Topic Editor: Grant E. Fraser, M.D., FRACGP, FACRRM, ASTEM

Review Date: 01/12/2012

Definition

Chronic obstructive pulmonary disease (COPD) refers to a group of diseases causing chronic airflow obstruction which is not fully reversible. COPD is associated with an abnormal inflammatory response of the lungs to noxious particles or gases. This condition is generally progressive and results from any one - or combination of the following:

• Asthma (less common)
• Chronic bronchitis
• Emphysema

Description

• COPD is a condition of airflow obstruction which affects normal breathing
• It is both treatable and preventable, but not reversible
• COPD is a leading cause of morbidity and mortality worldwide and imposes a significant burden in terms of disability and impaired quality of life
• Smoking, infection, and other environmental factors cause inflammatory changes in lung tissue, a protease-antiprotease imbalance, and oxidative stress leading to characteristic pathological lesions
• Chronic airflow limitation is the main feature of COPD, and is caused by a combination of small airway disease (obstructive bronchiolitis) and parenchymal destruction (emphysema)
• Emphysema is the permanent abnormal enlargement of air spaces distal to the terminal bronchioles
• Chronic Bronchitis is defined as chronic or recurrent bronchial hypersecretion for a minimum of 3 months per year for at least two consecutive years
• The spirometric classification of disease severity is measured as the FEV1/FVC ratio (forced expiratory volume in 1 s/forced vital capacity). COPD stages:
• Stage I (Mild): FEV1/FVC <0.70; FEV1 = 80% predicted
• Stage II (Moderate): FEV1/FVC <0.70; 50% = FEV1 <80% predicted
• Stage III (Severe): FEV1/FVC <0.70; 30% = FEV1 <50% predicted
• Stage IV (Very Severe): FEV1/FVC <0.70; FEV1 <30% predicted or FEV1 <50% of predicted plus chronic respiratory failure
• Proper pharmacologic therapy and pulmonary rehabilitation can reduce the symptoms of COPD, improve health status and exercise tolerance, and help prevent or reduce the frequency of COPD exacerbations
• Diminishing further exposure to environmental agents (particularly cigarette smoke) is critical in slowing disease progression

Epidemiology

Incidence/prevalence

• COPD became the third leading cause of death in the U.S. in 2008
• COPD was the underlying cause in approximately 1 in 20 deaths in the U.S.
• In people aged >25 years, COPD-related mortality was 126,005 deaths in the US in 2006, an 8% increase over 2000
• According to the National Health and Nutrition Examination Survey (NHANES), among people aged 25 to 75 years, the estimated prevalence for mild COPD was 6.9%, and moderate COPD was 6.6%
• The incidence of COPD is unclear with a wide range of estimates available. It is an underdiagnosed condition, with approximately 24 million people in the U.S. felt to have this condition
• The National Institute for Occupational Safety and Health 1997-2004 statistics looking at worker in the U.S. estimated COPD prevalence:
• 6.5% of current smokers
• 4.4% of former smokers
• 2.7% of non smokers

Age

• The incidence of COPD is higher among people aged >40 years, and increases steeply with age, with the highest prevalence among those >60 years of age

Gender

• Recent data from developed countries shows that the prevalence of COPD is similar in both men and women
• Chronic bronchitis is more prevalent in women (57.6 vs. 28.6 per 1,000) than men; whereas emphysema has similar prevalence (17.3 vs. 16.3 per 1,000)
• COPD mortality among men has declined in the US among men from 57.0 per 100,000 in 1999 to 46.4 per 100,000 in 2006. No significant change in mortality has been observed among women, and was estimated to 34.2 per 100,000 in 2006

Risk Factors

• Aging
• Asthma or bronchial hyperreactivity
• Chronic bronchitis
• Exposures to air pollution, dust, smoke - especially from biofuels or 2nd hand tobacco smoke
• Genetic predisposition (deficiency of alpha-1 antitrypsin - accounts for <5% of cases)
• Infection (HIV, tuberculosis)
• Respiratory infection in childhood
• Smoking (80-90% of cases)
• Socioeconomic status (poorer have higher risk)

Etiology

Genetic factors, environmental influence, and genotype-environment interactions play a role in the pathogenesis of COPD

• The etiological factors of COPD include:
• Smoking is the dominant factor in the development and progression of COPD, and accounts for 80% to 90% of COPD cases
• Occupational and environmental exposure to various pollutants and noxious particles and gases
• Alpha 1-antitrypsin deficiency is observed in 1% to 3% of patients with COPD Alpha 1-antitrypsin deficiency in combination with smoking or other environmental factors markedly the risk of COPD and results in earlier age symptomatic disease
• Childhood respiratory infections can lead to changes in airway responsiveness

History

The history depends upon which underlying condition is predominant in the patient's COPD.

