• April 02, 2008, Relenza (zanamivir): GlaxoSmithKline informed healthcare professionals of changes to the warnings and precautions sections of prescribing information for Relenza. There have been reports (mostly from Japan) of delirium and abnormal behavior leading to injury in patients with influenza who are receiving neuraminidase inhibitors, including Relenza.
• March 4, 2008, Tamiflu (oseltamivir phosphate): Roche and the U.S. Food and Drug Administration (FDA) informed healthcare professionals of neuropsychiatric events associated with the use of Tamiflu, in patients with influenza. Roche has updated the PRECAUTIONS section of the package insert to include the new information and guidance under the Neuropsychiatric Events heading.

Note from the National Guideline Clearinghouse (NGC) and the Institute for Clinical Systems Improvement (ICSI): For a description of what has changed since the previous version of this guidance, refer to "Summary of Changes -- January 2007."

The recommendations for the diagnosis and management of stable chronic obstructive pulmonary disease (COPD) are presented in the form of an algorithm with 15 components, accompanied by detailed annotations. An algorithm is provided for Chronic Obstructive Pulmonary Disease; clinical highlights and selected annotations (numbered to correspond with the algorithm) follow.

Class of evidence (A-D, M, R, X) and conclusion grade (I-III, Not Assignable) definitions are repeated at the end of the "Major Recommendations" field.

Clinical Highlights

• Assess patients for symptoms and risk factors for COPD including asking about tobacco use/exposure at every visit. (Annotations #1, 2)
• Establish diagnosis and severity of COPD through spirometry, pre-and post-bronchodilator, and chest radiograph in addition to history and physical examination. (Annotation #3)
• After establishing severity, assess patient needs for pharmacologic and non-pharmacologic treatment and provide appropriate therapy as indicated. (Annotation #11, 12, 13)
• Management of COPD should include an education plan suited to the patient's specific needs, encouragement of exercise, tobacco use cessation, and other behavioral changes, and monitoring of immunization status. (Annotations #2, 13)
• A trial of inhaled steroids is indicated for symptoms not controlled by scheduled bronchodilators. (Annotation #11)
• A course of systemic steroids is beneficial for COPD exacerbations. (Annotation #6)
• Tiotropium offers significant advantages compared to other bronchodilators to patients whose symptoms are not controlled by albuterol. (Annotation #11)
• For patients with severe symptoms, despite maximal medical therapy, lung volume reduction surgery and transplantation may be an option. (Annotation #15)
• Patients should be regularly assessed for hypoxemia; appropriate oxygen therapy should be prescribed accordingly. (Annotation #14)
• Physicians should discuss advance directives/health care directives and goals of care as early as possible. (Annotation #15)

Chronic Obstructive Pulmonary Disease Algorithm Annotations

1. Symptoms of or Risk Factors for COPD

   COPD may be indicated by the presence of one of the following symptoms:

   • Chronic cough (duration greater than three months) with or without sputum production
   • Dyspnea with or without wheezing

   COPD should also be considered if the patient has one or more of the following risk factors:

   • History of tobacco use or prolonged exposure to second-hand or environmental smoke
   • Asthma
   • Environmental exposure to occupational dust and chemicals (e.g. cadmium)
   • Alpha₁ - antitrypsin deficiency
   • Chronic respiratory infections

2. Ask About Tobacco Use/Exposure at Every Visit

   Key Points:

   • Tobacco cessation and oxygen therapy are the only interventions proven to prolong survival of patients with COPD.

   Ten to fifteen percent of long-term smokers develop COPD with accelerated rates of decline in forced expiratory volume in one second (FEV₁). Advice and support from physicians and other health professionals are potentially powerful influences on tobacco cessation. According to the U.S. Surgeon General, tobacco use is one of the most important public health issues of our time. The National Cancer Institute, which is the primary federal agency for tobacco control, states that the keys to patient awareness and education about tobacco cessation in a clinical setting are:

   ASK about tobacco use at every visit

   ADVISE all users to stop

   ASSESS users' willingness to make a quit attempt

   ASSIST users' efforts to quit

   ARRANGE follow-up

   Reinforcement of tobacco cessation and follow-up for patients with COPD are extremely important. Pharmacotherapy, social support, and skills training/problem solving are the key treatments for tobacco cessation. Nicotine patches, nasal sprays, inhalers, and oral medication are all available to help patients achieve cessation.

   For more information about tobacco cessation, please refer to the National Guideline Clearinghouse (NGC) summary of the Institute for Clinical Systems Improvement (ICSI) Tobacco Use Prevention and Cessation for Adults and Mature Adolescents guideline and the U.S. Department of Health and Human Services Clinical Practice Guideline, "Treating Tobacco Use and Dependence."

   Evidence supporting this recommendation is of classes: A, R

3. Establish Diagnosis of COPD

   Key Points:

   The American Thoracic Society (ATS) defines COPD as follows:

   • COPD is a disease characterized by the presence of airflow obstruction due to chronic bronchitis or emphysema; the airflow obstruction is generally progressive, may be accompanied by airway hyperreactivity, and may be partially reversible.
   • Chronic bronchitis is defined as the presence of chronic productive cough for three months in each of two successive years in a patient in whom other causes of chronic cough have been 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.

   The diagnosis of COPD should be suspected based on the patient's medical history and physical examination, but requires spirometry to determine the degree of airflow limitation.

   Signs/symptoms for which COPD may be suspected:

   • Wheezing, prolonged expiratory phase of respiration, rhonchi, and cough
   • Dyspnea (exertional or at rest)
   • Chronic sputum production
   • Hyperinflation of the chest with increased anterior-posterior (A-P) diameter
   • Use of accessory muscles of respiration
   • Pursed-lip breathing
   • Signs of cor pulmonale:
     • Increased pulmonic component of the second heart sound
     • Neck vein distention
     • Lower extremity edema
     • Hepatomegaly

       Note: Finger clubbing is not characteristic of COPD and should alert the clinician to another condition such as idiopathic pulmonary fibrosis (IPF), cystic fibrosis, lung cancer, or asbestosis.

   Airflow obstruction is measured by spirometry and shows a reduced forced expiratory volume in one second (FEV₁) and FEV₁/FVC (forced vital capacity) ratio. Measuring pre-and post-bronchodilator spirometry is important to identify those patients with partial reversibility of airflow obstruction. Partial reversibility is defined as improvement in airflow by 12% of baseline and 200 mL after administration of a bronchodilator.

