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Health Care GuidelineICSII NSTITUTE FOR C LINICAL

S YSTEMS I MPROVEMENT

Health Care Guideline:

Chronic Obstructive Pulmonary Disease

These clinical guidelines are designed to assist clinicians by providing an analytical framework for the evaluation and treatment of patients, and are not intended either to replace a clinician's judgment or to establish a protocol for all patients with a particular condition. A guideline will rarely establish the only approach to a problem.

Sixth Edition January 2007

Work Group LeaderJames Mickman, MDPulmonology & Critical Care Medicine, HealthPartners Medical Group

Work Group MembersFamily MedicineAllen Horn, MD CentraCare ClinicG. Paul Kerestes, MDAllina Medical ClinicNursing and Health EducationCatherine Youngman, RN HealthPartners Medical GroupPharmacyStefanie Larson, RPHPark Nicollet Health ServicesPulmonary & Critical Care MedicineDelmar Gillespie, MDMayo ClinicCharlene McEvoy, MDHealthPartners Regions HospitalRespiratory TherapyScott Copeman, RRT, RCP Mayo ClinicJeff Norton, CRT, RCPFairview Health ServicesMeasurement and Implementation AdvisorTeresa Hunteman, RRT, CPHQICSIFacilitatorLinda Setterlund, MAICSI

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I ICSI NSTITUTE FOR C LINICAL S YSTEMS I MPROVEMENT

Copyright © 2007 by Institute for Clinical Systems Improvement 1

A = AnnotationSymptoms of or risk factors for COPD

1

A

Ask about tobacco use/exposure at every visit

2

A

Establish diagnosis of COPD• Medical history• Physical examination• Spirometry (pre- and post-bronchodilator)• Chest radiograph

3

A

Acute exacerbation?

4

A

Evaluation

5

A

Treatment

6

A

Establish severity of stable COPD• Mild• Moderate• Severe

10

A

Positive response to treatment?

7

A

Step-care – pharmacologic approach for managing

stable COPD

11

A

Other pharmacologic treatment

12

A

Non-pharmacologic treatment – applicable to all levels of severity• Encourage exercise• Education• Pulmonary rehab program for moderate, severe disease

13

A

Assess for hypoxemia and hypercapnia and treat if

indicated

14

A

Long-term management• Schedule regular follow-up visits• Evaluation and monitoring of comorbidities• Refer to pulmonary specialist• Surgical options for severe disease• Discuss health care directives (advance directives) and goals of care

15

A

yes

yes

Admit to hospital –out of guideline

9

A

Arrange for follow-up

8

no

A

no

Institute for Clinical Systems Improvement

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Algorithms and Annotations ................................................................................................................1-41Algorithm ..............................................................................................................................................1Foreword

Scope and Target Population ..........................................................................................................3Clinical Highlights and Recommendations ....................................................................................3Priority Aims ..................................................................................................................................3Related ICSI Scientific Documents ................................................................................................4Brief Description of Evidence Grading ..........................................................................................4Disclosure of Potential Conflict of Interest ....................................................................................4

Annotations ...........................................................................................................................................5-36Appendices ............................................................................................................................................37-41

Appendix A – Estimated Comparative Daily Dosage for Inhaled Corticosteroids ..............................................................................................................37Appendix B – Medicare Standard for Oxygen Coverage ...............................................................38Appendix C – Summary of Structure and Services – Pulmonary Rehabilitation Program ..............................................................................................39-41

Supporting Evidence ..............................................................................................................................42-59Evidence Grading System .....................................................................................................................43-44 References .............................................................................................................................................45-51 Conclusion Grading Worksheets ...........................................................................................................52-59

Conclusion Grading Worksheet A – Annotation #11 (Pharmacological Management) .................52-59Support for Implementation ................................................................................................................60-65

Priority Aims and Suggested Measures ................................................................................................61-62Measurement Specifications ...........................................................................................................63

Key Implementation Recommendations ...............................................................................................64Knowledge Products and Resources .....................................................................................................64 Other Resources Available ....................................................................................................................65

Table of Contents

Chronic Obstructive Pulmonary Disease Sixth Edition/January 2007


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Foreword

Scope and Target PopulationAlthough chronic obstructive pulmonary disease (COPD) can occur in adults of any age, especially smokers, it most commonly occurs in people 45 years and older. The target population for this guideline is people with symptoms of stable COPD as well as acute exacerbations of COPD.

Clinical Highlights and Recommendations• 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. (Annotations #11, 12, 13)

• Management of COPD should include an education plan suited to the patient's specific needs, encourage-ment 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)

Priority Aims 1. Increase the quality and use of spirometry testing in the diagnosis of patients with COPD.

2. Increase the number of patients with COPD who receive information on the options for tobacco cessa-tion and information on the risks of continued smoking.

3. Reduce COPD exacerbation requiring emergency department (ED) evaluation or hospital admission.

4. Increase the appropriate use of pharmacotherapy prescribed for patients with COPD.

5. Increase patients' education and management skills with COPD.

6. Increase the number of patients with COPD presenting with an acute exacerbation who have an oxymetric evaluation.



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Related ICSI Scientific DocumentsRelated Guidelines

• Diagnosis and Management of Asthma

• Emergency and Inpatient Management of Asthma

• Respiratory Illness in Adults and Children

• Tobacco Use Cessation and Prevention in Adults

• Palliative Care

Technology Assessment Reports

• Lung Volume Reduction Surgery for Emphysema (#23, 2003)

• Case Management for Chronic Illness, the Frail Elderly, and Acute MI (#44, 1998)

• Pulmonary Rehabilitation for Chronic Obstructive Pulmonary Disease ( #32, 1997)

Patient and Family Guidelines

• Chronic Obstructive Pulmonary Disease for Patients and Families

Evidence GradingIndividual research reports are assigned a letter indicating the class of report based on design type: A, B, C, D, M, R, X.

Key conclusions are assigned a conclusion grade: I, II, III, or Grade Not Assignable.

A full explanation of these designators is found in the Supporting Evidence section of the guideline.

Disclosure of Potential Conflict of InterestIn the interest of full disclosure, ICSI has adopted the policy of revealing relationships work group members have with companies that sell products or services that are relevant to this guideline topic. The reader should not assume that these financial interests will have an adverse impact on the content of the guideline, but they are noted here to fully inform readers. Readers of the guideline may assume that only work group members listed below have potential conflicts of interest to disclose.

No work group members have potential conflicts of interest to disclose.

ICSI's conflict of interest policy and procedures are available for review on ICSI's Web site at http://www.icsi.org.

Chronic Obstructive Pulmonary Disease Foreword Sixth Edition/January 2007


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Algorithm Annotations

1. Symptoms of or Risk Factors for COPDCOPD 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 secondhand 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 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. Phar-macotherapy, social support and skills training/problem solving are the key treatments for tobacco cessa-tion. Nicotine patches, nasal sprays, inhalers and oral medication are all available to help patients achieve cessation (Dale, 2001; Institute for Clinical Systems Improvement, 2000; U.S. Department of Health and Human Services, 2000).

For more information about tobacco cessation, please refer to the ICSI Tobacco Use Prevention and Cessa-tion for Adults and Mature Adolescents guideline and the U.S. Department of Health and Human Services Clinical Practice Guideline, Treating Tobacco Use and Dependence.

Supporting evidence is of classes: A, R



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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 progres-sive, 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 examina-tion, 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 asbes-tosis.

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 bronchodi-lator.

Chronic Obstructive Pulmonary Disease Algorithm Annotations Sixth Edition/January 2007


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• 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 (Wilt, 2005).

Pre- and Post-bronchodilator 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 differentation. 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, formal spirometry in a PFT lab should be consid-ered. Full PFTs with lung volumes and Diffusion Capacity (DLCO) are not 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) (ATS, 1991) and with the ATS' Statement on Standardization of Spirometry 1994 update (ATS, 1994).

• The spirometer must meet or exceed requirements proposed by the ATS.

• Automated maneuver acceptability and reproducibility messages must be displayed and reported. Spirometers should produce a paper record.

• The use of a nose clip for all spirometric maneuvers is strongly recommended.

• Subjects may be studied in either the sitting or standing position.

• Universal precautions should be applied in all instances in which there is potential for blood and body fluid exposure. Appropriate use of gloves and hand washing are highly recommended.