• COPD of any etiology:
• Breathlessness
• Chest tightness
• Chronic cough
• Diminished exercise tolerance
• Family history of COPD
• Fatigue (severe and very severe COPD)
• History of asthma, respiratory infection in childhood, or other respiratory diseases
• History of exposure to risk factors like tobacco smoking, occupational dust, chemicals, noxious particles or gases
• Presence of comorbidities such as heart diseases, osteoporosis, musculoskeletal disorders and malignancies
• Progressive dyspnea or dyspnea on exertion
• Wheezing
• Chronic Bronchitis:
• Chronic sputum production
• Edema (from cor pulmonale)
• Frequent/recurrent pulmonary infections
• Gender more likely to be female
• Emphysema:
• Anorexia (severe and very severe emphysema)
• Muscle wasting (severe and very severe emphysema)
• Weight loss (severe and very severe emphysema)

Physical findings on examination

• Physical examination is rarely diagnostic in COPD due to very low sensitivity and specificity
• The following physical signs may be present but their absence does not exclude the diagnosis:
• Central cyanosis or bluish discoloration of the mucosal membranes may be present
• Distant heart sounds (especially with emphysema)
• Hyperinflation of chest (barrel shaped chest) is observed in advanced COPD
• Increased respiratory rate at rest (>20 breaths/minute)
• Muscle wasting/cachexia (advanced emphysema)
• Pursed lip breathing may be present to slow the expiratory flow and permit more efficient lung emptying
• Signs of right heart failure such as ankle or lower leg swelling, increase jugular venous pressure (in chronic bronchitis)
• Use of accessory muscles of breathing (scalene and sternocleidomastoid muscles)
• Reduced breath sounds on auscultation, wheezing during quiet breathing, inspiratory crackles; heart sounds are best heard over the xiphoid area
• Chronic bronchitis patients are commonly referred to as "blue bloaters" as their propensity is obesity and right heart failure (cor pulmonale) with edema
• Emphysema patients are commonly referred to as "pink puffers" as their propensity is barrel chest, cachexia, and muscle wasting

Blood test findings

• Complete blood count (CBC): Polycythemia indicating arterial hypoxemia and anemia are often present. Low hematocrit indicates poor prognosis
• Alpha-1 antitrypsin deficiency screening: Recommended in the patients who have a strong family history of the disease, or in Caucasian individuals who developed COPD at a young age (<45 years). Alpha-1 antitrypsin deficiency is considered if serum concentration is less than 15% to 20% of normal value
• Arterial blood gas (ABG): Hypercapnia and hypoxia may be present. PaO2 60 mm of Hg with or without PaCO2 <50 mm of Hg is suggestive of respiratory failure. Venous blood gas is adequate in most cases, so long as pulse oximetry is generating a quality wave form

Radiographic findings

• Chest X-ray:
• Though rarely diagnostic in COPD, it may be useful in excluding other possible pathologies that may coexist with or mimic COPD
• Useful to evaluate for pneumonia, congestive failure, pulmonary effusion, lung mass, and pneumothorax
• COPD-associated changes include signs of hyperinflation, ie, flattened diaphragm, increased volume of the retrosternal air space, rapid tapering of vascular markings, and lung hyperlucency. May see bullae in some cases
• CT scan: May be used to evaluate pulmonary embolus, bronchial wall thickening, or to further classify disease

Other diagnostic tests findings

• Spirometry is the gold standard for diagnosis of COPD. Such testing confirms this diagnosis by demonstrating airway obstruction, and also classifies the severity of disease. Spirometry documents the ratio of volume of air forcibly exhaled from the point of maximal inspiration (forced vital capacity, FVC) and forced expiratory volume in one second (FEV1). Post-bronchodilator FEV1/FVC <0.70 confirms airflow limitation consistent with a diagnosis of COPD. This test is useful for following disease progression over time