   • Spirometry

     Spirometry is an established and important method of measuring lung function for the diagnosis and management of patients with COPD. It is recommended for symptomatic patients at risk of COPD, particularly smokers greater than 45 years of age, and for regular follow-up of patients with documented COPD.

     Pre and Post-bronchodilator Forced Expiratory Volume in One Second (FEV₁)

     It is important to distinguish COPD from asthma, because treatment and prognosis differ. Measurement of pre and post-bronchodilator FEV₁ can assist with this differentiation. In asthma, the spirometric abnormality tends to return to normal with bronchodilators, although this distinction between COPD and asthma is not strictly rigid. Factors commonly used to distinguish COPD from asthma include age of onset, smoking history, triggering factors, and occupational history.

     If the quality of available spirometry is questionable, then formal spirometry in a pulmonary function test (PFT) lab should be considered. Full PFTs with lung volumes and Diffusion Capacity (DLCO) are neither recommended nor necessary to establish diagnosis or severity of COPD.

     Spirometry, interpretation strategies, selection of reference values, and quality control should be performed in compliance with the Standards on Spirometry published by the American Thoracic Society (ATS) and with the ATS Statement on Standardization of Spirometry 1994 update. Refer to the original guideline document for additional details.

     Although peak flow meters should not be used to diagnose or monitor COPD, monitoring of peak expiratory flow (PEF) at home and at work can be used in certain situations to determine reversibility of and variability in airway obstruction.

     Evidence supporting this recommendation is of class: R

   • Chest Radiograph

     A chest radiograph is recommended at the time of diagnosis to exclude other causes. The chest radiograph in COPD is often normal but may show signs of hyperinflation, a flattened diaphragm, or bullae.

   • Bronchitis and Emphysema

     The airflow obstruction in COPD may be due to chronic bronchitis or emphysema. Chronic bronchitis is defined as the presence of a chronic productive cough for three months in each of two successive years in a patient in whom other causes of chronic cough have been excluded.

     Emphysema is defined as an abnormal permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls, without obvious fibrosis. Radiographically, bullae may be visible on a chest computerized tomography scan or occasionally on a chest radiograph. Clinically, emphysema typically presents with a non-productive or minimally-productive cough and progressive dyspnea. Since both chronic bronchitis and emphysema result in airflow limitation, management goals are similar.

   • Differential Diagnosis

     In addition to asthma, possible differential diagnoses for COPD include bronchiectasis, cystic fibrosis, obliterative bronchiolitis, congestive heart failure, and upper airway lesions.

     For more information on diagnosis and treatment of asthma, please refer to the NGC summary of the ICSI guideline Diagnosis and Management of Asthma.

   For definition of COPD from other guidelines, recommended tools for diagnosis of COPD from other guidelines, and reversibility testing (measurement of pre- and post-bronchial dilator) refer to the original guideline document.

4. Acute Exacerbation?

   Signs and symptoms of an acute exacerbation of COPD may include any of the following:

   • Increased dyspnea
   • Increased heart rate
   • Increased cough
   • Increased sputum production
   • Change in sputum color or character
   • Use of accessory muscles of respiration
   • Peripheral edema
   • Development or increase in wheeze
   • Change in mental status
   • Fatigue
   • Fever
   • Increased respiratory rate
   • Decrease in FEV₁ or peak expiratory flow
   • Hypoxemia
   • Chest tightness

   Change in mental status or a combination of two or more of the following new symptoms indicates a severe acute exacerbation:

   • Dyspnea at rest
   • Respiratory rate of greater than 25 breaths per minute
   • Heart rate of greater than 110 beats per minute
   • Use of accessory muscles of respiration

5. Evaluation

   When a patient with known COPD presents with a moderate to severe acute exacerbation, the following key elements of the history, physical examination, and laboratory/radiology evaluation should be considered:

   History

   • Baseline respiratory status
   • Present treatment regimen and recent medication use
   • Signs of airway infection (e.g., fever and/or change in volume and/or color of sputum)
   • Duration of worsening symptoms
   • Limitation of activities
   • History of previous exacerbations
   • Increased cough
   • Decrease in exercise tolerance
   • Chest tightness
   • Change in alertness
   • Other non-specific symptoms including malaise, difficulty sleeping, and fatigue
   • Symptoms associated with comorbid acute and chronic conditions
   • Although rarely used, non-selective beta-blockers may contribute to bronchospasms

   Physical Examination

   • Measurement of heart rate and blood pressure
   • Measurement of respiratory rate
   • Measurement of pulse oximetry
   • Measurement of temperature
   • Respiratory distress
   • Accessory respiratory muscle use
   • Increased pulmonary findings (e.g., wheezing, decreased air entry, prolonged expiratory phase, etc.)
   • Peripheral edema
   • Somnolence and/or hyperactivity
   • Acute comorbid conditions

   Laboratory/Radiology

   • Chest x-ray (in patients with suspected pneumonia)
   • Arterial blood gases (ABG) (if O₂ saturation less than 88%, positive history of hypercapnia, questionable accuracy of oximetry, somnolence, or other evidence of impending respiratory failure [e.g., respiratory rate greater than 40 breaths per minute])
   • Theophylline level (if theophylline is being utilized)
   • White blood count (WBC) (in patients with suspected severe respiratory infection)
   • A sputum culture and antibiogram, if available, should be performed when an infectious exacerbation does not respond to initial antibiotic treatment. It is important that the sputum specimen is of good quality
   • Brain Natriuretic Peptide (BNP), a simple blood lab test, can be of some use in evaluating a patient presenting with dyspnea, although its interpretation needs to be carefully applied along with clinical and other lab data such as chest x-ray and echocardiogram. Its sensitivity and specificity in this setting increase at levels above 400 but do not differentiate between acute left ventricular (LV) failure, cor pulmonale or pulmonary embolism. It is of particular value if the level is very low. The probability of LV failure as a cause of dyspnea is less than 10% if the BNP is less than 100.

   In patients with an acute COPD exacerbation, spirometry is of little value. For that reason, oximetry and/or ABG should be monitored.

   There is little evidence regarding the contribution of additional laboratory testing or the usefulness of electrocardiography or echocardiography in an acute exacerbation of COPD. They may be a useful consideration if the diagnosis is unclear, in order to evaluate other comorbid conditions.

   Evidence supporting this recommendation is of class: B, M, R

6. Treatment

   Key Points:

   • Albuterol is the preferred bronchodilator in the setting of an acute exacerbation of COPD because of its rapid onset of action.
   • Ipratropium may be added to produce additive bronchodilation and allow the use of lower doses of albuterol.
   • Steroids should be used in acute exacerbations.
   • It is mandatory to check oxygen saturation or ABG measurement.