• Patients suspected of having M. tuberculosis or other airborne organisms should be tested in areas complying with the U.S. Public Health Service recommendations for air exchange and ventilation.

• Daily calibration prior to testing using a calibrated known volume syringe with a volume of at least 3 liters performed to manufacturer's recommendations is recommended. A log documenting instrument calibrations should be maintained.

• Discussion of spirometry results with current smokers should be accompanied by strong advice to quit smoking and referral to smoking cessation resources.

(AARC Clinical Practice Guideline, 1996; American Thoracic Society, 1991; American Thoracic Society, 1995; Ferguson, 2000; American Thoracic Society, 1994)

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.

Supporting evidence 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.



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• 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 and 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, manage-ment 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 ICSI Diagnosis and Treatment of Asthma guideline.

Definition of COPD from Other Guidelines:The Global Initiative for Chronic Obstructive Lung Disease (Global Initiative for Chronic Obstructive Lung Disease) defines COPD as follows:

• A preventable and treatable disease characterized by chronic airflow limitation that is not fully reversible. Airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs.

(Global Initiative for Chronic Obstructive Lung Disease, 2006)

The British Thoracic Society (BTS) defines COPD as follows:

• A chronic, slowly progressive disorder characterized by airflow obstruction that does not change markedly over several months. Most of the lung function impairment is fixed, although some reversibility can be produced by bronchodilator.

• The diagnosis requires a history of chronic progressive symptoms (cough and/or wheeze and/or breathlessness), objective evidence of airway obstruction – ideally by spirometric testing – that does not return to normal with treatment.

• The presence of chronic cough and sputum production for at least three months of two consecutive years in the absence of other diseases is used as a definition of chronic bronchitis, but does not necessarily signify the presence of airway obstruction or a diagnosis of COPD.

(British Thoracic Society, 1997)

The European Respiratory Society (ERS) defines COPD as follows:

• A disorder characterized by reduced maximum expiratory flows and slow, forced emptying of the lungs; features do not change markedly over several months

• Airflow limitation due to varying combinations of airway disease and emphysema

• Patients exhibit minimal reversibility of airflow limitation with bronchodilators

(European Respiratory Society, 1995)



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Recommended Tools for the Diagnosis of COPD from Other Guidelines• Spirometry is recommended by ATS, BTS, ERS and GOLD

• Pre- and post-bronchodilator recommended by ATS, BTS, ERS and GOLD

• Chest radiograph recommended by ATS, ERS and GOLD. BTS recommends chest radiograph if disease is severe

• Resting oxygen saturation measurement suggested by ERS in moderate or severe disease, and BTS in severe disease

• ABG recommended by ERS in moderate or severe disease or if oxygen saturation is less than 92%, by ATS in moderate or severe disease, and by BTS and GOLD in severe disease

• Screening for alpha1-antitrypsin concentration recommended by ERS, GOLD and ATS in patients who develop COPD at a young age

Reversibility Testing (measurement of pre- and post-bronchial dilator)• NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (Global Initiative for Chronic

Obstructive Lung Disease):

- Generally performed only once at time of diagnosis, this test is useful to help rule out asthma, to establish a patient's best attainable lung function, to gauge a patient's prognosis, and to guide treat-ment decisions.

- Even patients who do not show a significant FEV1 response to a short-acting bronchodilator test can benefit symptomatically from long-term bronchodilator treatment.

• British Thoracic Society, COPD Guidelines Group of the Standards of Care Committee:

- A positive bronchodilator response (FEV1 greater than 200 mL and 15% over baseline value) suggests asthma.

- More than 20% variability in absolute measurement of serial PEF may suggest asthma.

• European Respiratory Society (ERS):

- Atopy and marked improvement of spirometry with administration of bronchodilators or glucocor-ticosteroids favor the diagnosis of asthma.

- Testing of bronchoconstrictor response is of doubtful clinical value in patients with established airflow limitation.

• American Thoracic Society (ATS):

- Significant reversibility is indicated by an increase of over 12% and 200 mL after inhaling a short-acting bronchodilator.

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



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• Increased sputum production

• Change in sputum color or character


• 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


5. EvaluationWhen 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



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• 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)

• 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)

• WBC (in patients with suspected severe respiratory infection)

• A sputum culture and an antibiogram, if available, should be performed when an infectious exac-erbation does not respond to initial antibiotic treatment (Global Initiative for Chronic Obstructive Lung Disease, 2006). 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 (McCullough, 2002). 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 (Maisel, 2002).

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

There is little evidence regarding the contribution of additional laboratory testing or the usefulness of electro-cardiography 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.

(McCrory, 2001)

Supporting evidence is of classes: B, M, R



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6. Treatment

Key Points:

• Albuterol is the preferred bronchodilator in the setting of an acute exacerba-tion 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.

BronchodilatorsAlbuterol 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 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 (Moayyedi, 1995; O'Driscoll, 1989; Patrick, 1990; Turner, 1997).

Supporting evidence is of classes: A, M

Role of Levalbuterol (Xopenex®) in COPDThere 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 broncho-dilator, 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 demon-strate 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 (Costello, 1999; Nelson, 1999; Scott, 2003).

Supporting evidence is of classes: C, R

SteroidsStudies have shown benefits of systemic steroids in the outpatient management of COPD exacerbation. Doses of oral prednisone 30-60 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 (Davies, 1999; McEvoy, 2000; Niewoehner, 1999).




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AntibioticsIf the acute exacerbation of COPD is clearly post-viral, antibiotics may not be necessary. In the presence of a more 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, 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 (Anthonisen, 1987; Amsden, 2003; Chodosh, 1998).

Oxygen saturation/ABG measurementOxymetric evaluation of patients with COPD exacerbations is mandatory. Patients with O2 satura-tions of 80%-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 (Bone, 1978).

Supporting evidence is of class: 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-UpA 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 GuidelineThe 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 symp-toms

• Increasing hypoxemia despite supplemental oxygen



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• 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

(McCrory, 2001)

Supporting evidence 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.

Table ICategory 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 inbreath sounds, presence of wheezes)

Hypoxemia may be present

Severe 30 to 50 Dyspnea with any exertion or at rest

Wheeze and cough often prominent

Very severe Less than 30 Lung hyperinflation usual; cyanosis,peripheral edema and polycythemia inadvanced disease

Hypoxemia and hypercapnia are common

Adapted from NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD)workshop summary.

The best correlation with morbidity and mortality is decrease in FEV1. With FEV1 greater than 1.0 L, there is a slight increase in mortality at 10 years. With FEV1 less than 0.75 L, the approximate mortality rate at one year is 30%, and at 10 years is 95%. Because of the relationship of prognosis and FEV1, the severity



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of COPD is staged on the basis of this spirometry measurement. Patients are categorized as mild, moderate or severe. The COPD work group selected the COPD severity categories recommended by GOLD because they are straightforward and correlate with clinical experience. However, it is clear that there are wide-spread differences relative to disease severity classification among published guidelines (Hodgkin, 1990; Pauwels, 2001).


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

Key Points:

• Drug therapy is determined by severity of symptoms.Each step in Table II 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 is attached in Appendix A, "Esti-mated Comparative Daily Dosage for Inhaled Corticosteroids."



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Table IISTEP PHARMACEUTICAL INTERVENTION DOSING INFORMATION AND

COMMENTS

1

Consider Step 2 ifsymptoms persist

Inhaled short-acting bronchodilator Short-acting beta agonist (albuterol ispreferred)2-4 puffs as needed (every 4-6 hours)See Annotation #11

2 Continue PRN inhaled short-actingbronchodilator PLUS scheduled dosing ofone of the following:

• Tiotropium (Spiriva®)• Salmeterol* (Serevent® Discus)

one capsule (inhaled) daily1 puff twice daily

• Formoterol* (Foradil®) 1 puff (12 mcg) twice daily• Albuterol (Proventil®, Ventolin®) 2-4 puffs 4 times a day• Ipratropium (Atrovent®) 2-4 puffs 4 times a day• Albuterol + Ipratropium (Combivent®)

2-4 puffs 4 times a day

• Levalbuterol (Xopenex®) 0.63-1.25 mg every 6-8 hours vianebulizer2 puffs every 4-6 hours

Consider Step 3 ifsymptoms persist3

Consider Step 4 ifsymptoms persist

Continue therapy specified in Step 2 andperform corticosteroid trial.Assess symptoms before and after trialperiod, especially cough and sputumproduction. Also measure post-bronchodilator FEV1, 6-minute walk beforeand after trial.

