for the Diagnosis, Management, and Prevention of COPD.
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Additional pulmonary function testing is necessary only in specific circumstances, such as before lung volume reduction surgery (see Chronic Obstructive Pulmonary Disease (COPD): Surgery). Other test abnormalities may include increased total lung capacity, functional residual capacity, and residual volume, which can help distinguish COPD from restrictive pulmonary disease, in which these measures are diminished; decreased vital capacity; and decreased single-breath diffusing capacity for carbon monoxide (DLco). Decreased DLco is nonspecific and is reduced in other disorders that affect the pulmonary vascular bed, such as interstitial lung disease, but can help distinguish emphysema from asthma, in which DLco is normal or elevated.
Imaging tests:
The chest x-ray may have characteristic findings. Changes in emphysema can include lung hyperinflation manifested as a flat diaphragm (ie, increase in the angle formed by the sternum and anterior diaphragm on a lateral film from the normal value of 45° to > 90°), rapid tapering of hilar vessels, and bullae (ie, radiolucencies > 1 cm surrounded by arcuate, hairline shadows). Other typical findings include widening of the retrosternal airspace and a narrow cardiac shadow. Emphysematous changes occurring predominantly in the lung bases suggest α1-antitrypsin deficiency (see Chronic Obstructive Pulmonary Disease (COPD): α1-Antitrypsin Deficiency). The lungs may look normal or have increased lucency secondary to loss of parenchyma. Chest x-rays of patients with chronic obstructive bronchitis may be normal or may demonstrate a bibasilar increase in bronchovascular markings as a result of bronchial wall thickening.
Prominent hila suggest large central pulmonary arteries that may signify pulmonary hypertension. Right ventricular enlargement that occurs in cor pulmonale may be masked by lung hyperinflation or may manifest as encroachment of the heart shadow on the retrosternal space or by widening of the transverse cardiac shadow in comparison with previous chest x-rays.
CT scans may reveal abnormalities that are not apparent on the chest x-ray, and these abnormalities may suggest coexisting or complicating diseases, such as pneumonia, pneumoconiosis, or lung cancer. CT helps assess the extent and distribution of emphysema, estimated either by visual scoring or with analysis of the distribution of lung density. These parameters may be useful in preparation for lung volume reduction surgery. Indications for obtaining CT scans in patients with COPD include evaluation for lung volume reduction surgery, suspicion of coexisting or complicating diseases that are not clearly evident or excluded by chest x-ray, and suspicion of malignancy.
Adjunctive tests:
α1-Antitrypsin levels should be measured in patients < 50 yr with symptomatic COPD and in nonsmokers of any age with COPD to detect α1-antitrypsin deficiency (see Chronic Obstructive Pulmonary Disease (COPD): α1-Antitrypsin Deficiency). Other indications of α1-antitrypsin deficiency include a family history of premature COPD or infantile liver disease, lower-lobe distribution of emphysema, and COPD associated with antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis. If levels of α1-antitrypsin are low, the diagnosis should be confirmed by establishing the α1-antitrypsin phenotype.
The ECG, often performed to exclude cardiac causes of dyspnea, typically demonstrates diffusely low QRS voltage with a vertical heart axis caused by lung hyperinflation and increased P-wave voltage or rightward shifts of the P-wave vector caused by right atrial enlargement in patients with advanced emphysema. Findings of right ventricular hypertrophy include an R or R′ wave as tall as or taller than the S wave in lead V1; an R wave smaller than the S wave in lead V6; right-axis deviation > 110° without right bundle branch block; or some combination of these. Multifocal atrial tachycardia, an arrhythmia that can accompany COPD, manifests as a tachyarrhythmia with polymorphic P waves and variable PR intervals.
Echocardiography is occasionally useful for assessing right ventricular function and pulmonary hypertension, although it is technically difficult in patients with COPD. It is most often indicated when coexistent left ventricular or valvular heart disease is suspected.