   Bronchodilators

   Albuterol is the preferred bronchodilator in the setting of an acute exacerbation of COPD because of its rapid onset of action. Serial administration is indicated until either relief of symptoms and improvement in signs of respiratory failure is achieved, or side effects of tachycardia and/or tremor develop. If clinical improvement does not occur before side effects develop, ipratropium may be added to produce additive bronchodilation and allow the use of lower doses of albuterol, thus diminishing dose-dependent toxicity. However, no study has examined the benefit of using both agents concurrently. Administration of either agent by metered dose inhaler (MDI) with a spacer or by nebulization is acceptable, though the patient may be too dyspneic to retain a MDI puff effectively, or severe coughing may prevent effective employment. In such cases, nebulization is necessary and arrangement for home use should be made.

   Evidence supporting this recommendation is of classes: A, M

   Role of Levalbuterol (Xopenex®) in COPD

   There are many theoretical advantages of levalbuterol over albuterol in the treatment of bronchospasm. Albuterol is a racemic combination of two isomers: the "R" isomer (levalbuterol) that is a potent bronchodilator, and the "S" isomer that has been shown in animal studies to counteract bronchodilation and can promote inflammation. Unfortunately, clinical studies in human subjects with bronchospasm have not consistently shown greater bronchodilation or fewer side effects of levalbuterol over equivalent doses of a racemic agent such as albuterol. In individual patients with COPD and acute bronchospasm, who demonstrate excessive tachycardia and/or tremor, ipratropium is the next bronchodilator of choice. Levalbuterol may be an acceptable alternative as a trial agent, especially in patients whose bronchospasm worsens or shows no improvement on ipratropium.

   Evidence supporting this recommendation is of classes: C, R

   Steroids

   Studies have shown benefits of systemic steroids in the outpatient management of COPD exacerbation. Doses of oral prednisone 30 to 60 mg per day should be used for 10 to 14 days. If longer durations are needed, consider a tapering schedule. There is no need to discontinue inhaled steroids while the patient is taking oral prednisone. In fact, the inhaled steroid may serve as a "systemic-steroid-sparing-agent" and the concomitant use may minimize the dose of systemic steroids needed to diminish airway inflammation.

   Evidence supporting this recommendation is of classes: A, R

   Antibiotics

   If the acute exacerbation of COPD is clearly post-viral, antibiotics may not be necessary. In the presence of prolonged illness, especially with purulent sputum, an antibiotic is warranted. The choice of antibiotic is controversial, and needs to be tailored to the individual situation. "First-line agents," such as amoxicillin, trimethoprim/sulfamethoxazole (TMP/SMX), and doxycycline are often effective. If the incidence of resistant organisms is 25% or higher in the community, the use of a "second-line agent" may be preferable. These second-line agents include second-generation cephalosporins, azithromycin, clarithromycin, and amoxicillin/clavulanate.

   Oxygen Saturation/ABG Measurement

   Oxymetric evaluation of patients with COPD exacerbations is mandatory. Patients with O₂ saturations of 80% to 90% on room air can be titrated with supplemental O₂ to a saturation level of 90% with little concern of significant hypercarbia, unless such intervention results in somnolence. In such cases, or if the O₂ saturation is less than 80% upon presentation, an ABG should be obtained. If the pH is less than 7.32, admission to the hospital should be arranged because of the risk of acute respiratory failure. If outpatient management has been decided upon, the patient should be ambulated to determine what O₂ flow is needed to maintain O₂ saturations at 90% while walking. Home O₂ then needs to be arranged.

   Evidence supporting this recommendation is of classes: D

7. Positive Response to Treatment?

   The following criteria may be used as evidence of improvement in COPD exacerbation:

   • Decrease in cough, sputum production, fever, or dyspnea
   • Decrease in respiratory rate
   • Decrease in heart rate
   • Decrease in accessory muscle use
   • Increase in function and endurance

8. Arrange for Follow-Up

   A follow-up appointment between the primary care clinician and the patient should occur within one to four weeks to reassess management strategies and supplemental oxygen needs.

9. Admit to Hospital – Out of Guideline

   The following may be indications to consider hospital admission for an acute exacerbation of COPD:

   • Marked increase in intensity of symptoms, such as sudden development of resting dyspnea
   • History of severe COPD, especially if mechanical ventilation was required
   • Onset of new physical signs (e.g., cyanosis, peripheral edema)
   • Failure of exacerbation to respond to initial outpatient medical management
   • High risk comorbidities, pulmonary (e.g., pneumonia requiring hospitalization) or cardiac symptoms
   • Increasing hypoxemia despite supplemental oxygen
   • New or worsening CO₂ retention or Ph less than 7.32
   • Marked decrease in ability to ambulate, eat, or sleep due to dyspnea
   • History of prolonged, progressive symptoms
   • Newly occurring arrhythmias
   • Diagnostic uncertainty
   • Older age
   • Insufficient home support
   • Decrease in alertness

   Evidence supporting this recommendation is of class: M

10. Establish Severity of Stable COPD

    Key Points:

    • Both spirometry and/or signs and symptoms are used to establish severity.

    The signs, symptoms, and airflow limitation in COPD vary with the severity of the disease. The severity of COPD may be categorized according to the following table:

    Category of COPD	FEV1 (% predicted)	Typical Symptoms and Signs
    Mild	80 or greater	No abnormal signs Cough (+ sputum) Little or no dyspnea
    Moderate	Between 80 and 50	Breathlessness (+ wheeze on moderate exertion) Cough (+ sputum) Variable abnormal signs (general reduction in breath sounds, presence of wheezes) Hypoxemia may be present
    Severe	30 to 50	Dyspnea with any exertion or at rest Wheeze and cough often prominent Lung hyperinflation usual; cyanosis, peripheral edema and polycythemia in advanced disease Hypoxemia and hypercapnia are common
    Very Severe	Less than 30

    Adapted from the National Heart, Lung and Blood Institute/World Health Organization (NHLBI/WHO) Global Initiative for Chronic Obstructive Lung Disease workshop summary.

    Evidence supporting this recommendation is of class: R

11. Step-Care - Pharmacologic Approach for Managing Stable COPD

    Key Points:

    • Drug therapy is determined by severity of symptoms.

    Each step in the Table below represents an intervention that should be considered only if the previous course of action fails to improve symptoms of COPD. Step 1 is an intervention that is generally associated with mild COPD. Step 2 is associated with moderate COPD. Steps 3 and 4 are associated with severe and very severe COPD.