Prednisone oral 30-40 mg/day for 2-4weeks or inhaled corticosteroid (seeAppendix A) at less than 2000 mcg for 6-8 weeks/day or dose equivalent ofanother inhaled steroid for 6-8 weeks(Approximately 15% of patients whoundergo a corticosteroid trial will haveimproved symptoms and post-bronchodilator FEV1)

* Tiotropium is the preferred scheduled bronchodilator.

POSITIVE RESPONSE: greater than or equal to 15%improvement in post-bronchodilator FEV1, symptoms,improvement in 6-minute walk

PHARMACEUTICAL INTERVENTIONTaper off or discontinue oral corticosteroids andprescribe or continue inhaled corticosteroids.

NEGATIVE RESPONSE: less than 15% improvement inpost-bronchodilator FEV1 or no improvement in symptoms

PHARMACEUTICAL INTERVENTIONDiscontinue corticosteroids and consider theophylline asadjunctive therapy with inhaled bronchodilators (ß2agonists and/or anticholinergic)

Step 4: Response After Step 3

negativepositive



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Bronchodilator Medications

Albuterol or IpratropiumAlbuterol and ipratropium are equipotent as bronchodilators, improving dyspnea and exercise tolerance equally well. No dramatic evidence showing an advantage of either albuterol or ipratropium as a sched-uled first-step therapy for COPD symptoms or improved quality of life has been shown in the medical literature.

Albuterol is recommended as the first-line treatment for patients with symptoms of mild COPD because the onset of bronchodilator effect (15 minutes) is more rapid than ipratropium (30-90 minutes). The dose-response curve of albuterol for improvement in FEV1 continues to increase to at least eight puffs. Ipratropium is to be used on a regularly scheduled basis rather than as needed (PRN) because its' dose-response time is too long to titrate its use to control symptoms.

Ipratropium bronchodilator duration (two puffs for four hours) is greater than albuterol (two puffs for two or three hours). The dose-response curve for ipratroprium levels off above six puffs, whereas therapeutic efficacy for albuterol continues to increase at higher doses, although side effects such as tremor can develop. Studies were small and may not have been of a statistical power to detect differences between bronchodilators.

(Blosser, 1995; Easton, 1986; Rennard, 1996)

Clinicians should consider replacing ipratropuim with tiotropium as a scheduled bronchodilator because it provides improved benefits and only requires once-a-day dosing (Oostenbrink, 2004).

Supporting evidence is of classes: A, M

Combination Albuterol and IpratropiumMany studies show that the combination of ipratropium 0.5 mg and albuterol 2.5 mg provides greater bron-chodilator effect compared to each alone; however, the same effect could probably be achieved by doubling the dose of either agent. This is reflective of the additive bronchodilator effect of both, as expected. No study compares the combination of ipratropium and albuterol to an equivalent dose of albuterol or ipratropium (e.g., four puffs of combination to four puffs of albuterol or ipratropium).

One study also showed that patients randomized to albuterol two puffs four times/day had 18% more COPD exacerbations than those randomized to ipratropium two puffs four times/day (therefore "more expensive" p<0.05). Baseline FEV1 and FVC with ipratropium was greater than with albuterol after 90 days (p<0.05 and <0.01). No significant difference in quality of life was demonstrated, however. After 90 days, the albuterol group was less responsive to albuterol than the ipratropium group was responsive to albuterol (p>0.0001).

(Dorinsky, 1999; Moayyedi, 1995)

Supporting evidence is of class: A

TiotropiumTiotropium, a new dry powder, once-daily long-acting anticholinergic, was compared to salmeterol in a six-month study. Significant improvements in bronchodilation, symptoms and quality of life were demonstrated by tiotropium over salmeterol. Improved morning pre-dose bronchodilation was also seen at six months (Donahue, 2004). Due to these benefits and the once-daily dosing, tiotropium offers significant advantages as a scheduled bronchodilator to patients whose symptoms are not controlled by albuterol. Tiotropium replaces the use of ipratropium in the setting of stable COPD. Tiotropium has additive effects to long-acting beta-agonists (Cazzola, 2004; van Noord, 2006). In patients with moderate to severe COPD, tiotropium has also been demonstrated to significantly reduce both exacerbations and hospitalizations when added to the COPD treatment regimen (Niewoehner, 2005).



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If a patient with COPD has unacceptable symptoms while on tiotropium, a long-acting beta-agonist can be added (van Noord, 2006).

No studies have compared the additive effects of tiotropium with steroids as a single agent in effectiveness of COPD management.


Long-Acting Beta-Agonists (LABAs)

FormoterolTwice-daily dosing of formoterol offers advantages similar to those of salmeterol. Data also show that formoterol has quicker onset of action than salmeterol (Dahl, 2001; Kottakis, 2002).

SalmeterolGlaxo-Wellcome, Inc., maker of salmeterol, funded a study that showed salmeterol gave greater increase in FEV1 and FVC than albuterol or ipratropium, much longer duration of BD and, therefore, greater "area under the curve." Improvements in dyspnea and exercise tolerance were similar to those using ipratropium. Sixteen weeks of salmeterol therapy provided an increased baseline FEV1 of 7%. Salmeterol at doses of eight puffs produced no significant cardiovascular effects in patients with COPD (heart rate or PVCs). However, tremor developed after four puffs. Quality of life indicators increased with salmeterol compared to PRN use of albuterol. Significant evidence exists for salmeterol to be used as a scheduled treatment for COPD. When compared to other beta-agonists, its benefits include a higher and more prolonged BD effect. In addition, salmeterol's twice-daily dosing compared to four times/day dosing required by albuterol and ipratropium may improve compliance (Matera, 1995; Matera, 1996; Patakas, 1998).


SummaryAlbuterol 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 that is a suitable agent for scheduled administra-tion. [Conclusion Grade II: See Conclusion Grading Worksheet A – Annotation #11 (Pharmacological Management)]

(Brusasco, 2003; Donohue, 2002; Hvizdos, 2002)


Systemic Corticosteroid Trials• Prednisone up to 40 mg/day for 10-14 days (ATS, 1995)

• Prednisone 30 mg/day for two weeks or inhaled corticosteroid for six weeks (BTS, 1997)

• A trial of prednisone (0.4-0.6 mg/kg for two to four weeks or inhaled corticosteroids at less than 2,000 mcg/day for six to eight weeks) may be used to test reversibility of airflow (ERS, 1995).



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Every-other-day dosing of oral corticosteroids may minimize side effects yet still provide anti-inflammatory benefits. The value of oral corticosteroids in treating stable COPD is controversial. While oral cortico-steroids are useful in treating acute exacerbations, their long-term use in stable COPD is beneficial in only 10%-15% of cases.


Inhaled CorticosteroidsAirway inflammation is a prominent feature in some patients with COPD. Although the benefits of inhaled corticosteroids are well established in asthma, their utility for the chronic management of COPD is contro-versial. Previous studies have shown that inhaled corticosteroids do not decelerate the rate of decline in expiratory flow volumes over time in patients with COPD. A recent meta-analysis showed that high doses (but not medium or low doses) of inhaled corticosteroids did slow the rate of decline in forced expiratory volume in one second (FEV1) in patients with COPD. Another study suggested that inhaled corticosteroids may reduce airway hyperreactivity and decrease clinical symptoms of COPD, including dyspnea and cough.

The effects of inhaled corticosteroids on clinical outcomes such as COPD exacerbation rates, hospital readmission rates, and mortality have been evaluated. A systematic review of all placebo-controlled, randomized trials of inhaled corticosteroids given for at least six months for stable COPD demonstrated a beneficial effect in reducing rates of COPD exacerbation. In this review, the use of inhaled corticosteroid therapy reduced the rate of exacerbations with similar benefits in those who were and were not pretreated with systemic steroids. Inhaled corticosteroid therapy was also associated with increased rates of oropha-ryngeal candidiasis and skin bruising over placebo. The effects on bone mineral density and mean cortisol concentrations were variable. No effects on mortality were seen.

In contrast, in a population-based cohort study, patients who received inhaled corticosteroid therapy after hospitalization discharge for COPD had a relative risk reduction for all-cause mortality of 29% and for repeat hospitalization of 24%.