CBC is of little diagnostic value in the evaluation of COPD but may show erythrocythemia (Hct > 48%) if the patient has chronic hypoxemia. Patients with anemia (for reasons other than COPD) have disproportionately severe dyspnea.
Evaluation of exacerbations:
Patients with acute exacerbations usually have combinations of increased work of breathing, low O2 saturations on oximetry, diaphoresis, tachycardia, anxiety, and cyanosis. However, patients with exacerbations accompanied by retention of CO2 may be lethargic or somnolent, a very different appearance. All patients requiring hospitalization for acute exacerbations should undergo ABG sampling to quantify hypoxemia and hypercapnia. Hypercapnia may exist with hypoxemia.
Findings of Pao2 < 50 mm Hg or Paco2 > 50 mm Hg in the setting of respiratory acidemia define acute respiratory failure (see Respiratory Failure and Mechanical Ventilation). However, some patients chronically manifest such levels of Pao2 and Paco2 in the absence of acute respiratory failure.
A chest x-ray is often obtained to check for pneumonia or pneumothorax. Rarely, infiltrates in patients receiving chronic systemic corticosteroids may represent Aspergillus pneumonia.
Yellow or green sputum is a reliable indicator of sputum neutrophils and suggests bacterial colonization or infection. Culture is usually done in hospitalized patients but is not usually necessary in outpatients. In samples from outpatients, Gram stain usually shows neutrophils with a mixture of organisms, often gram-positive diplococci (Streptococcus pneumoniae), gram-negative bacilli (H. influenzae), or both. Other oropharyngeal commensal organisms, such as Moraxella (Branhamella) catarrhalis, occasionally cause exacerbations. In hospitalized patients, cultures may demonstrate resistant gram-negative organisms (eg, Pseudomonas) or, rarely, Staphylococcus.
Prognosis
Severity of airway obstruction predicts survival in patients with COPD. The mortality rate in patients with an FEV1 > 50% of predicted is slightly greater than that of the general population. If the FEV1 is 0.75 to 1.25 L, 5-yr survival is about 40 to 60%; if < 0.75 L, about 30 to 40%.
More accurate prediction of death risk is possible by simultaneously measuring body mass index (B), the degree of airflow obstruction (O, which is the FEV1), dyspnea (D, which is measured with a Modified Medical Research Council [MMRC] dyspnea scale, and exercise capacity (E, which is measured with a 6-min walking test); this is the BODE index. Also, cardiac disease, anemia, resting tachycardia, hypercapnia, and hypoxemia decrease survival, whereas a significant response to bronchodilators predicts improved survival. Risk factors for death in patients with acute exacerbation requiring hospitalization include older age, higher Paco2, and use of maintenance oral corticosteroids. (Details
for calculating the BODE index are available at ICU Medicus.)
Patients at high risk of imminent death are those with progressive unexplained weight loss or severe functional decline (eg, those who experience dyspnea with self-care, such as dressing, bathing, eating). Mortality in COPD may result from intercurrent illnesses rather than from progression of the underlying disease in those who have stopped smoking. Death is generally caused by acute respiratory failure, pneumonia, lung cancer, cardiac disease, or pulmonary embolism.
Treatment
of Stable COPD
COPD management involves treatment of chronic stable disease and of exacerbations. Treatment of cor pulmonale, a common complication of long-standing, severe COPD, is elsewhere (see Cardiac Tumors).
Treatment of chronic stable COPD aims to prevent exacerbations and improve lung and physical function through drug and O2 therapy, smoking cessation, exercise, enhancement of nutrition, and pulmonary rehabilitation. Surgical treatment of COPD is indicated for selected patients.