• Acute respiratory distress syndrome
• Asthma
• Bronchiectasis
• Bronchiolitis obliterans
• Congestive heart failure
• Diffuse panbronchiolitis
• Gastroesophageal reflux disease
• Lung cancer
• Pleural effusion
• Pneumonia or other pulmonary infection/abscess/tuberculosis
• Pneumothorax
• Primary alveolar hypoventilation
• Pulmonary embolism

General treatment

• The goals of treatment are to relieve symptoms, minimize disease progression and exacerbations, improve exercise tolerance, prevent and treat complications, and improve the quality of life
• To prevent disease progression and decline in lung function, priority should be given to measures such as smoking cessation, protection from environmental or occupational pollution, and early treatment of infective complications

• Medications have not been shown to modify the typical progressive decline in lung function seen in COPD
• Pharmacotherapy currently prevents and controls symptoms and/or complications
• Treatment regimens depend on disease severity, complications, comorbidities, and general health status
• Bronchodilators
• Bronchodilators are the key therapy used for symptomatic management of COPD
• These agents relax airway smooth muscles and improve lung emptying during tidal breathing
• There are three groups of bronchodilators commonly in use:
• ß2-agonists
• Anticholinergic drugs
• Methylxanthines
• Bronchodilator choice depend upon patient characteristics and individual response
• Bronchodilators may be used on a regular basis to prevent or reduce symptoms, or as needed for relief of persistent or worsening symptoms
• The inhaled route is preferred due to side effect profile. Long acting inhaled bronchodilators are the most typical mainstay of treatment
• Beta 2-agonist:
• Short-acting beta 2-agonists include albuterol, metaproterenol, levalbuterol, perbuterol, and terbutaline. Their effect usually wears off within 4 to 6 hours
• Long-acting beta 2-agonists include arformoterol, formoterol, indacaterol, and salmeterol. The duration of their effect is usually 12 hours or more, and offer an alternative for patients with nighttime or early morning symptoms
• Anticholinergic drugs: These agents include aclidinium, ipratropium, oxitropium, and tiotropium. The mechanism is blockade of acetylcholine M3 receptors. There is an increased risk of urinary retention , especially in men with evidence of benign prostatic hypertrophy
• Methylxanthines: Although these agents (theophylline and aminophylline) have less bronchodilator effect than ß2-agonists or anticholinergic agents, they have an effect on systemic and pulmonary vascular dilatation, increase salt and water excretion, and stimulate the central nervous system and can be effective in patients with COPD. They have a narrow therapeutic window and risk of toxicity
• Phosphodiesterase-4 inhibitors: This drug (roflumilast) selectively inhibits phosphodiesterase-4. Research indicates a modest (15%) decreased rate of moderate to severe COPD exacerbations with this drug
• Glucocorticosteroids:
• The role of glucocorticosteroids in the management of COPD has yet to be established. These drugs can be administered inhaled, injected or orally
• Inhaled glucocorticosteroids (beclomethasone,budesonide, ciclesonide, fluticasone, and memetasone) do not modify the long-term decline of FEV1 in patients with COPD, but are recommended for symptomatic relief in patients with an FEV1 50% predicted (Stage III: Severe COPD and Stage IV: Very Severe COPD) and repeated exacerbations
• Inhaled glucocorticosteroids should be considered in moderate to severe COPD with frequent exacerbations
• Oral or systemic glucocorticosteroids (dexamethasone, methylprednisolone, prednisone, or prednisolone) may be used during exacerbations and to test reversibility of the airflow limitation. Due to lack of evidence, long-term systemic use of corticosteroids is not recommended. Despite this, the occasional COPD patient may require systemic steroids in the event they are unable to be successfully weaned onto inhaled agents (generally require pulmonologist review in such cases)

• In patients with moderate to very severe COPD, regular use of a long-acting inhaled bronchodilator is recommended when symptoms are not relieved or if regular use is required of as-needed short acting bronchodilators
• Regular treatment with long-acting bronchodilators may be more effective and convenient for many patients
• The combination of a long acting beta agonist and long acting anticholingergic agent appears more effective than either agent alone
• Theophylline or roflumilast may be added for symptom control in patients on regular long-acting bronchodilators who have disabling breathlessness. Side effect profile and narrow therapeutic window may be a concern with these agents
• In patients with severe to very severe COPD, or with a history of repeated exacerbations, regular treatment with an inhaled glucocorticosteroid should be added to long-acting inhaled bronchodilators to reduce the frequency of exacerbations and improve health status. Avoid chronic treatment with oral glucocorticosteroids