(Alsaeedi, 2002; Burge, 2000; Lung Health Study Research Group, 2000; Paggiaro, 1998; Sin, 2001; van Grunsven, 1999; Vestbo, 1999; Weir, 1993)

Two recent large studies compared the effects of combined fluticasone and salmeterol to placebo in patients with severe but stable COPD. Those randomized to combination therapy had significant improvement in symptoms, spirometry, quality of life, and exacerbations. However, 50% of patients were current smokers. Subgroup analysis was not published in these papers, leaving questions regarding whether these beneficial effects are expected in non-smoking patients without evidence of airway inflammation (Hannania, 2003; Calverley, 2003).

There is evidence that a trial of oral prednisone may not accurately predict which patients will respond to inhaled steroids (Senderovitz, 1999; Boothman-Burrell, 1997; Shim, 1985).

Supporting evidence is of classes: A, B, M

Methods of Drug DeliveryMetered 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 proper inhaler technique for optimal drug delivery. Evidence of the effectiveness of one type of spacer over another is variable and controversial.



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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 (UN Environment Programme, 2000).

MDIs that use CFCs as a propellant will not be removed until sufficient alternatives exist to serve patient needs. The 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 synchro-nize 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.

Table II contrasts features of conventional pressurized MDIs and DPIs.

Table III: Contrasting Features of Conventional Pressurized Metered-Dose Inhaler and Dry Powder Inhaler

MDI DPI

1. Aerosol generation dependent on propellants. 1. Aerosol generation does not require anypropellants.

2. Requires coordination of actuation withinhalation.

2. Relatively easy to administer, since it isbreath-activated.

3. With correct technique, the lung deposition ofthe drug is 10%-15%.

3. Lung deposition of the drug is similar toproperly used MDI (in some studiesdeposition is greater in DPI than MDI).

4. With add-on spacer device, may be improveddrug deposition into the lungs andoropharyngeal side effects may be reduced.

4. No add-on spacer device needed.

5. Because of propellants and other additives,patients “feel” the drug delivered.

5. Patient may not “feel” the drug delivered andmay be uncertain of the drug dosing.

6. No dose indicators. Risk of continued use ofempty inhaler.

6. Newer multidose DPIs have a window withdose indicator.

Adapted from Vaswani, 1998.

Nebulizers

Aerosol particle diameters range from 1-5 mcg in SVN (small volume nebulizer), 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:



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• Patients incapable of performing MDI or DPI maneuver

• Adults who have a vital capacity less than 1.5 times their predicted tidal volume (7mL/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.

The following is a comparison of the advantages and disadvantages of aerosol delivery via nebulizer.

Table IV: Comparison of Nebulizers and MDIs

Nebulizers

Advantages Disadvantages

Pneumatic small volume nebulizers (SVN)Limited patient coordination Expensive compressed gas source required

High dose levels possible Greater time required (expense)

Continuous therapy available Some medications not readily available

No chlorofluorocarbon (CFC) release

Covered by Medicare

Ultrasonic small volume nebulizers (USN)Less patient coordination Expensive initial purchase

Fast delivery Contamination possible

No CFC release or compressed gas source Electrical or mechanical malfunctionrequired Not portable

Some medications not available

Adapted from Ward, 1997.

TheophyllineTheophylline has a narrow therapeutic index with potentially significant adverse effects and drug interac-tions that must be carefully considered and closely monitored during therapy.

The use of theophylline for COPD has decreased over the past decade for various reasons. Newer inha-lational therapies have potentially equal or greater efficacy. There is concern about adverse reaction and drug-interaction profiles of theophylline. Based upon a retrospective valuation of 3,720 patients with COPD enrolled in 10 bronchodilator clinical trials from 1987 to 1995, the percentage of patients receiving oral theophylline decreased significantly from 63% to 29% related to changing prescribing and COPD manage-ment practices (Van Andel, 1999).

The mechanisms of action of theophylline in COPD remain unclear. The assumption that theophylline relaxes bronchial smooth muscle by inhibiting phosphodiesterase, subsequently leading to an increase of cAMP, is no longer generally accepted as the predominant mode producing efficacy. Newer proposed mechanisms of action include antagonism of the effects of prostaglandins and adenosine; alternation of calcium metabolism by cells; inhibition of mediator release, membrane phospholipid methylation, and calcium ion influx in mast cells; and the inhibition of specific phosphodiesterase enzymes, leading to smooth muscle relaxation and inhibition of inflammatory cell function (Vaz Fragoso, 1993).



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A table of drug interactions with theophylline has been published (Michalets, 1998).

There is general agreement among previously published consensus guidelines for the management of COPD that theophylline has a role after inhaled bronchodilators prove inadequate; however, there is disagreement as to whether theophylline should be considered before or after corticosteroid use. There is considerable evidence that theophylline provides significant improvement in spirometry and/or symptoms – such as dyspnea – of patients with COPD and particularly chronic stable disease and in combination with other bronchodilator therapies. Theophylline may also improve mucociliary clearance, diaphragmatic strength, cardiovascular function, central respiratory drive and exercise capacity. The degree of efficacy of theoph-ylline in patients with COPD, however, may be influenced by the chronicity and severity of obstruction, duration of therapy, and extent of follow-up evaluation, and the use must be individualized to the patient and clinical situation.

Potential adverse effects with theophylline are gastrointestinal irritation (nausea, dyspepsia and GERD) due to increased gastric acid secretion, irritability, tremor and sleep disturbance.

Theophylline has a narrow therapeutic index: seizures and tachyarrhythmias correlate positively with higher serum concentrations. Theophylline is extensively hepatically metabolized primarily by cytochrome P4501A2. As a result, several drugs, cigarette smoking and hepatic insufficiency, in addition to cardiac decompensation and age, may alter theophylline's clearance.

Supporting evidence is of classes: D, R

12. Other Pharmacologic TreatmentAntibioticsThe routine use of antibiotics is not recommended except for treatment of bacterial exacerbations of COPD.

AntitussivesRegular 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 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 obstruc-tive pulmonary disease" (U.S. Food and Drug Administration, 2000).


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Dosage and Cost

a. Amantadine: 100 mg twice daily x 7 days $

b. Rimantadine: 100 mg twice daily x 7 days $$

c. Zanamivir 10 mg (2 inhalations) every 12 hr for 5 days $$$

d. Oseltamivir 75 mg by mouth twice daily for 5 days $$$$

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

MucolyticsIn 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.

(Houtmeyers, 1999; Parvez, 1996; Petty, 1990; Rubin, 1999; Rubin, 1996)

Supporting evidence is of classes: A, C, R

Oral Beta-AgonistsInhaled 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 or older. Immunization with pneumococcal and influenza vaccines are recom-mended by the U.S. Public Health Service's Advisory Committee on Immunization Practices to reduce infectious complications involving the respiratory tract (Centers for Disease Control,1999; Centers for Disease Control, 1997; Murphy, 1992).

Pneumococcal

The American Thoracic Society and the U.S. Public Health Service's Advisory Committee on Immu-nization Practices (ACIP) recommends 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. See the ICSI Immunizations guideline for Adults.



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Influenza

Influenza vaccine should be provided on an annual basis because of new antigens and waning immu-nity 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 (Couch, 2000).


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" later in this annotation. For patients who do not have access to a pulmonary rehab program, it is reasonable to prescribe a regular exercise schedule.

• Education

Considerations

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.

Patient Education Model

The following 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 Transtheo-retical Change Model (Prochaska Model), which emphasizes recognition of patients' stages of readiness to incorporate educational messages into long-term behavior change.

Patient education should be tailored based on learning-needs assessments. It is important to develop a plan that includes the educator, patient and family. Learning assessment and feedback tools should:

• incorporate COPD needs and interventions within a conceptual behavior change model,

• be flexible enough to fit the various office practice models (step-care model with stages of change), and

• be flexible enough to match the cultural and learning styles of the intended target population.



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Core Learning Needs/Objectives

• Knowledge of Basic Facts about COPD

- What is COPD?

- What symptoms are related to COPD?

- What causes COPD? (emphasis on tobacco use)

- What diagnostic testing is usually necessary?