Drug
therapy:
Recommended drug therapy is summarized in Table 2: Chronic Obstructive Pulmonary Disease (COPD): Stages and Treatment of COPD. Inhaled bronchodilators are the mainstay of COPD management; drugs include β-agonists and anticholinergics (antimuscarinics), which are equally effective. Patients with mild (stage 1) disease are treated only when symptomatic. Those with stage 2 or higher COPD should be taking one or both of these classes of drugs, regularly to increase pulmonary function and exercise capacity. The frequency of exacerbations can be reduced with the use of anticholinergics, inhaled corticosteroids, or long-acting β-agonists. However, there is no evidence that regular bronchodilator use slows deterioration of lung function. The initial choice among short-acting β-agonists, long-acting β-agonists, anticholinergics (which have a greater bronchodilating effect), and combination β-agonist and anticholinergic therapy is often a matter of tailoring cost and convenience to the patient's preferences and symptoms.
In treatment of chronic stable disease, administration by metered-dose inhaler or dry-powder inhaler is preferred over nebulized home treatment; home nebulizers are prone to contamination from incomplete cleaning and drying. Patients should be taught to exhale to functional residual capacity, inhale the aerosol slowly to total lung capacity, and hold the inhalation for 3 to 4 sec before exhaling. Spacers help ensure optimal delivery of drug to the distal airways and reduce the importance of coordinating activation of the inhaler with inhalation. Some spacers alert the patient if they are inhaling too rapidly.
β-Agonists relax bronchial smooth muscle and increase mucociliary clearance. Albuterol aerosol, 2 puffs (90 to 100 μg/puff) inhaled from a metered-dose inhaler 4 to 6 times/day prn, is usually the drug of choice because of low cost. Long-acting β-agonists are preferable for patients with nocturnal symptoms or for those who find frequent dosing inconvenient. Options include salmeterol powder, 1 puff (50 μg) inhaled bid, and formoterol powder, one puff (12 μg) inhaled bid. The dry-powder formulations may be more effective for patients who have trouble coordinating use of a metered-dose inhaler. Patients should be taught the difference between short-acting and long-acting drugs, because long-acting drugs that are used as needed or more than twice/day increase the risk of cardiac arrhythmias. Adverse effects commonly result from use of any β-agonist and include tremor, anxiety, tachycardia, and mild, temporary hypokalemia.
Anticholinergics relax bronchial smooth muscle through competitive inhibition of muscarinic receptors (M1, M2, and M3). Ipratropium is most commonly used because of low cost and ready availability; dose is 2 to 4 puffs (18 μg/puff) from a metered-dose inhaler q 4 to 6 h. Ipratropium has a slower onset of action (within 30 min; peak effect in 1 to 2 h), so a β2-agonist is often prescribed with it in a single combination inhaler or as a separate as-needed rescue drug. Tiotropium , a long-acting quaternary anticholinergic inhaled as a powder formulation, is M1 and M3 selective and may therefore have an advantage over ipratropium , because M2 receptor blockade (as occurs with ipratropium ) may limit bronchodilation. Dose is one inhalation (18 μg) once/day. Adverse effects of all anticholinergics are pupillary dilation, blurred vision, and dry mouth.
Inhaled corticosteroids inhibit airway inflammation, reverse β-receptor down-regulation, and inhibit leukotriene and cytokine production. They do not alter the course of pulmonary function decline in COPD patients who continue to smoke, but they do improve symptoms and short-term pulmonary function in some patients, are additive to the effect of bronchodilators, and may diminish the frequency of COPD exacerbations. They are indicated for patients who have repeated exacerbations or symptoms despite optimal bronchodilator therapy. Dose depends on the drug; examples include fluticasone 500 to 1000 μg/day and beclomethasone 400 to 2000 μg/day. The long-term risks of inhaled corticosteroids in older people are not proven but probably include osteoporosis and cataract formation. Long-term users therefore should undergo periodic ophthalmologic and bone densitometry screening and should possibly receive supplemental calcium, vitamin D, and a bisphosphonate as indicated. Corticosteroid therapy should be stopped if no subjective or objective improvement results (eg, after a few months).
Combinations of a long-acting β-agonist (eg, salmeterol ) and an inhaled corticosteroid (eg, fluticasone ) are more effective than either drug alone in the treatment of chronic stable disease.