    A table of estimated comparative daily dosages for inhaled corticosteroids appears in Appendix A, "Estimated Comparative Daily Dosage for Inhaled Corticosteroids" in the original guideline document.

    Step-Care Pharmacologic Treatment of COPD

    Step	Pharmaceutical Intervention	Dosing Information and Comments
    1 Consider Step 2 if symptoms persist	Inhaled short-acting bronchodilator	Short-acting beta agonist (albuterol is preferred) 2 to 4 puffs, as needed (every 4 to 6 hours) See Annotation #11 in the original guideline document
    2	Continue as needed (PRN) inhaled short-acting bronchodilator PLUS scheduled dosing of one of the following:
    Consider Step 3 if symptoms persist	Tiotropium (Spiriva®) Salmeterol* (Serevent® Discus) Formoterol* (Foradil®) Albuterol (Proventil®, Ventolin®) Ipratropium (Atrovent®) Albuterol + Ipratropium (Combivent®) Levalbuterol (Xopenex®)	One capsule (inhaled) daily 1 puff twice daily 1 puff (12 micrograms) twice daily 2 to 4 puffs, 4 times a day 2 to 4 puffs, 4 times a day 2 to 4 puffs, 4 times a day 0.63 to 1.25 mg every 6 to 8 hours via nebulizer 2 puffs every 4 to 6 hours
    3 Consider Step 4 if symptoms persist	Continue therapy specified in Step 2 and perform corticosteroid trial Assess symptoms before and after trial period, especially cough and sputum production. Also measure post-bronchodilator FEV1 6-minute walk before and after trial	Prednisone oral 30 to 40 mg/day for 2 to 4 weeks or inhaled corticosteroid (see Appendix A in the original guideline document) at less than 2,000 micrograms for 6 to 8 weeks/day or dose equivalent of another inhaled steroid for 6 to 8 weeks (Approximately 15% of patients who undergo a corticosteroid trial will have improved symptoms and post-bronchodilator FEV1)
    *Tiotropium is the preferred scheduled bronchodilator.

     

    Step 4: Response After Step 3
    Positive Response: greater than or equal to 15% improvement in post-bronchodilator FEV1, symptoms, improvement in 6-minute walk Pharmaceutical Intervention: Taper off or discontinue oral corticosteroids and prescribe or continue inhaled corticosteroids.	Negative Response: less than 15% improvement in post-bronchodilator FEV1 or no improvement in symptoms Pharmaceutical Intervention: Discontinue corticosteroids and consider theophylline as adjunctive therapy with inhaled bronchodilators (beta2-agonists and/or anti-cholinergic)

    Bronchodilator Medications

    Summary

    Albuterol is the preferred agent for as needed control of symptoms in patients with mild COPD and as an additive as needed agent to a scheduled bronchodilator in patients with more severe COPD because the onset of bronchodilator effect (15 minutes) is more rapid than ipratropium (30–90 minutes).

    Tiotropium has been shown to be a superior scheduled bronchodilator to salmeterol and ipratropium.

    As a scheduled bronchodilator, salmeterol has the main advantage of requiring only twice-daily dosing, and therefore may improve compliance.

    Albuterol and ipratropium are equipotent as bronchodilators, improving dyspnea and exercise tolerance equally well. Salmeterol is a long-acting bronchodilator which is a suitable agent for scheduled administration. [Conclusion Grade II: See Conclusion Grading Worksheet A - Annotation #11 (Pharmacological Management) in the original guideline document]

    Supporting evidence is of classes: A, R

    Refer to the original guideline document for additional information on bronchodilator medications and systemic and inhaled corticosteroids.

    Methods of Drug Delivery

    Metered Dose Inhaler (MDI) with Spacer

    Some studies support the use of spacers to obtain effective MDI drug delivery. The increased distance slows the velocity of the fine particles, increasing their chances of reaching the bronchial tree. It is of utmost importance to train and retrain patients, nurses, physicians, and pharmacists in the proper inhaler technique for optimal drug delivery. Evidence of the effectiveness of one type of spacer over another is variable and controversial.

    Chlorofluorocarbons (CFCs) are freon compounds commonly used as propellants in commercial aerosols including MDIs. Concerns have been raised about the toxicity of freon and its role in depleting the ozone layer. The production of ozone-depleting substances is being phased out worldwide under terms of an international agreement. Since most MDIs in the U.S. contain CFCs as propellants, they will eventually need to be reformulated.

    MDIs that use CFCs as a propellant will not be removed until sufficient alternatives exist to serve patient needs. The Food and Drug Administration (FDA) is developing strategies to ensure that patients in the U.S. who rely on MDIs to maintain their health will have continued access to an array of safe and effective treatment options.

    Non-freon alternatives include hydrofluorocarbons (HFAs). These non-freon formations are well-tolerated and equally efficacious when compared with compounds containing freon.

    Dry Powder Inhaler (DPI)

    DPIs are an alternative to MDIs that are strongly supported by study data. DPIs deliver drugs in dry-powder form without the use of propellants. In addition, DPIs are breath-activated, eliminating the need to synchronize inhalation with actuation.

    DPIs have been developed as a response to concerns about freon toxicity. Newer DPI products deliver pure drug from self-enclosed, multiple-dose devices that help avoid the potential adverse effects of additives used in MDIs.

    Refer to Table III in the original guideline document for information on contrasting features of conventional pressurized MDI and DPI.

    Nebulizers

    Aerosol particle diameters range from 1 to 5 micrometers in small volume nebulizer (SVN) which are comparable with MDI or DPI. Studies have shown no difference in the efficacy of the delivery methods. Reports suggest that between 47% and 89% of adults may have unacceptable inhaler technique. Clinical situations in which nebulized therapy is preferable to either MDI or DPI include:

    • Patients incapable of performing MDI or DPI maneuver
    • Adults who have a vital capacity less than 1.5 times their predicted tidal volume (7 mL/kg)

    Aerosol therapy via nebulizer is generally considered expensive, inconvenient, and inefficient. Nebulizer therapy should be considered a second choice when compared with other modes of aerosol delivery (e.g., MDIs and DPIs).

    Refer to Table IV in the original guideline document for comparison of nebulizers and MDIs.

    Theophylline

    Theophylline has a narrow therapeutic index with potentially significant adverse effects and drug interactions that must be carefully considered and closely monitored during therapy.

    Refer to the original guideline document for additional information on theophylline.