- Role of medications and modes of delivery

- Importance of appropriate immunizations

• Skills (with or without a return visit by the patient to demonstrate skill improvement)

- Recognize symptoms of infections and exacerbations

- Breathing and physical exercise (at least lower extremity)

- Medication use and proper technique for inhalers (MDI/DPI), spacers, nebulizers, oxygen

- Environmental modification – energy conservation, irritants

• Attitude

- Smoking cessation and dangers of continued use (from ICSI Tobacco Cessation guide-line)

- Nutrition and exercise

- Quality of life factors – dyspnea, fatigue, fear and depression

- Coping skills – relaxation techniques, stress management and understanding of need to have COPD under control

• Partnership in Care

- Written plan (with and without symptoms), exercise and medication diary

- When to call the clinic or seek emergency help

- Other educational support resources (e.g., pulmonary rehabilitation, tobacco cessation)

Comprehensive programs, e.g., formal pulmonary rehabilitation, may expand on the above learning needs, as well as phase in additional health-related behavioral advice based on severity, resources and learning capacity of individual patients.

How Does the Practitioner Know That Patient Education Is Making a Difference?

In developing this patient education model, the ICSI COPD guideline work group identified a number of individual outcomes to be achieved through guided self-management that incorporate a process of education with objective monitoring and an explicit action plan. Individual outcomes to help practitio-ners know if education is making a difference include the following:

• Initiation of treatment for acute exacerbation is quicker



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• Decreased missed work days

• Improved self-efficacy and ability to perform ADLs

• Increased adherence to and use of medications (psychomotor skills)

• Variable impact on general quality of life measures

Barriers to Patient Education

Barriers to successful implementation of patient education and subsequent long-term behavior change include individual educator and organizational factors such as:

• lack of education due to insufficient time, resources or finances of patient;

• inconsistent messages from health care team/sites;

• ineffective communication of goals/planning change;

• patient's fear of change and/or of not meeting expectations/lack of confidence in ability to understand and manage illness (self-efficacy);

• non-adherence; and

• insufficient time or resources for response or feedback on illness from practitioner.

Educational Framework/Themes for COPD

Definitions

In general, health education is concerned with a person's learning to live life in the healthiest way possible. Patient (health) education can be defined as: (Bartlett, 1985; Stewart, 1966)

• A process that is intended to improve the patient's level of knowledge, skill and attitude to effectively adopt or reinforce healthy behaviors.

• The process involving a planned learning experience using a combination of methods such as teaching, counseling and behavior modification techniques that influence an individual's knowledge and health behavior. The intent would be to prevent, promote, maintain or modify a jointly developed set of health-related behaviors for a given patient with COPD.

Self-efficacy is defined as a person's belief in his/her own capacity to perform a specific task. These expectations about personal success determine a patient's motivation to participate in behavior changes. For providers of care interacting with patients, outcome expectancy (conviction that certain behaviors will lead to certain outcomes) are influenced by efficacy expectancy (conviction that one can successfully execute the behavior required to produce the outcome). Personal experience is the most dependable source of self-efficacy, which in turn may influence health belief and need for further self-change (Celli, 1996; Scherer, 1996).

Conceptual Models

There are many theoretical frameworks for patient education that may be useful for various aspects of COPD care. Two frameworks that have been extensively studied and may be applicable to the COPD population include the Transtheoretical Change Model and the Precede-Proceed Model. Two areas where these have been applied include smoking cessation and physical activity.



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General Goals

In order to be effective, patient education needs to be developed as an integral part of a disease manage-ment strategy with the goals of:

• increasing awareness and understanding of basic disease pathophysiology,

• facilitating long-term change toward health-preserving or enhancing attitudes and behaviors (improved self-efficacy and quality of life), and

• minimizing adverse effects from inappropriate use of therapeutic alternatives or interactions with recommended treatments by the care team.

A key theme in overall health education is consistency of educational messages between access points and along a time continuum tailored to meet the patient's learning needs and readiness to change.

Critical Components

The critical components of educator training and integration of the educator's role into the care process are: 1) communication skills, 2) interpersonal interactions and 3) ability to empathize with patient's needs and prioritize/evaluate desired reality-based behavior change(s). The interactive process between educator and patient occurs in the context of a created environment or learning space arising from each individual's internal state and his/her local external environment, and involves five interrelated domains: physiologic, psychologic, sociocultural, developmental and spiritual (Clark, 1994; Narsavage, 1997).

The literature review related to impact and cost effectiveness of educational interventions in COPD is minimal and of variable quality for definitive recommendation.

Educational programs should be of graded intensity and should be consistent with emphasis on tailoring to three levels:

1. Core messages to all patients as one-on-one office sessions

2. Add facilitator or peer-led support groups and other community resources

3. Add comprehensive rehab components (with or without specialty referral)

Three chronic conditions that may be useful to benchmark for program design and implementation process include asthma, diabetes and osteoarthritis.

How Does the Practitioner Know That Education Is Making a Difference?

There are several conclusions reached in the research reviewed.

• There is no evidence to indicate that education alone can improve pulmonary function. Educa-tion is most effective when coupled with exercise programs and timely access to supportive care teams.

• There may be improvement in quality of life for patients receiving education about COPD, but the data is subjective and not consistently demonstrated. The meta-analysis conducted on 65 studies concluded that education alone had significant beneficial effect only on psychomotor skills (inhaler technique). There were only three relevant studies to review the effects of educa-tion alone, making conclusions on other outcomes unreliable.

• Education alone may reduce patients' use of short-acting ß2-agonists by as much as one-half.

• Self-management studies did demonstrate statistical differences in response to changes in symp-toms; one study showed patient initiation of prednisone 27% greater than control and antibiotic



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therapy 37% greater than control. Other studies showed improvement in self-efficacy but no changes in overall quality of life.

• Progressive muscle relaxation has been shown to reduce psychological distress and dyspnea.

(Bauldoff, 1997; Devine, 1996; Folgering, 1994; Gibson, 1999; Ketelaars, 1994; Scherer, 1998; Watson, 1997)

Supporting evidence is of classes: A, C, D, M, R, X

Pulmonary Rehabilitation Program for Moderate to Severe DiseaseThe 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."

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, typi-cally 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 (Berry, 2003).

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

A multidisciplinary 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.

(American Thoracic Society [ATS], 1995; American Thoracic Society, 1999; Cambach, 1999; Donado, 1998; GOLD, 2006; Grosbois, 1999; Institute for Clinical Systems Improvement, 1997; Lacasse, 1997; Man, 2004; Resnikoff, 1998)

Supporting evidence is of classes: A, C, M, R



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14. Assess for Hypoxemia and Hypercapnia and Treat If Indicated

Key Points:

• Assess for hypoxemia and consider assessment for hypercapnia.HypoxemiaProgressive hypoxemia is commonly associated with COPD patients. Hypoxemia can rapidly lead to clinical deterioration. By preventing or correcting cellular hypoxia, the treatment of hypoxemia can be life-preserving. Long-term oxygen supplementation has been demonstrated to improve survival in hypoxemic patients with COPD. However, tissue hypoxia may not always be adequately prevented or treated by simply addressing the hypoxemia. Rather, the physician must carefully evaluate the full scope of the oxygen transport and delivery (Medical Research Council Working Party, The, 1981; Weitzenblum, 1985).

The evaluation of gas exchange status by arterial blood gas (ABG) measurement is recommended for initia-tion 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 ECG or echo), or altered mental status;

3. problematic heart failure; and

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.

Supporting evidence is of classes: A, C

Nocturnal HypoxiaDuring 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

(Carskadon, 1981; Gimeno, 1986; Little, 1999; Nocturnal Oxygen Therapy Trial Group, 1980)

Supporting evidence is of classes: A, C, D



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Screening for Nocturnal HypoxiaScreening 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 down-loaded. If a significant portion of the night's data indicates oxygen saturations below 88%, supplemental oxygen should be provided empirically at 1-2 L/min. Home oximetry can be repeated at that level to verify correction of hypoxia (Hoch, 1990; Knight, 1987).

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

Support evidence is of class: C

HypercapniaIn an ambulatory, stable patient with COPD, assessment for hypercapnia by arterial blood gases (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 ICSI Diagnosis and Treatment of Obstructive Sleep Apnea Hypopnea Syndrome guideline.