Oral or systemic corticosteroids should usually not be used to treat chronic stable COPD.
Theophylline plays only a small role in the treatment of chronic stable COPD and now that safer, more effective drugs are available. Theophylline decreases smooth muscle spasm, enhances mucociliary clearance, improves right ventricular function, and decreases pulmonary vascular resistance and arterial pressure. Its mode of action is poorly understood but appears to differ from that of β2-agonists and anticholinergics. Its role in improving diaphragmatic function and dyspnea during exercise is controversial. Low-dose theophylline (300 to 400 mg/day) has anti-inflammatory properties and may enhance the effects of inhaled corticosteroids.
Theophylline can be used for patients who have not adequately responded to inhaled agents and who have shown symptomatic benefit from a trial of the drug. Serum levels need not be monitored unless the patient does not respond to the drug, develops symptoms of toxicity, or is questionably adherent; slowly absorbed oral theophylline preparations, which require less frequent dosing, enhance compliance. Toxicity is common and includes sleeplessness and GI upset, even at low blood levels. More serious adverse effects, such as supraventricular and ventricular arrhythmias and seizures, tend to occur at blood levels > 20 mg/L. Hepatic metabolism of theophylline varies greatly and is influenced by genetic factors, age, cigarette smoking, hepatic dysfunction, and some drugs, such as macrolide and fluoroquinolone antibiotics and nonsedating histamine2 blockers.
Oxygen
therapy:
Long-term O2 therapy prolongs life in COPD patients whose Pao2 is chronically < 55 mm Hg. Continual 24-h use is more effective than a 12-h nocturnal regimen. O2 therapy brings Hct toward normal levels; moderately improves neuropsychologic factors, possibly by facilitating sleep; and ameliorates pulmonary hemodynamic abnormalities. O2 therapy also increases exercise tolerance in many patients.
O2 saturation should be measured during exercise and while at rest. Similarly, a sleep study should be considered for patients with advanced COPD who do not meet the criteria for long-term O2 therapy while they are awake (see Table 3: Chronic Obstructive Pulmonary Disease (COPD): Indications for Long-Term O2 Therapy in COPD) but whose clinical assessment suggests pulmonary hypertension in the absence of daytime hypoxemia. Nocturnal O2 may be prescribed if a sleep study shows episodic desaturation to ≤ 88%. Such treatment prevents progression of pulmonary hypertension, but its effects on survival are unknown.
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Table 3
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Indications for Long-Term
O2 Therapy in COPD
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Pao2 ≤ 55 mm Hg or Sao2 ≤ 88%* in patients receiving optimal medical regimen for at least 30 days†
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Pao2 = 55 to 59 mm Hg or Sao2 ≤ 89%* for patients with cor pulmonale or erythrocytosis (Hct > 55%)
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Can be considered for Pao2 ≥ 60 mm Hg or Sao2 ≥ 90%* for patients whose room-air Pao2 is ≤ 55 mm Hg or Sao2 ≤ 88% during exercise or sleep
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Pao2 = partial pressure of arterial O2; Sao2 = arterial O2 saturation.
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*Arterial O2 levels measured at rest during air breathing.
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†Patients who are recovering from an acute respiratory illness and who meet the listed criteria should be given O2 and rechecked on room air in 30 days.
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O2 is administered by nasal cannula at a flow rate sufficient to achieve a Pao2 > 60 mm Hg (Sao2 > 90%), usually ≤ 3 L/min at rest. O2 is supplied by electrically driven O2 concentrators, liquid O2 systems, or cylinders of compressed gas. Concentrators, which limit mobility but are the least expensive, are preferable for patients who spend most of their time at home. Such patients require small O2 tanks for backup in case of an electrical failure and for portable use.
A liquid system is preferable for patients who spend much time out of their homes. Portable canisters of liquid O2 are easier to carry and have more capacity than portable cylinders of compressed gas. Large compressed-air cylinders are the most expensive way of providing O2 and should be used only if no other source is available. All patients must be taught the dangers of smoking during O2 use.