• Vaccines: The influenza vaccine can reduce the risk of serious respiratory infection or death by approximately 50% in COPD patients. Pneumococcal polysaccharide vaccine is recommended in COPD patients with comorbidities such as cardiovascular disease
• Alpha-1 antitrypsin augmentation therapy: Recommended in young patients with severe hereditary alpha-1 antitrypsin deficiency and established emphysema
• Antibiotics: Antibiotic therapy has no benefit on the frequency of exacerbations in COPD other than treating infectious exacerbations of COPD. Acute exacerbations are usually treated with basic oral antibiotics such as amoxicillin, doxycycline or trimethoprim-sulfamethoxazole. For severe exacerbations, amoxicillin-clavulanate, azithromycin, clarithromycin, 2nd or 3rd generation cephalosporins, of advanced fluoroquinolones (such as levofloxacin) may be appropriate
• Mucolytic: May offer some benefit to patients with viscous sputum, although their use is generally not recommended
• Antioxidant agents: Small studies have reported the positive role of antioxidants, particularly N-acetylcysteine, in reducing the frequency of exacerbations
• Immunoregulators: May be used to decrease the severity and frequency of exacerbations
• Antitussives: May be helpful in the symptomatic relief of cough, however regular use in stable COPD is not recommended
• Narcotics: In patients with very severe COPD, oral parenteral opioids are effective in treating dyspnea; however they may have serious adverse effects

• Rehabilitation: Non-pulmonary problems such as relative social isolation, altered mood states (depression), muscle wasting, weight loss and exercise de-conditioning may be addressed by pulmonary rehabilitation
• The goals of pulmonary rehabilitation are to improve quality of life by reducing dyspnea and fatigue, and increasing physical and emotional participation in everyday activities

• Oxygen therapy may be lifesaving in COPD exacerbations. Long-term administration has been shown to increase survival in patients with chronic respiratory failure. The goal is to raise baseline PaO2 to 8.0 kPa (60 mm Hg) and/or SaO2 to 90%
• Long-term oxygen is recommended in patients with very severe COPD (Stage IV) with PaO2 at or below 7.3 kPa (55 mm Hg) or SaO2 at or below 88%, with or without hypercapnia or in patients with the evidence of cardiac failure or polycythemia with PaO2 between 7.3 kPa (55 mm Hg) and 8.0 kPa (60 mm Hg), or SaO2 of 88%

• Noninvasive ventilation (CPAP, BiPAP) may be used in patients with stable, very severe COPD with or without CO2 retention. Support may improve survival but not the quality of life
• Noninvasive ventilation is first line therapy in severe exacerbations with respiratory failure as its early use often avoids need for intubation
• Non-invasive ventilation requires a conscious patient who is capable of protecting their airway
• Intubation in severe exacerbation needs careful consideration and discussion depending upon the patient's status, stage of disease and overall prognosis. In some cases, end of life care and palliation is more appropriate

Surgical treatment is recommended in patients who do not respond to the pharmacotherapy. The three main surgical procedures that provide benefit in COPD include:

• Bullectomy:
• Bullectomy is recommended in cases in which giant bullae occupy a third or more of the hemithorax, and there is substantial compressive pressure on the underlying normal lung tissue, dyspnea, and exercise limitation
• Bullectomy may improve lung function and reduce symptoms by allowing less diseased compressed surrounding lung to expand
• Lung volume reduction surgery (LVRS):
• The National Emphysema Treatment Trial (NETT) identified that LVRS decreased mortality rate, and improved the quality of life and exercise tolerance in patients with upper lobe-predominant emphysema and low exercise capacity
• Lung transplantation:
• COPD is the most common indication for the lung transplantation. The first lung transplant for advanced emphysema was performed in 1970
• Lung transplantation, where available, is recommended in cases of severe emphysema (FEV1 25% to 30% of predicted normal values or rapid decline in lung function), significant hypoxemia, hypercapnia, and secondary pulmonary hypertension despite maximal medical therapy
• Both unilateral and bilateral transplantation are possible. Lung transplant significantly improves pulmonary function, exercise capacity, and quality of life in highly selected patients. The survival benefit from lung transplantation remains unclear