(American Thoracic Society [ATS], 1995; Dunn, 1991; Lopez-Majano, 1973)




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Oxygen TherapyImportant 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.*

• 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 PaO2 of greater than 55 mm Hg, or SaO2 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 SaO2 greater than 89%. Titrate sleep liter-flow to eight-hour sleep of SaO2 greater than 89%.

• Consider referral for sleep evaluation if patient experiences cyclic desaturation during sleep but is normoxemic at rest.

• Recheck Sa O2 or PaO2 in one-three months if hypoxia developed during an acute exacerbation. Rechecks should be performed annually if hypoxia is discovered in an outpatient with stable COPD.

* Appendix B contains a summary of Medicare Oxygen Coverage Guidelines.

Oxygen Delivery MethodsThe 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 (AARC, 1996).

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%-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.

(Bower, 1988; Gibson, 1976; Kory, 1962; Soffer, 1985)

Supporting evidence is of classes: C, D, M

COPD and Air TravelAirline 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



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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 (Berg, 1992; Dilliard, 1991).

Supporting evicence is of class: D

Use of supplemental O2 for patients with COPD and not currently on supplemental O2

Regression equations have been validated that 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 (Cummins, 1989; Dilliard, 1989; Lien, 1998).


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 VisitsFollow-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.

Severity Regular Follow-Up VisitMild YearlyModerate Three to six monthsSevere Two to four months or more frequently as needed

Evaluation and Monitoring of ComorbiditiesIn 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, ECG, etc.) and referral to clinical specialists should be used whenever symptoms (e.g., hemoptysis) suggest one of these conditions (Global Initiative for Chronic Obstructive Lung Disease, 2006).



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Refer to Pulmonary SpecialistObtaining 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 A1-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 treat-ment;

• if symptoms are not consistent with the lung function deficit as measured by pulmonary function tests;

• for patients 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; and

• for patients who have been hospitalized for COPD.

Surgical Options for Severe DiseaseLung 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/perfu-sion 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, comple-tion of a pulmonary rehabilitation program, full pulmonary function tests, chest CT, echocardiogram, and possibly a right heart catheterization and a radionuclide stress test.



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6. LVRS should only be performed in medical centers with appropriately trained surgeons and avail-ability of necessary equipment.

(American Thoracic Society, 1995; Institute for Clinical Systems Improvement, 2003; National Emphysema Treatment Trial Research Group, 2003)


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 funcion and improve symptoms. CT scan is essential in evaluating these patients and referral to a pulmonary specialist is indicated (Boushy, 1968; Laros, 1986).

Supporting evidence is of class: D

Lung Transplantation

Unilateral or bilateral lung transplantation is a treatment option in highly selected patients with severe COPD (Arcosoy, 1999). A few studies show improvement in quality of life parameters but no increase of survivability (Hosenpud, 1998).

General selection guidelines for candidate selection for lung transplantation in COPD patients

Relative contraindications Age limitsHeart-lung transplants ~55 yrsDouble lung transplant ~60 yrsSingle lung transplant ~65 yrs

Symptomatic osteoporosisOral corticosteroids greater than 20 mg day-1 prednisonePsychosocial problemsRequirement for invasive mechanical ventilation

Absolute contraindications Severe musculoskeletal disease affecting the thoraxSubstance addiction within previous six monthsDysfunction of extrathoracic organ, particularly renal dysfunctionHIV infectionActive malignancy within two years except basal or squamous cell

carcinoma of skinHepatitis B antigen positivelyHepatitus C with biopsy-proven evidence of liver disease

Following the position of the American Thoracic Society and the European Respiratory Society (ATS/ERS COPD Standards, 2004), 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

(Celli, 2004)

A number of studies show that single lung transplant is safer and gives equal or improved spirometric parameters as compared to bilateral lung transplant (Bando, 1995; Arcosoy, 1999). Survival after transplant



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is 81.7%, 61.9% and 43.4% at one, three and five years. Perioperative mortality, rejection, bronchiolitis obliterans, cytomegalovirus, fungal and bacterial infections, and lymphoproliferative disease are associated with transplant surgery. Donor lung availability, high initial and ongoing immunosuppressive regimen costs are also considerations that must be considered.

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


Discuss Health Care Directives (Advance Directives) or Living Will and Durable Power of Attorney for Health CareMany 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 designate with all COPD patients at routine outpatient visits.

In patients with severe disease, it is also helpful to discuss specific treatment preferences. Treatment prefer-ences 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 reassure 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 prefer-ences 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 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.



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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.

For more information on living wills, please consult your state's statutes outlining requirements for health care directives.

(Emanuel, 1991; Hansen-Flaschen, 1997; Heffner, 1996)

See the ICSI Palliative Care guideline for more information regarding end-of-life care.




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Appendix A – Estimated Comparative Daily Dosage for Inhaled Corticosteroids


Sources: Drugs Facts and Comparisons, 06/2005; Thomson Micromedex® Health Care Series 2006

Estimated Comparative Daily Dosage for Inhaled CorticosteroidsAll Daily Dosing Should be Divided Into Two Doses Except for Mometasone and Triamcinolone

Drug Low Dose Medium Dose High DoseMometasone furoate(Asmanex®) 220mcg/inhalation

220 mcg (1 inhalation)1 dose per day

440-660 mcg (2-3inhalations)1 dose per day

880 mcg (4 inhalations)1 dose per day

Beclomethasonedipropionate

HFA (hydrofluoroalkane)formulation withstrengths of 40 mcg/puffand 80 mcg/puff(Qvar®)

40-160 mcg

(1-4 puffs - 40 mcg)(1-2 puffs - 80 mcg)

160-320 mcg


320-640 mcg


Budesonide DPI200 mcg/dose(Pulmicort®)

For nebulization:strengths 0.25 mg/2 mLand 0.5 mg/2 mL

200-400 mcg(1-2 inhalations)

0.25 mg daily


0.5 mg/day (as 0.25 mgtwice daily or 0.5 mgdaily)


1.0 mg/day (as 0.5 mgtwice daily or 1.0 mgdaily)

Flunisolide (Aerobid®)250 mcg/puff

Flunisolide Hemihydrate(Aerospan®) 80mcg/inhalation

500-1,000 mcg(2-4 puffs)


1,000-2,000 mcg(4-8 puffs)


2,000 mcg(8 puffs)


Fluticasone (Flovent®)HFA: 44, 110, 220mcg/puff

DPI (Rotadisk®) orDiskus®: 50, 100, 250mcg/dose

88-264 mcg(2-6 puffs - 44 mcg) OR(2 puffs - 110 mcg)

(2-6 inhalations - 50 mcg)

264-660 mcg(2-6 puffs - 110 mcg)

(3-6 inhalations -100 mcg)

660-1760 mcg(6-16 puffs - 110 mcg) OR(3-8 puffs - 220 mcg)

(6-20 inhalations - 100mcg) OR(2-8 inhalations - 250 mcg)

Combination Product –fluticasonepropionate/salmeterolDPI (Advair®)

100 mcg fluticasone/50mcg salmeterol – oneinhalation every 12 hrs

250 mcgfluticasone/50 mcgsalmeterol – oneinhalation every 12 hrs

500 mcg fluticasone/50mcg salmeterol – oneinhalation every 12 hrs

Triamcinolone acetonide100 mcg/puff(Azmacort®)

400-1,000 mcg(4-10 puffs) divided 3-4times daily

1,000-2,000 mcg(10-20 puffs) divided 3-4times daily

2,000 mcg(20 puffs) divided 3-4times daily

NOTES:• The most important determinant of appropriate dosing is the clinician's judgment of the patient's response to

therapy. The clinician must monitor the patient's response on several clinical parameters and adjust the doseaccordingly. The stepwise approach to therapy emphasizes that once control of COPD is achieved, the dose ofmedication should be carefully titrated to the minimum dose required to maintain control, thus reducing thepotential for adverse effect.

• MDI dosages are expressed as the actuator dose (the amount of drug leaving the actuator and delivered to thepatient), which is the labeling required in the United States. This is different than the dosage expressed as thevalve dose (the amount of drug leaving the valve, all of which is not available to the patient), which is used inmany European countries and in some scientific literature. Dry powder inhaler (DPI) doses are expressed as theamount of drug in the inhaler following activation.


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Appendix B – Medicare Standard for Oxygen Coverage


Oxygen TherapyMedicare Standards for Oxygen Coverage include the following parameters:

Laboratory Evidence• Testing must be performed either with the patient in a chronic stable state as an outpatient, or

within two days prior to discharge from an inpatient facility to home.