Various devices can conserve the amount of O2 used by the patient, either by using a reservoir system or by permitting O2 flow only during inspiration. Systems with these devices correct hypoxemia as effectively as do continuous flow systems.
Some patients need supplemental O2 during air travel, because flight cabin pressure in commercial airliners is low. Eucapnic COPD patients with a sea level Pao2 > 68 mm Hg generally have an in-flight Pao2 > 50 mm Hg and do not require supplemental O2. All COPD patients with a sea level Pao2 ≤ 68 mm Hg, hypercapnia, significant anemia (Hct < 30), or coexisting heart or cerebrovascular disease should use supplemental O2, during long flights and should notify the airline when making their reservation. The airline can provide supplemental O2, and most require a minimum notice of 24 h, a physician's statement of necessity, and an O2 prescription before the flight. Patients should bring their own nasal cannulas, because some airlines provide only face masks. Patients are not permitted to transport or use their own liquid O2, but many airlines now permit use of portable battery-operated O2 concentrators, which also provide a suitable O2 source upon arrival.
Smoking
cessation:
Smoking cessation (see Smoking Cessation) is both extremely difficult and extremely important; it slows but does not halt the progression of airway inflammation (see Fig. 1: Chronic Obstructive Pulmonary Disease (COPD): Changes in lung function (percentage of predicted FEV1) in patients who quit smoking compared with those who continue.). Simultaneous use of multiple strategies is most effective: establishment of a quit date, behavior modification techniques, group sessions, nicotine replacement therapy (by gum, transdermal patch, inhaler, lozenge, or nasal spray), varenicline or bupropion , and physician encouragement. Quit rates > 50% at 1 yr have not been demonstrated even with the most effective interventions, such as use of bupropion combined with nicotine replacement or use of varenicline alone.
Vaccinations:
All patients with COPD should be given annual influenza vaccinations. If a patient is unable to receive a vaccination or if the prevailing influenza strain is not included in the annual vaccine formulation, prophylactic treatment ( amantadine , rimantadine , oseltamivir , or zanamivir) is appropriate during community influenza outbreaks. Pneumococcal polysaccharide vaccine, although of unproven efficacy in COPD, has minimal adverse effects and should probably also be administered.
Nutrition:
COPD patients are at risk of weight loss and nutritional deficiencies because of a 15 to 25% increase in resting energy expenditure from breathing; a higher energy cost of daily activities; reduced caloric intake relative to need because of dyspnea; and the catabolic effect of inflammatory cytokines such as TNF-α. Generalized muscle strength and efficiency of O2 use are impaired. Patients with poorer nutritional status have a worse prognosis, so it is prudent to recommend a balanced diet with adequate caloric intake in conjunction with exercise to prevent or reverse malnutrition and muscle atrophy. However, excessive weight gain should be avoided, and obese patients should strive to gradually reduce body fat. Studies of nutritional supplementation alone have not shown improvement in pulmonary function or exercise capacity. Trials of anabolic steroids (eg, megestrol , oxandrolone ), growth hormone supplementation, and TNF antagonists in reversing malnutrition and improving functional status and prognosis in COPD have been disappointing.
Pulmonary
rehabilitation:
Pulmonary rehabilitation programs serve as adjuncts to drug treatment to improve physical function; many hospitals and health care organizations offer formal multidisciplinary rehabilitation programs. Pulmonary rehabilitation includes exercise, education, and behavioral intervention. Treatment should be individualized; patients and family members are taught about COPD and medical treatments, and the patient is encouraged to take as much responsibility for personal care as possible.