    Evidence supporting this recommendation is of classes: D, R

12. Other Pharmacologic Treatment

    Antibiotics

    The routine use of antibiotics is not recommended except for treatment of bacterial exacerbations of COPD.

    Antitussives

    Regular use of antitussives is not recommended in COPD since cough can have a significant protective effect.

    Antiviral Agents

    Treatments other than vaccination are available to treat influenza, but are not a substitute for vaccination unless it is contraindicated. Amantadine (Symmetrel®) and rimantadine (Flumadine®) are indicated for symptomatic treatment and prophylaxis of influenza A, which is more prevalent and more severe than influenza B. If started within the first 48 hours of symptom onset, amantadine and rimantadine may reduce the duration and symptoms by 50%.

    Zanamivir (Relenza®) and oseltamivir (Tamiflu®) are also available. Zanamivir must be inhaled whereas oseltamivir is available orally. Zanamivir and oseltamivir may be considered for treatment if there is an outbreak of influenza B. These medications are, however, very costly relative to their benefits.

    A consumer information report from the Food and Drug Administration (FDA) regarding Relenza® and chronic lung disease issued in October, 2000, included a caution that "some patients have had bronchospasm (wheezing) or serious breathing problems when they used Relenza®. Many, but not all, of these patients had previous asthma or chronic obstructive pulmonary disease. Relenza® has not been shown to shorten the duration of influenza in people with these diseases. Because of the risk of side effects, and because it has not been shown to help them, Relenza® is not generally recommended for people with chronic respiratory disease such as asthma or chronic obstructive pulmonary disease."

    Refer to the original guideline document for information on costs of antiviral agents.

    Leukotriene Modifiers

    This drug class has not been adequately tested in COPD patients and cannot be recommended until additional evidence relative to its efficacy is available.

    Mucolytics

    In theory, reducing mucus viscosity and enhancing cough clearance or mucociliary clearance of mucus could improve pulmonary function and reduce the incidence of respiratory infections in individuals with COPD. Ideally, treatment would result in both objective (increase in FEV₁) and subjective (better sense of well-being) improvement for those individuals.

    To date, there has been no conclusive evidence for significant improvement in pulmonary function with any of the agents studied so far. Guaifenesin is widely used as an over-the-counter expectorant but documented objective or even subjective improvement has not been consistently demonstrated. Iodinated glycerol was once thought to promote a decrease in symptoms and overall improvement in subjects with COPD, but this result could not be confirmed in subsequent investigations.

    Some evidence for improvement in subjects with chronic bronchitis is present using other agents including inhaled surfactant, amiloride, hypertonic saline, N-acetylcysteine, and acetylcysteine, but for now is not substantial enough to be conclusive. Albuterol may have some effect in improving mucociliary clearance, which may add to its utility as a bronchodilator.

    Evidence supporting this recommendation is of classes: A, C, R

    Oral Beta Agonists

    Inhaled bronchodilator therapy is preferred.

    Vaccines

    Influenza and pneumococcal pneumonia together are the sixth leading cause of death in the U.S. among persons 65 years of age and older. Immunization with pneumococcal and influenza vaccines are recommended by the U.S. Public Health Service's Advisory Committee on Immunization Practices to reduce infectious complications involving the respiratory tract.

    Pneumococcal

    The American Thoracic Society and the U.S. Public Health Service's Advisory Committee on Immunization Practices (ACIP) recommend pneumococcal vaccine for all COPD patients. Pneumococcal vaccination is generally good for life, but revaccination may provide additional protection in certain groups. The risks of revaccination are minimal, and the ACIP recommends revaccination once for COPD patients if at least five years have passed since receipt of the previous dose. Immunize at age 65 if not done previously. Refer to the NGC summary of the ICSI guideline Immunizations for adults.

    Influenza

    Influenza vaccine should be provided on an annual basis because of new antigens and waning immunity from the previous year. The optimal time for influenza vaccination is usually from early October through mid-November. To avoid a missed opportunity, vaccination can be done as soon as vaccine is available, but not prior to September. Vaccine may be given even after flu activity is known to be occurring in the community.

    Evidence supporting this recommendation is of class: R

13. Non-Pharmacologic Treatment Applicable to All Levels of Severity

    Key Points:

    • Treatment of COPD should also include an education plan suited to the patient's specific needs along with encouragement of exercise.
    • Pulmonary rehabilitation programs are effective in improving exercise capacity, quality of life, and perception of symptoms.

    • Encourage Exercise

      Regular exercise has been shown to reduce symptoms of COPD and improve the quality of life in patients with COPD. See "Pulmonary Rehabilitation Program for Moderate to Severe Disease" below. For patients who do not have access to a pulmonary rehab program, it is reasonable to prescribe a regular exercise schedule.

    • Education

      Patient education for those with COPD may be complex. Education methods aimed at continuous improvement should be incorporated into educational strategies that take the long-term relationships between patients and health care professionals into account.

      Refer to the original guideline document for presentation of a Patient Education Model. The model presents core learning needs and objectives along with some examples of tools to assist individual clinicians in designing a patient education plan. This model is based on the Transtheoretical Change Model (Prochaska Model), which emphasizes recognition of patients' stages of readiness to incorporate educational messages into long-term behavior change.

    Evidence supporting this recommendation is of classes: A, C, D, M, R, X

    Pulmonary Rehabilitation Program for Moderate to Severe Disease

    The primary goal of pulmonary rehabilitation is to decrease respiratory symptoms and improve quality of life. Pulmonary rehabilitation, with a multidisciplinary approach including education and exercise training, should be considered for COPD patients who have functional limitations that affect their quality of life, have maximized on standard medical therapy, and are not limited by other serious or unstable medical conditions. For willing patients who are able to learn about their disease and are motivated to participate in a comprehensive rehabilitation program, selecting a program that emphasizes regular in-home exercise verified by an exercise log is strongly recommended. Long-term benefits from programs after completion have not been demonstrated except for home-based exercise programs. A summary of structures and services in pulmonary rehabilitation is attached in Appendix C "Summary of Structure and Services - Pulmonary Rehabilitation Program" of the original guideline document.

    Studies of pulmonary rehabilitation programs for patients with COPD, including an ICSI Technology Assessment, found the following:

    Pulmonary rehabilitation programs standardly available in the United States are effective in improving exercise capacity, quality of life, and perception of symptoms but only for the duration of the program, typically 8–12 weeks. Deterioration toward baseline after completion of the program can be routinely expected, unless the patient continues to participate in an exercise program. Pulmonary function measurements are not beneficially affected.