Medications indicated with specific doses

Short acting-Beta 2-agonist

• Albuterol [Oral]
• Adult dosing
• Albuterol [Inhaled]
• Adult dosing
• Levalbuterol
• Adult dosing
• Metaproterenol [Inhaled]
• Adult dosing
• Pirbuterol [Inhaled]
• Adult dosing
• Terbutaline [Oral]
• Adult dosing
• Terbutaline [SC]
• Adult dosing

• Salmeterol
• Adult dosing
• Formoterol
• Adult dosing
• Arformoterol [Inhaled]
• Adult dosing
• Indacaterol [Inhaled]
• Adult dosing

• Ipratropium [Inhaled]
• Adult dosing
• Tiotropium [Inhaled]
• Adult dosing
• Aclidinium [Inhaled]
• Adult dosing

• Theophylline [IV]
• Adult dosing
• Theophylline [Oral]
• Adult dosing
• Aminophylline [Oral]
• Adult dosing
• Aminophylline [IV]
• Adult dosing

• Roflumilast
• Adult dosing
• Albuterol/ipratropium [Inhaled]
• Adult dosing
• Budesonide/formoterol [Inhaled]
• Adult dosing
• Fluticasone/salmeterol [Inhaled]
• Adult dosing

• Prednisone
• Adult dosing
• Methylprednisolone [Injectable]
• Adult dosing
• Methylprednisolone [Oral]
• Adult dosing

Inhaled glucocorticosteroids

• Budesonide [Inhaled]
• Adult dosing
• Fluticasone [Inhaled]
• Adult dosing
• Ciclesonide [Inhaled]
• Adult dosing
• Mometasone [Inhaled]
• Adult dosing
• Beclomethasone [Inhaled]
• Adult dosing

Dietary or Activity restriction

• Patients who are either overweight or underweight may have a worse prognosis; an ideal body weight should be maintained
• Avoid high-carbohydrate diets and extremely high caloric intake to reduce the risk of hypercarbia
• Pulmonary rehabilitation is recommended to improve the quality of life including dyspnea, fatigue, emotional function and physical activities
• Creatine supplementation may increase muscle mass and peripheral muscle strength

Disposition

Admission criteria

• Patients with chronic/acute respiratory failure with hypoxia, and/or hypercapnia will need admission. Cases that require mechanical ventilation will need intensive care admission
• Patients presenting with COPD exacerbation, and serious comorbidities like congestive heart failure, dehydration, pneumonia, acute coronary syndrome, pulmonary embolism, or cardiac arrhythmia may require admission

Discharge Criteria

• Ambulatory patients with oxygen saturation (>92%)
• Patients with adequate gas exchange, hemodynamically stable, with follow-up arranged may go home with temporary oxygen therapy for hypoxia if otherwise well
• Patients who are stable clinically after only minimal treatment, who are able to continue a prescribed regimen at home

Monitoring

• Daily to monthly follow-up for unstable patients is typical (depending upon details, recent hospitalization and degree of illness)
• Stable patients can generally be reviewed as needed and approximately every 6 months
• Monitor arterial blood gas (ABG) yearly or more often depending on the condition
• Pulmonary function test should be performed yearly to monitor disease progression
• In patients on theophylline therapy, check theophylline level with every dose adjustment, and at least every 6 months once stable

Complications

• Arrhythmias
• Bullous lung disease
• Cor pulmonale (right sided heart failure)
• Depression
• Hypoxia
• Malnutrition
• Pneumothorax
• Poor sleep quality
• Pulmonary hypertension
• Respiratory failure
• Recurrent pneumonia
• Secondary polycythemia

Prognosis

Factors associated with poor prognosis in COPD include

• Advanced age
• Continued smoking
• Comorbidities (eg, alpha 1 antitrypsin deficiency, cor pulmonale, pulmonary hypertension)
• Initial FEV1 value <50% or continuous decline in FEV1
• Low hematocrit
• Malnutrition
• Poor response to bronchodilators

Associated conditions

• Asthma
• Atrial fibrillation
• Body mass index (increased or decreased)
• Cardiovascular diseases
• Depression
• Diabetes
• Dyslipidemia
• Heart failure
• Lung cancer
• Osteoporosis
• Respiratory infections
• Sleep apnea