An exercise program can be helpful in the home, in the hospital, or in institutional settings. Graded exercise can ameliorate skeletal muscle de-conditioning resulting from inactivity or prolonged hospitalization for respiratory failure. Specific training of respiratory muscles is less helpful than general aerobic conditioning. A typical training program begins with slow walking on a treadmill or unloaded cycling on an ergometer for a few minutes. Duration and exercise load are progressively increased over 4 to 6 wk until the patient can exercise for 20 to 30 min nonstop with manageable dyspnea. Patients with very severe COPD can usually achieve an exercise regimen of walking for 30 min at 1 to 2 mph. Maintenance exercise should be performed 3 to 4 times/wk to maintain fitness levels. O2 saturation is monitored, and supplemental O2 is provided as needed. Upper extremity resistance training helps the patient in performing daily tasks, such as bathing, dressing, and housecleaning. The usual benefits of exercise are modest increases in lower extremity strength, endurance, and maximum O2 consumption.
A carefully integrated rehabilitation program helps patients with severe COPD accommodate to physiologic limitations while providing realistic expectations for improvement. Patients should be taught ways to conserve energy during activities of daily living and to pace their activities. Difficulties in sexual function should be discussed and advice given on using energy-conserving techniques for sexual gratification.
The benefits of rehabilitation are greater independence and improved quality of life and exercise capacity. Pulmonary rehabilitation typically does not improve pulmonary function or increase longevity, however. Patients with severe disease require a minimum of 3 mo of rehabilitation to benefit and should continue with maintenance programs.
Specialized programs are available for patients who remain ventilator-dependent after acute respiratory failure. Some patients can be liberated from the ventilator entirely, whereas others can remain off the ventilator during the day. For patients with adequate home support, training of family members can permit some patients to be sent home with ventilators.
Surgery:
Surgical options for treatment of severe COPD include lung volume reduction and transplantation.
Lung volume reduction by resection of nonfunctioning emphysematous areas improves exercise tolerance and decreases 2-yr mortality in patients with severe, predominantly upper-lung emphysema who have low baseline exercise capacity after pulmonary rehabilitation. Other patients may experience symptom relief and improved exercise capacity after surgery, but mortality has been the same as or increased when compared with that for drug therapy. Long-term effects of the procedure are unknown. Improvement is less than that with lung transplantation. The mechanism of improvement is believed to be enhanced lung recoil and improved diaphragmatic function. Operative mortality is about 5%. The best candidates for lung volume reduction are those with an FEV1 20 to 40% of predicted, a DLCO > 20% of predicted, significantly impaired exercise capacity, heterogeneous pulmonary disease on CT with an upper-lobe predominance, Paco2 < 50 mm Hg, and absence of severe pulmonary hypertension and coronary artery disease.
Rarely, patients have extremely large bullae that compress the functional lung. These patients can be helped by surgical resection of these bullae, with resulting relief of symptoms and improved pulmonary function. Generally, resection is most beneficial for patients with bullae affecting > 1/3 of a hemithorax and an FEV1 about ½ the predicted normal value. Improved pulmonary function is related to the amount of normal or minimally diseased lung tissue that was compressed by the resected bullae. Serial chest x-rays and CT scans are the most useful procedures for determining whether a patient's functional status is due to compression of viable lung by bullae or to generalized emphysema. A markedly reduced DLCO (< 40% predicted) indicates widespread emphysema and suggests a poorer outcome from surgical resection.
Since 1989, single-lung transplantation has largely replaced double-lung transplantation in patients with COPD. Candidates for transplantation are patients < 60 yr with an FEV1 < 25% predicted after bronchodilator therapy or with severe pulmonary hypertension. The goal of lung transplantation is to improve quality of life, because survival time is rarely increased. The 5-yr survival after transplantation for emphysema is 45 to 60%. Lifelong immunosuppression is required, with the attendant risk of opportunistic infections.
Treatment
of Acute COPD Exacerbation
The immediate objectives are to ensure adequate oxygenation and near-normal blood pH, reverse airway obstruction, and treat any underlying cause.