    Pulmonary rehabilitation programs are generally safe for COPD patients.

    There is evidence that a long term, structured exercise program can provide benefit for up to 18 months.

    Supervised follow-up may be helpful in maintaining improvements although more studies are needed.

    A multi-disciplinary approach, including exercise, maximizes the benefits of a pulmonary rehabilitation program when compared to a limited program focusing on education alone.

    There is a need for additional research to clarify questions related to patient selection, program components (including contents, duration, intensity, and site), and long-term effects. In addition, there is a need to validate and standardize the outcome variables used to assess change.

    Please refer to the ICSI Technology Assessment Report, Pulmonary Rehabilitation for Chronic Obstructive Pulmonary Disease, #32 for full discussion.

    Evidence supporting this recommendation is of classes: A, C, M, R

14. Assess for Hypoxemia and Hypercapnia and Treat if Indicated

    Key Points:

    • Assess for hypoxemia and consider assessment for hypercapnia.

    Hypoxemia

    The evaluation of gas exchange status by ABG measurement is recommended for initiation of oxygen therapy as well as to determine PCO₂ and acid-base status. Assessment for long-term oxygen needs by arterial blood gas analysis should be considered for stable outpatients with:

    1. Severe airflow obstruction
    2. Symptomatic dyspnea with polycythemia, pulmonary hypertension (by electrocardiogram or echo), or altered mental status
    3. Problematic heart failure
    4. Severe symptoms out of proportion to the degree of airway obstruction

    Pulse oximetry cannot determine acid-base status and is not considered sufficiently accurate to replace ABG (available) measurement in an initial assessment. ABG measurement can be used to confirm the accuracy of pulse oximetry at rest and with exercise when oximetry is less reliable.

    Evidence supporting this recommendation is of classes: A, C

    Nocturnal Hypoxia

    During sleep, even in individuals without COPD, minute ventilation decreases. In patients with COPD whose O₂ saturation is already low or borderline, this hypoventilation results in hypoxia, which can exacerbate or precipitate pulmonary hypertension. Sleep disruption from hypoxia or sleep apnea can induce daytime hypersomnolence and may worsen symptoms of COPD.

    Risk factors for hypoxia during sleep:

    • Severe COPD, especially with resting oxygen saturation less than 88% or exercise-induced hypoxia
    • Evidence of cor pulmonale
    • Daytime hypersomnolence in the absence of sleep deprivation
    • Polycythemia

    Evidence supporting this recommendation is of classes: A, C, D

    Screening for Nocturnal Hypoxia

    Screening for nocturnal hypoxia can be done easily and inexpensively with overnight pulse oximetry in the home. The oximeter is returned to the clinic, where the overnight oximetry and heart rate data are downloaded. If a significant portion of the night's data indicates oxygen saturations below 88%, supplemental oxygen should be provided empirically at 1 to 2 L/min. Home oximetry can be repeated at that level to verify correction of hypoxia.

    The patient should be referred to a sleep specialist to rule out sleep-related disordered breathing if additional abnormalities are present.

    Evidence supporting these recommendations is of class: C

    Hypercapnia

    In an ambulatory, stable patient with COPD, assessment for hypercapnia by ABGs should be considered in the following circumstances:

    • Clinical suspicion of hypercapnia (asterixis, headache, hypersomnolence, altered mental status)
    • FEV₁ less than 1.0
    • Upon initiation of oxygen
    • Morbid obesity
    • Excessive daytime somnolence
    • Problematic right heart failure/cor pulmonale
    • Severe airflow obstruction

    Carbon dioxide (CO₂) retention may pose a threat in patients with impaired CO₂ ventilatory drive. Careful titration of supplemental oxygen should be performed in these patients. A pH drop along with a rise in PaCO₂ with initiation of oxygen therapy or an increase in inspired oxygen concentration is usually well tolerated in the ambulatory stable patient with COPD. If hypercapnia results in a decrease in mental status, the patient may need admission to a hospital for more intensive respiratory care and monitoring.

    In the unstable patient with resting hypercapnia, initiation of supplemental oxygen should be titrated upward, as there is a small risk of worsening CO₂ retention. Reassessment by ABG and clinical status looking for signs/symptoms of hypercapnia is suggested 30 minutes after initiation of oxygen.

    Hypercapnia does not require specific therapy, but instead, therapeutic intervention should be directed at correcting the hypoxemia. Nonetheless, a pH drop along with a rise in PaCO₂ with initiation of oxygen therapy, or an increase in inspired oxygen concentration is usually well tolerated in the ambulatory stable COPD patient. If hypercapnia results in a decrease in mental status, the patient may need admission to a hospital for more intensive respiratory care.

    These recommendations are further clarified in the NGC summary of the ICSI guideline Diagnosis and Treatment of Obstructive Sleep Apnea.

    Evidence supporting this recommendation is of classes: C, R

    Oxygen Therapy

    Important Points

    • Long-term oxygen therapy (more than 15 hours per day) improves survival and quality of life in hypoxemic patients.
    • ABG measurement is recommended for initiation of oxygen therapy as well as to determine PCO₂ and acid-base status.
    • Pulse oximetry is a good method for monitoring oxygen saturation and can be used in adjusting the oxygen flow setting.
    • Indications for long-term oxygen therapy have been adopted by Medicare as reimbursement criteria. (Appendix B in the original guideline document contains a summary of Medicare Oxygen Coverage Guidelines.)
    • Patients considered for long-term therapy may benefit from assessment by a pulmonologist.
    • Supplemental long-term oxygen therapy should be provided at a flow rate sufficient to produce a resting P_aO₂ of greater than 55 mm Hg, or S_aO₂ greater than 89%.
    • Titrate liter-flow to goal at rest: add 1 L/min during exercise or sleep or titrate during exercise to goal of S_aO₂ greater than 89%. Titrate sleep liter-flow to eight-hour sleep of S_aO₂ greater than 89%.
    • Consider referral for sleep evaluation if patient experiences cyclic desaturation during sleep but is normoxemic at rest.
    • Recheck S_aO₂ or P_aO₂ in one to three months if hypoxia developed during an acute exacerbation. Rechecks should be performed annually if hypoxia is discovered in an outpatient with stable COPD.

    Oxygen Delivery Methods

    The dual-prong nasal cannula is the standard means of continuous flow oxygen delivery for the stable COPD patient with hypoxemia. It is not only well-tolerated, but is also simple and reliable. Care must be taken when assigning an estimated FiO₂ to patients as this low-flow system can have great fluctuations.