• If the test is not taken under these conditions, additional documentation must be obtained from the physician.

PaO2 SaO2 Additional Documentation

55 mm Hg or less 88% orless

None

55-59 mm Hg 89% Congestive Heart Failure/Edema

EKG evidence of “P” pulmonale with P wave greater than 3mm in lead I, II, III, or AVF Hematocrit greater than 56%

60 mm Hg 90% orgreater

Coverage rare or unlikely; requires extensive physiciandocumentation for approval

• Requires recertification and retesting 61-90 days after the initial start of therapy.

Portable Oxygen• May qualify as a system by itself or as a complement to stationary oxygen system.

• If the patient qualifies for reimbursement under the oxygen coverage guidelines noted previ-ously, and the patient is mobile within the home.

Oxygen PrescriptionOxygen for patients with COPD is covered under Medicare. The prescription for home oxygen therapy must include:

• flow rate: liters/minute – flow rate must be increased during exercise and sleep,

• duration of need: specific number of months or indefinitely,

• laboratory evidence,

• blood gas or oximetry required while at rest on room air, and

• acceptable PaO2 or SaO2.

Diagnosis • Severe primary lung disease (includes COPD, emphysema, chronic bronchitis)

• Secondary conditions related to lung disease

• Significant hypoxemia in the chronic stable state

Additional medical documentation: other forms of treatment have been tried and have not been successful and oxygen therapy is still required

Start of therapy: within one month of last visit


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Appendix C – Summary of Structure and Services – Pulmonary Rehabilitation Program


Disciplines involved in pulmonary rehabilitation can include, but are not limited to the following:

Physicians Nurses

Respiratory Therapists Physical Therapists

Occupational Therapists Cardiorespiratory Technicians

Recreational Therapists Clerics

Dieticians Pharmacists

Exercise Physiologists Psychologists

Social Workers Psychiatrists

Interventions can generally be divided into education, exercise/conditioning, psychosocial/psychological aspects and medical intervention.

Education

• Basic lung anatomy and physiology/COPD pathophysiology

• Breath retraining

1. Diaphragmatic breathing

2. Pursed-lip breathing

• Diet and nutrition

• Energy conservation

• Safe travel

• Airway management

• Benefits of exercise

• Safe use of oxygen

• Role of medications

1. How medications work

2. Long-term control: medications that prevent symptoms

3. Stress importance of using medications

• Skills of using medications

1. Metered dose inhaler (MDI) use (patient should demonstrate correct inhaler technique)

2. Small volume nebulizer (SVN)

3. Spacer/holding chamber use


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• Symptom assessment and knowledge of when to seek medical help

• Smoking cessation

• Environmental irritant avoidance

• Respiratory and chest therapy techniques

Exercise/Conditioning

• Lower extremity training/exercise

• Upper extremity training/exercise

• Inspiratory muscle training/exercise

• Emphasis on in-home exercise as lifestyle change

Psychosocial/Psychological aspects

• Counseling

1. Stress management

2. Coping skills, anxiety, panic control

Medication

Patients may benefit from antidepressants.

Indications for Referral

• Symptomatic COPD (characterized by airway obstruction and reduced expiratory airflow)

• Functional limitations that affect quality of life

• Has a medical regimen that has been maximized, e.g. bronchodilator, oxygen therapy

• Able to learn about the disease; patients who are mentally capable of learning about their disease have improved outcome including decreased anxiety and fear

• Motivated to participate in a pulmonary rehabilitation program

Relative contraindications for participation in pulmonary rehabilitation

• Patients with conditions that might interfere with the patient undergoing a rehabilitation program, e.g. coronary artery disease, cognitive impairment interfering with learning, severe psychiatric disturbances.

• Patients with conditions that might place the patient at risk during exercise training; many patients with COPD are older with a history of cigarette smoking and are at risk for heart disease. Cardiac and pulmonary stress testing should be routinely performed to exclude silent cardiac disease and assure safety during exercise training.

Appendix C – Summary of Structure and Services – Chronic Obstructive Pulmonary Disease Pulmonary Rehabilitation Program Sixth Edition/January 2007


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Types of Rehabilitation Programs

Type of Program Advantages Disadvantages

Hospital or Community-basedOutpatient PulmonaryRehabilitation

Widely available

Less costly

Potential transportation issues

Long-term benefits have notbeen demonstrated

Less intrusive to family Inability to observe home plan

Home Program Transportation not an issue Potential inability formultidisciplinary team toparticipate

Familiar surroundings mayfacilitate better adherence togoals

Patient may not have access toexercise equipment

Long-term benefits have beendemonstrated

Lack of supervision by trainedpersonnel

Appendix C – Summary of Structure and Services – Chronic Obstructive Pulmonary Disease Pulmonary Rehabilitation Program Sixth Edition/January 2007

Availability of references

References cited are available to ICSI participating member groups on request from the ICSI office. Please fill out the reference request sheet included with your guideline and send it to ICSI.

�2Copyright © 2007 by Institute for Clinical Systems Improvement

Released in January 2007 for Sixth Edition. The next scheduled revision will occur within 12 months.

Contact ICSI at: 8009 34th Avenue South, Suite 1200; Bloomington, MN 55425; (952) 814-7060; (952) 858-9675 (fax)

Online at http://www.ICSI.org


Document Drafted Jan – Jun 2000

First Edition Dec 2001

Second Edition Jan 2003

Third Edition Jan 2004

Fourth Edition Begins Jan 2005

Fifth Edition Jan 2006

Sixth Edition Begins Feb 2007

Supporting Evidence:


Original Work Group MembersJeff Rabatin, MDPulmonary & Critical Care Medicine Mayo ClinicMary Stadick, MAFacilitatorICSISuzanne Tschida, PharmDPharmacy, Health EducationHealthPartners Medical GroupCatherine Youngman, RNNursing, Health Education HealthPartners Medical Group

Janine Graham, RN, CCMCase Management, Health Education Aspen Medical GroupAllen Horn, MDFamily PracticeCentraCareJames Mickman, MDPulmonary & Critical Care MedicineHealthPartners Medical GroupAshok M. Patel, MDPulmonary & Critical Care Medicine, Work Group LeaderMayo Clinic

Scott Copeman, RRTRespiratory TherapyMayo ClinicTom Dashiell, MDInternal MedicineHealthEast ClinicsBeth Duffy, RRTRespiratory Therapy, Health Education HealthPartners Medical GroupJane GendronMeasurement AdvisorICSI


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I. CLASSES OF RESEARCH REPORTS

A. 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

B. 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

II. CONCLUSION GRADES

Key conclusions (as determined by the work group) are supported by a conclusion grading worksheet that summarizes the important studies pertaining to the conclusion. Individual studies are classed according to the system defined in Section I, above, and are assigned a designator of +, -, or ø to reflect the study quality. Conclusion grades are determined by the work group based on the following definitions:

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 minor 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 conclusion 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.

Evidence Grading System



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

The symbols +, –, ø, and N/A found on the conclusion grading worksheets are used to designate the quality of the primary research reports and systematic reviews:

+ indicates that the report or review has clearly addressed issues of inclusion/exclusion, bias, generaliz-ability, and data collection and analysis;

– indicates that these issues have not been adequately addressed;

ø indicates that the report or review is neither exceptionally strong or exceptionally weak;

N/A indicates that the report is not a primary reference or a systematic review and therefore the quality has not been assessed.