The underlying cause of an acute exacerbation is usually unknown, although some acute exacerbations result from bacterial or viral infections. Smoking, irritative inhalational exposure, and high levels of air pollution also contribute. Mild exacerbations often can be treated on an outpatient basis in patients with adequate home support. Elderly frail patients and patients with comorbidities, a history of respiratory failure, or acute changes in ABG measurements are admitted to the hospital for observation and treatment. Patients with life-threatening exacerbations manifested by uncorrected moderate to severe acute hypoxemia, acute respiratory acidosis, new arrhythmias, or deteriorating respiratory function despite hospital treatment should be admitted to the ICU and their respiratory status monitored frequently.
Oxygen:
Most patients require O2 supplementation, even those who do not need it chronically. Hypercapnia may worsen in patients given O2. This worsening has traditionally been thought to result from an attenuation of hypoxic respiratory drive. However, increased V/Q mismatch probably is a more important factor. Increased V/Q mismatch occurs because O2.
Attenuates hypoxic pulmonary vasoconstriction, which minimizes V/Q mismatch by decreasing perfusion of the most poorly ventilated areas of the lungs. The Haldane effect may also contribute to worsening hypercapnia, although this is controversial. The Haldane effect is a decrease in hemoglobin's affinity for CO2, which results in increased amounts of CO2 dissolved in plasma. O2 administration, even though it may worsen hypercapnia, is recommended; many COPD patients have chronic as well as acute hypercapnia and thus severe CNS depression is unlikely unless pCO2 exceeds 85 mm Hg. The target level for pO2 is about 60 mm Hg; higher levels offer little advantage and increase the risk of hypercapnia. O2 is given via Venturi mask so it can be closely regulated, and the patient is closely monitored. Patients whose condition deteriorates with O2 therapy (eg, those with severe acidemia or CNS depression) require ventilatory assistance.
Many patients who require home O2 for the first time when they are discharged from the hospital after an exacerbation improve within 30 days and no longer require O2. Thus, the need for home O2 should be reassessed 30 days after discharge.
Ventilatory
assistance:
Noninvasive positive-pressure ventilation (eg, pressure support or bi-level positive airway pressure ventilation by face mask [see Respiratory Failure and Mechanical Ventilation: Noninvasive positive pressure ventilation (NIPPV)]) is an alternative to full mechanical ventilation. Noninvasive ventilation appears to decrease the need for intubation, reduce hospital stay, and reduce mortality in patients with severe exacerbations (defined as a pH < 7.30 in hemodynamically stable patients not at immediate risk of respiratory arrest). Noninvasive ventilation appears to have no effect in patients with less severe exacerbation. However, it may be indicated for patients in this group whose ABGs worsen despite initial drug or O2 therapy or who appear to be imminent candidates for full mechanical ventilation but who do not require intubation for control of the airway or sedation for agitation. Deterioration on noninvasive ventilation necessitates invasive mechanical ventilation.
Deteriorating ABG levels and mental status and progressive respiratory fatigue are indications for endotracheal intubation and mechanical ventilation. Ventilator settings, management strategies, and complications are discussed elsewhere (see Respiratory Failure and Mechanical Ventilation). Risk factors for ventilatory dependence include an FEV1 < 0.5 L, stable ABGs with a Pao2 < 50 mm Hg, or a Paco2 > 60 mm Hg, severe exercise limitation, and poor nutritional status. Therefore, a discussion of the patient's wishes regarding intubation and mechanical ventilation should be initiated and documented (see Medicolegal Issues: Advance Directives). However, overconcern with possible ventilator dependence should not delay management of acute respiratory failure.
If a patient requires prolonged intubation (eg, > 2 wk), a tracheostomy is indicated to facilitate comfort, communication, and eating. With a good multidisciplinary rehabilitation program, including nutritional and psychologic support (see Diagnostic and Therapeutic Pulmonary Procedures: Pulmonary Rehabilitation), many patients who require prolonged mechanical ventilation can be successfully liberated and can return to their former level of function.
Drug therapy:
β-Agonists and anticholinergics, with or without corticosteroids, should be started concurrently with O2 therapy (regardless of how O2 is administered) with the aim of reversing airway obstruction.