    Reservoir cannulas, demand pulse delivery devices, and transtracheal oxygen delivery are oxygen-conserving devices that can improve the portability of oxygen therapy, reduce the overall costs of home oxygen therapy, especially in patients requiring higher flow rates, and can more effectively treat refractory hypoxemia. These devices function by delivering all of the oxygen during early inhalation. They reduce oxygen requirements by 25 to 75% compared to continuous flow oxygen. Disadvantages of these devices are that they are bulky on the face, mechanically more complicated, and require additional care as well as additional training of the user.

    Evidence supporting this recommendation is of classes: C, D, M

    COPD and Air Travel

    Airline travel is safe for most patients with COPD. Hypoxemic patients should be evaluated clinically, and a decision should be made regarding oxygen requirements. Patients with COPD receiving continuous oxygen at home will require supplementation during flight. A doctor's order is required for patients who need supplemental oxygen during air travel. Special arrangements with oxygen or equipment suppliers and the airline must be made at least 48 hours prior to departure. Patients should check with airlines for restrictions and special arrangements that apply.

    Evidence supporting this recommendation is of class: D

    Use of Supplemental O₂ for Patients with COPD and Not Currently on Supplemental O₂

    Regression equations have been validated which predict pO₂ at usual atmospheric pressures in aircraft. These predict that patients with FEV₁ less than 80% and pO₂ less than 80 will have in-flight pO₂ less than 55% and therefore should be prescribed supplemental O₂ at 2 L/M (liters/minute). Patients with underlying cardiovascular or cerebrovascular disease should be prescribed O₂ if their FEV₁ and pO₂ are even higher.

    Evidence supporting this recommendation is of classes: D, R

15. Long-Term Management

    Key Points:

    • Obtaining the opinion of a pulmonary specialist may be beneficial at any stage of the disease.
    • For patients with severe symptoms, despite maximal medical therapy, lung volume reduction surgery and transplantation may be an option. Referral to a pulmonologist should be made to evaluate candidacy.
    • Physicians are encouraged to initiate and facilitate conversations about living wills and durable power of attorney for health care.

    Schedule Regular Follow-Up Visits

    Follow-up visits should be jointly established between primary care physicians and pulmonary specialists, and should be tailored to the learning stage and comorbidities of individual patients.

    The exact frequency of clinician visits is a matter of clinical judgment; however, the following may serve as a general guide for patients with stable COPD.

    Mild Severity: Follow-up yearly

    Moderate Severity: Follow-up 3 to 6 months

    Severe: Follow-up two to four months or more frequently as needed

    Evaluation and Monitoring of Comorbidities

    In treating patients with COPD, it is important to consider the presence of concomitant conditions such as bronchial carcinoma, tuberculosis, sleep apnea, depression, osteoporosis, and heart failure. The appropriate diagnostic tools (chest radiograph, electrocardiogram, etc.) and referral to clinical specialists should be used whenever symptoms (e.g., hemoptysis) suggest one of these conditions.

    Refer to Pulmonary Specialist

    Obtaining the opinion of a pulmonary specialist may be beneficial at any stage of the disease. Referral may be indicated to confirm the diagnosis, facilitate tobacco cessation, and optimize appropriate treatment.

    Referral may be indicated:

    • For patients under age 40 years or with a family history of emphysema or alpha₁-antitrypsin deficiency in order to identify the deficiency and treat and screen family members
    • To confirm diagnosis, rule out other etiologies, symptoms and complexities, and to optimize treatment
    • If symptoms are not consistent with the lung function deficit as measured by pulmonary function tests
    • For patient with frequent infections and/or possible bronchiectasis
    • For assessment of long-term treatment with oral corticosteroids if results of steroid trial are unclear
    • To identify and assess patients for possible lung volume reduction surgery or lung transplantation
    • For patients with rapid decline in FEV₁ to optimize early intervention
    • For patients with smoking history of less than 10 pack-years to exclude/confirm diagnosis
    • For patients with frequent exacerbations
    • For patients who have been hospitalized for COPD

    Surgical Options for Severe Disease

    Lung Volume Reduction Surgery for Emphysema

    The goal of lung volume reduction surgery (LVRS) is to relieve disabling dyspnea in patients in whom emphysema has limited activities of daily living and has proved refractory to optimal medical management. Following surgery, improvement has been noted in lung elastic recoil, respiratory function, ventilation/perfusion matching, and cardiovascular function. A variety of surgical approaches and reduction techniques have been used. Results of the National Emphysema Treatment Trial (NETT) have been published.

    1. Overall, LVRS did not demonstrate a survival advantage over medical therapy. LVRS only yielded a survival advantage for patients with upper lobe emphysema and low baseline exercise capacity. LVRS demonstrated increased mortality and no functional improvement for patients with non-upper lobe emphysema.
    2. LVRS only showed improvement in exercise capacity among a small subgroup of patients: those with upper lobe emphysema. Most patients' improvements returned to baseline after two years.
    3. Significantly more patients with upper lobe emphysema randomized to LVRS had improved quality of life after two years as compared to non-surgical patients.
    4. Due to the strictness of the exclusion criteria, conclusions from the NETT trial cannot be extended to the general population of patients with emphysema.
    5. Pre-operative evaluation includes ability to complete a six-minute walk of over 140 meters, completion of a pulmonary rehabilitation program, full pulmonary function tests, chest computed tomography (CT), echocardiogram, and possibly a right heart catheterization and a radionuclide stress test.
    6. LVRS should only be performed in medical centers with appropriately trained surgeons and availability of necessary equipment.

    Evidence supporting this recommendation is of classes: A, R

    Bullectomy

    Giant bullous emphysema is a rare subset of patients in whom single or multiple large bullae encompass 30% or more of a hemithorax, often displacing potentially functional lung tissue as these large airspaces increase in volume. In appropriate cases, surgical resection of these bullae can restore significant pulmonary function and improve symptoms. CT scan is essential in evaluating these patients and referral to a pulmonary specialist is indicated.

    Evidence supporting this recommendation is of class: D

    Lung Transplantation

    Unilateral or bilateral lung transplantation is a treatment option in highly selected patients with severe COPD. A few studies show improvement in quality of life parameters but no increase of survivability.