Synonyms/Abbreviations

Synonym

• Chronic bronchitis
• Chronic obstructive pulmonary disease
• Emphysema

Abbreviations

• COPD

ICD9-CM

• 496 Chronic airway obstruction

ICD-10-CM

• J44.9 Chronic obstructive pulmonary disease, unspecified

1. Global strategy for the diagnosis, management, and prevention of COPD. Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011. http://www.goldcopd.org/guidelines-global-strategy-for-diagnosis-management.html. Last assessed Oct 22, 2012.
2. Celli BR, MacNee W, ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004;23(6):932-46.
3. Halbert RJ, Natoli JL, Gano A, et al. Global burden of COPD: systematic review and meta-analysis. Eur Respir J. 2006;28(3):523-32.
4. Valvi D, Mannino DM, Müllerova H, et al. Fibrinogen, chronic obstructive pulmonary disease (COPD) and outcomes in two United States cohorts. Int J Chron Obstruct Pulmon Dis. 2012;7:173-82.
5. Centers for Disease Control and Prevention. Chronic Obstructive Pulmonary Disease (COPD). http://www.cdc.gov/copd/index.htm. Updated March 1, 2012. Last assessed Oct 23, 2012
6. Silverman EK, Speizer FE. Risk factors for the development of chronic obstructive pulmonary disease. Med Clin North Am. 1996;80(3):501-22.
7. Carlin BW. COPD and associated comorbidities: a review of current diagnosis and treatment. Postgrad Med. 2012;124(4):225-40.
8. Mannino DM, Buist AS. Global burden of COPD: risk factors, prevalence, and future trends. Lancet. 2007;370(9589):765-73.
9. Barnes TA, Fromer L. Spirometry use: detection of chronic obstructive pulmonary disease in the primary care setting. Clin Interv Aging. 2011;6:47-52.
10. Siafakas NM, Vermeire P, Pride NB, et al. Optimal assessment and management of chronic obstructive pulmonary disease (COPD). The European Respiratory Society Task Force. Eur Respir J. 1995;8(8):1398-420.
11. COPD Working Group. Pulmonary rehabilitation for patients with chronic pulmonary disease (COPD): an evidence-based analysis. Ont Health Technol Assess Ser. 2012;12(6):1-75.
12. Fuld JP, Kilduff LP, Neder JA, et al. Creatine supplementation during pulmonary rehabilitation in chronic obstructive pulmonary disease. Thorax. 2005;60(7):531-7.
13. ZuWallack RL, Mahler DA, Reilly D, et al. Salmeterol plus theophylline combination therapy in the treatment of COPD. Chest. 2001;119(6):1661-70.
14. Drummond MB, Dasenbrook EC, Pitz MW, Murphy DJ, Fan E. Inhaled corticosteroids in patients with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA. 2008;300(20):2407-16.
15. Benditt JO. Surgical therapies for chronic obstructive pulmonary disease. Respir Care. 2004;49(1):53-61.
16. Criner GJ, Cordova F, Sternberg AL, et al. The National Emphysema Treatment Trial (NETT): Part I: Lessons learned about emphysema. Am J Respir Crit Care Med. 2011;184(7):763-70.
17. Rabe KF. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Br J Pharmacol. 2011;163(1):53-67.
18. American Lung Association. State of Lung Disease in Diverse Communities 2010. Chronic Obstructive Pulmonary Disease COPD. P35-40. Available at: http://www.lung.org/assets/documents/publications/solddc-chapters/copd.pdf. Last accessed 12 Jan 2013.
19. Chronic Obstructive Pulmonary Disease: Morbidity. The National Institute for Occupational Safety and Health (NIOSH). Available at: http://www2a.cdc.gov/drds/WorldReportData/FigureTableDetails.asp?FigureTableID=950&GroupRefNumber=T10-03. Last accessed 12 Jan 2013.
20. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individual with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003 Oct 1;168(7):818-900.
21. Stephenson A, Seitz D, Bell CM, Gruneir A, et. al. Inhaled anticholinergic drug therapy and the risk of acute urinary retention in chronic obstructive pulmonary disease: a population-based study. Arch Intern Med. 2011 May 23.
22. Oba Y, Lone NA. Efficacy and safety of roflumilast in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. Ther Adv Respir Dis. 2012 Nov 29.
23. The COPD-X Plan. Australian and New Zealand Guidelines for the management of Chronic Obstructive Pulmonary Disease. Available at http://www.copdx.org.au/executive-summary. Last accessed 12 January 2013.
24. Chen AM, Bollmeier SG, Finnegan PM. Long-acting bronchodilator therapy for the treatment of chronic obstructive pulmonary disease. Ann Pharmacother. 2008 Dec;42(12):1832-42.