Short-acting
β
-agonists are the cornerstone of drug therapy for acute exacerbations. The most widely used drug is albuterol , 2.5 mg by nebulizer or 2 to 4 inhalations (100 μg/puff) by metered-dose inhaler q 2 to 6 h. Inhalation using a metered-dose inhaler produces rapid bronchodilation; there are no data indicating that doses taken with nebulizers are more effective than the same doses correctly taken with metered-dose inhalers. In life-threatening exacerbations, risks of the exacerbation usually exceed those of high-dose β-agonists; thus, β-agonists may be given continuously via nebulizer until improvement occurs.
Ipratropium, the most commonly used anticholinergic, is effective in acute COPD exacerbations and should be given concurrently or alternating with β-agonists. Dosage is 0.25 to 0.5 mg by nebulizer or 2 to 4 inhalations (17 to 18 μg of drug delivered per puff) by metered-dose inhaler q 4 to 6 h. Ipratropium generally provides bronchodilating effect similar to that of usual recommended doses of β-agonists. The role of the longer-acting anticholinergic tiotropium in treating acute exacerbations has not been defined.
Corticosteroids should be begun immediately for all but mild exacerbations. Options include prednisone , 30 to 60 mg po once/day for 5 days or tapered over 7 to 14 days, or methylprednisolone , 60 to 500 mg IV once/day for 3 days and then tapered over 7 to 14 days. These drugs are equivalent in their acute effects; inhaled corticosteroids have no role in the treatment of acute exacerbations.
Methylxanthines, once considered essential to treatment of acute COPD exacerbations, are no longer used. Toxicities exceeded benefit.
Antibiotics are recommended for exacerbations in patients with purulent sputum. Some physicians give antibiotics empirically for change in sputum color or for nonspecific chest x-ray abnormalities. Routine cultures and Gram stains are not necessary before treatment unless an unusual or resistant organism is suspected (eg, in hospitalized, institutionalized, or immunosuppressed patients). Oral trimethoprim-sulfamethoxazole 160 mg/800 mg bid, amoxicillin 250 to 500 mg tid, tetracycline 250 mg qid, and doxycycline 50 to 100 bid given for 7 to 14 days are all effective and inexpensive first-line drugs for community-acquired exacerbations. Choice of drug is dictated by local patterns of bacterial sensitivity and patient history. If the patient is seriously ill or if clinical evidence suggests that the infectious organisms are resistant, more expensive 2nd-line drugs can be used. These drugs include amoxicillin-clavulanate 250 to 500 mg po tid; fluoroquinolones, such as ciprofloxacin , levofloxacin , or gatifloxacin ; 2nd-generation cephalosporins, such as cefuroxime or cefaclor ; and extended-spectrum macrolides, such as azithromycin or clarithromycin . These drugs are effective against β-lactamase–producing strains of H. influenzae and M. catarrhalis but have not been shown to be more effective than 1st-line drugs for most patients. Patients can be taught to recognize a change in sputum from normal to purulent as a sign of impending exacerbation and to start a 10- to 14-day course of antibiotic therapy. Long-term antibiotic prophylaxis is recommended only for patients with underlying structural changes in the lung, such as bronchiectasis or infected bullae.
Antitussives, such as dextromethorphan and benzonatate , have little role. Opioids (eg, codeine , hydrocodone, oxycodone ) should be used judiciously for relief of symptoms (eg, severe coughing paroxysms, pain) insofar as these agents may suppress a productive cough, impair mental status, and cause constipation.
End-of-Life
Care:
With very severe disease, particularly when death is imminent, exercise is unwarranted and activities of daily living are arranged to minimize energy expenditure. For example, the patient may arrange to live on one floor of the house, have several small meals rather than fewer large meals, and avoid wearing shoes that must be tied. End-of-life care should be discussed, including whether to pursue mechanical ventilation, the use of palliative sedation, and appointment of a surrogate medical decision-maker in the event of the patient's incapacitation.
Last full review/revision January 2007 by Robert A. Wise, MD
Content last modified January 2007
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