    General Selection Guidelines for Candidate Selection for Lung Transplantation in COPD Patients

    Relative Contraindications

    • Age limits:
      • Heart-lung transplants: approximately 55 yrs
      • Double lung transplant: approximately 60 yrs
      • Single lung transplant: approximately 65 yrs
    • Symptomatic osteoporosis
    • Oral corticosteroids greater than 20 mg day–1 prednisone
    • Psychosocial problems
    • Requirement for invasive mechanical ventilation

    Absolute Contraindications

    • Severe musculoskeletal disease affecting the thorax
    • Substance addiction within previous six months
    • Dysfunction of extrathoracic organ, particularly renal dysfunction
    • HIV infection
    • Active malignancy within two years except basal or squamous cell carcinoma of skin
    • Hepatitis B antigen positive
    • Hepatitis C with biopsy-proven evidence of liver disease

    Following the position of the American Thoracic Society and the European Respiratory Society, appropriate candidate selection is as follows:

    • FEV₁ less than or equal to 25% predicted (without reversibility) and/or
    • Resting room air PaCO₂ greater than 55 mm Hg and/or
    • Elevated PaCO₂ with progressive deterioration requiring long-term oxygen therapy
    • Elevated pulmonary arterial pressure with progressive deterioration

    For further information, the guideline developers recommend review of the American Thoracic Society COPD management recommendations at www-test.thoracic.org/COPD/10/surgery_for_copd.asp.

    Evidence supporting this recommendation is of classes: C, R

    Discuss Health Care Directives (Advance Directives) or Living Will and Durable Power of Attorney for Health Care

    Many patients have an interest in discussing living wills but their wishes tend to be passive and unspoken.

    Physicians are encouraged to initiate and facilitate conversations about living wills and durable power of attorney with all COPD patients at routine outpatient visits.

    In patients with severe disease, it is also helpful to discuss specific treatment preferences. Treatment preferences may include home care only, hospitalization for comfort care, initiation of full life support if there is a reasonable chance for recovery to functional independence, or continuation of indefinite life support in a chronic nursing facility.

    Objectives of Discussion

    1. To encourage physicians to discuss health care directives with COPD patients
    2. To give patients control over their end-of-life care decisions
    3. To ensure that patients' wishes will be carried out at the end of their life
    4. To increase the number of COPD patients who have written health care directives
    5. To increase the number of patients with severe COPD who have discussed specific treatment preferences and goals of care
    6. To name a durable power of attorney for health care or an appropriate surrogate decision maker

    Plan for Discussion

    • For the patient with moderate to severe COPD, at a routine office visit, ask the question, "Do you have a living will?"

      Action: If yes, ask what it consists of (especially whether there is a designation of durable power of attorney and who that person is) and request that a copy be placed in the patient's medical record.

      Action: If no, offer the patient written information on health care directives, encourage him/her to fill out a health care directive including designation of power of attorney for health care, and offer to discuss any questions at the next office visit.

    • For the patient with severe COPD, at a routine office visit ask the question, "What are your treatment preferences in regards to hospitalization, life support (including cardiopulmonary resuscitation [CPR], endotracheal intubation and non-invasive ventilation), and end-of-life care?"

      Action: Encourage the patient to discuss these treatment preferences with family or health care surrogate and record them in a health care directive.

      Action: Document the patient's treatment preferences in the patient's medical record and request that a copy of the health care directive be placed in the patient's medical record.

    Evidence supporting this recommendation is of classes: D, R

Definitions:

Conclusion Grades:

Grade I: The evidence consists of results from studies of strong design for answering the question addressed. The results are both clinically important and consistent with minor exceptions at most. The results are free of any significant doubts about generalizability, bias, and flaws in research design. Studies with negative results have sufficiently large samples to have adequate statistical power.

Grade II: The evidence consists of results from studies of strong design for answering the question addressed, but there is some uncertainty attached to the conclusion because of inconsistencies among the results from the studies or because of doubts about generalizability, bias, research design flaws, or adequacy of sample size. Alternatively, the evidence consists solely of results from weaker designs for the question addressed, but the results have been confirmed in separate studies and are consistent with minor exceptions at most.

Grade III: The evidence consists of results from studies of strong design for answering the question addressed, but there is substantial uncertainty attached to the conclusions because of inconsistencies among the results from different studies or because of serious doubts about generalizability, bias, research design flaws, or adequacy of sample size. Alternatively, the evidence consists solely of results from a limited number of studies of weak design for answering the question addressed.

Grade Not Assignable: There is no evidence available that directly supports or refutes the conclusion.

Classes of Research Reports:

1. Primary Reports of New Data Collection:

   Class A:

   • Randomized, controlled trial

   Class B:

   • Cohort study

   Class C:

   • Non-randomized trial with concurrent or historical controls
   • Case-control study
   • Study of sensitivity and specificity of a diagnostic test
   • Population-based descriptive study

   Class D:

   • Cross-sectional study
   • Case series
   • Case report
2. Reports that Synthesize or Reflect upon Collections of Primary Reports:

   Class M:

   • Meta-analysis
   • Systematic review
   • Decision analysis
   • Cost-effectiveness analysis

   Class R:

   • Consensus statement
   • Consensus report
   • Narrative review

   Class X:

   • Medical opinion

A detailed and annotated clinical algorithm is provided for Chronic Obstructive Pulmonary Disease.

ICSI, 8009 34th Avenue South, Suite 1200, Bloomington, MN 55425; telephone, (952) 814-7060; fax, (952) 858-9675; e-mail: icsi.info@icsi.org; Web site: www.icsi.org.

ICSI's conflict of interest policy and procedures are available for review on ICSI's website at www.icsi.org.

Electronic copies: Available from the Institute for Clinical Systems Improvement (ICSI) Web site.

Print copies: Available from ICSI, 8009 34th Avenue South, Suite 1200, Bloomington, MN 55425; telephone, (952) 814-7060; fax, (952) 858-9675; Web site: www.icsi.org; e-mail: icsi.info@icsi.org.

• Chronic obstructive pulmonary disease. Executive summary. Bloomington (MN): Institute for Clinical Systems Improvement, 2007 Jan. 1 p. Electronic copies: Available from the Institute for Clinical Systems Improvement (ICSI) Web site.
• ICSI pocket guidelines. April 2006 edition. Bloomington (MN): Institute for Clinical Systems Improvement, 2006. 298 p.

Print copies: Available from ICSI, 8009 34th Avenue South, Suite 1200, Bloomington, MN 55425; telephone, (952) 814-7060; fax, (952) 858-9675; Web site: www.icsi.org; e-mail: icsi.info@icsi.org.

Electronic copies: Available in Portable Document Format from the Institute for Clinical Systems Improvement (ICSI) Web site.

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