Chronic Obstructive Pulmonary Disease Evidence Grading System Sixth Edition/January 2007


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References

Alsaeedi A, Sin DD, McAlister FA. The effects of inhaled corticosteroids in chronic obstructive pulmo-nary disease: a systematic review of randomized placebo-controlled trials. Am J Med 2002;113:59-65. (Class M)

American Association for Respiratory Care (AARC). AARC Clinical Practice Guideline. Respir Care 1996;41:629-36. (Class R)

American Thoracic Society (ATS). ATS statement: standards for the diagnosis and care of patients with COPD. Am J Respir Crit Care Med 1995;152:S77-S120. (Class R)

American Thoracic Society. Lung function testing: selection of reference values and interpretative strategies. Am Rev Respir Dis 1991;144:1202-18. (Class R)

American Thoracic Society. Pulmonary rehabilitation-1999. Am J Respir Crit Care Med 1999;159:1666-82. (Class R)

American Thoracic Society. Standardization of spirometry. Am J Respir Crit Care Med 1995;152:1107- 36. (Class R)

Amsden GW, Baird IM, Simon S, Treadway G. Efficacy and safety of azithromycin vs levofloxacin in the outpatient treatment of acute bacterial exacerbations of chronic bronchitis. Chest 2003;123:772-77. (Class A)

Anthonisen NR, Manfreda J, Warren CPW, et al. Antibiotic therapy in exacerbations of chronic obstruc-tive pulmonary disease. Ann Intern Med 1987;106:196-204. (Class A)

Arcasoy SM, Kotloff RM. Lung transplantation. N Engl J Med 1999;340:1081-91. (Class R)

Bando K, Paradis IL, Keenan RJ, et al. Comparison of outcomes after single and bilateral lung trans-plantation for obstructive lung disease. J Heart Lung Transplant 1995;14:692-98. (Class C)

Bartlett EE. At last, a definition. Pat Educ Couns 1985;7:323-24. (Class not assignable)

Bauldoff GS, Hoffman LA. Teaching COPD patients upper extremity exercises at home. Perspect Resp Nurs 1997;8:3-4. (Class not assignable)

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Dale LC, Glover ED, Sachs DPL, et al. Bupropion for smoking cessation*/predictors of successful outcome. Chest 2001;199:1357-64. (Class A)

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Chronic Obstructive Pulmonary Disease References Sixth Edition/January 2007


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Emanuel LL, Barry MJ, Stoeckle JD, et al. Advance directives for medical care – a case for greater use. N Engl J Med 1991;324:889-95. (Class D)

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Hosenpud JD, Bennett LE, Keck BM, et al. Effect of diagnosis on survival benefit of lung transplanta-tion for end-stage lung disease. Lancet 1998;351:24-27. (Class C)

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Kory RC, Bergmann JC, Sweet RD, et al. Comparative evaluation of oxygen therapy techniques. JAMA 1962;179:123-28. (Class D)

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Laros CD, Gelissen HJ, Bergstein PGM, et al. Bullectomy for giant bullae in emphysema. J Thorac Cardiovasc Surg 91:63-70, 1986. (Class D)

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Patrick DM, Dales RE, Stark RM, et al. Severe exacerbations of COPD and asthma: incremental benefit of adding ipratropium to usual therapy. Chest 1990;98:295-97. (Class A)

Pauwels RA, Buist AS, Calverley P, et al. Global strategy for the diagnosis, management, and preven-tion of chronic obstructive pulmonary disease: NHLBI/WHO Global initiative for chronic obstructive lung disease (Global Initiative for Chronic Obstructive Lung Disease) workshop summary. Am J Respir Crit Care Med 2001;163:1256-76. (Class R)

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Resnikoff P, Ries A. Pulmonary rehabilitation and adjunctive measures. Resp Care Clin North Am 1998;4:475-91. (Class R)

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U.S. Department of Health and Human Services. Treating tobacco use and dependence. Clinical practice guideline. June 2000. (Class R)

U.S. Food and Drug Administration Consumer Information Report/Relenza October 2000. Available at: http://www.fda.gov/cder/consumerinfo/ (Class not assignable)

Van Andel AE, Reisner C, Menjoge SS, et al. Analysis of inhaled corticosteroid and oral theophylline use among patients with stable COPD from 1987 to 1995. Chest 1999;115:703-07. (Class D)

van Noord JA, Aumann JL, Janssens E, et al. Effects of tiotropium with and without formoterol on airflow obstruction and resting hyperinflation in patients with COPD. Chest 2006;129:509-17. (Class A)

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Watson PB, Town GI, Holbrook N, et al. Evaluation of a self-management plan for COPD. Eur Resp J 1997;10:1267-71. (Class A)

Weitzenblum E, Sutegeau A, Erhart M, et al. Long-term oxygen therapy can reverse the progression of pulmonary hypertension in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1985;131:493-98. (Class C)

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�2

Conclusion Grading Worksheet A – Annotation #11 (Pharmacological Management)


Wor

k G

roup

's C

oncl

usio

n:A

lbut

erol

and

ipra

tropi

um a

re e

quip

oten

t as b

ronc

hodi

lato

rs, i

mpr

ovin

g dy

spne

a an

d ex

erci

seto

lera

nce

equa

lly w

ell.

Sal

met

erol

is a

long

-act

ing

bron

chod

ilato

r tha

t is a

suita

ble

agen

t for

sche

dule

d ad

min

istra

tion.

Con

clus

ion

Gra

de:

II

Aut

hor/

Yea

rD

esig

nTy

peC

lass

Qua

l-ity +

,–,ø

Popu

latio

n St

udie

d/Sa

mpl

e Si

zePr

imar

y O

utco

me

Mea

sure

(s)/R

esul

ts (e

.g.,

p-va

lue,

conf

iden

ce in

terv

al, r

elat

ive

risk,

odd

s rat

io, l

ikel

i-ho

od ra

tio, n

umbe

r nee

ded

to tr

eat)

Aut

hors

' Con

clus

ions

/W

ork

Gro

up's

Com

men

ts (i

talic

ized

)

A c

ombi

natio

n of

clin

ical

reco

mm

ende

d do

sage

s of s

alm

eter

ol a

nd ip

ratro

pium

is n

ot m

ore

effe

ctiv

e th

an sa

lmet

erol

alo

ne in

pat

ient

s with

chr

onic

obs

truct

ive

pulm

onar

y di

seas

e.Re

spir

Med

199

6;90

:497

-499

.M

ater

a M

G,

Cap

uti M

,Ca

zzol

a M

(199

6)

RC

TA

–-1

2 m

ale

patie

nts,

stab

le C

OPD

-Incl

uded

: sm

okin

g hi

story

>10

pack

-yrs

; >40

yrs

old

-Exc

lude

d: h

istor

y of

asth

ma,

al-

lerg

ic rh

initi

s, or

ato

py; t

otal

bloo

d eo

sino

phil

coun

t>4

00m

m3

-Fou

r tre

atm

ents

:a.

salm

eter

ol h

ydro

xyna

phth

oate

(50µ

g) p

lus p

lace

bob.

ipra

tropi

um b

rom

ide

(40µ

g)pl

us p

lace

boc.

salm

eter

ol (5

0µg)

plu

sip

ratro

pium

(40µ

g)d.

pla

cebo

plu

s pla

cebo

-FEV

1 mea

sure

d at

bas

elin

e an

dfo

r 12

hour

s afte

r tre

atm

ent

-No

diffe

renc

es b

etw

een

grou

ps a

t bas

elin

e (b

efor

ean

y of

the

treat

men

ts)

-Pea

k re

spon

se fo

r sal

met

erol

(28.

8%) w

as g

reat

erth

an fo

r ipr

atro

pium

(26.

0%) b

ut e

quiv

alen

t to

sal-

met

erol

plu

s ipr

atro

pium

(28.

0%)

-All

activ

e tre

atm

ents

prod

uced

sign

ifica

nt b

ron-

chod

ilatio

n ef

fect

from

15

to 3

60 m

inut

es a

fter

treat

men

t vs.

plac

ebo

(p<0

.05)

; onl

y sa

lmet

erol

and

salm

eter

ol p

lus i

prat

ropi

um h

ad si

gnifi

cant

incr

ease

over

pla

cebo

for 1

2-ho

ur m

onito

ring

perio

d (p

<0.0

5)-M

ean

area

s und

er F

EV1 r

espo

nse-

time

curv

es w

ere:

2.67

for s

alm

eter

ol, 1

.06

for i

prat

ropi

um, a

nd 2

.71

for s

alm

eter

ol p

lus i

prat

ropi

um; a

reas

for a

ctiv

etre

atm

ents

wer

e al

l gre

ater

than

for p

lace

bo (p

<0.0

5);

salm

eter

ol a

nd sa

lmet

erol

plu

s ipr

atro

pium

wer

egr

eate

r tha

n ip

ratro

pium

alo

ne (p

<0.0

5); n

o di

ffer-

ence

bet

wee

n tw

o sa

lmet

erol

gro

ups

-Fift

y m

icro

gram

s sal

met

erol

has

a lo

nger

dura

tion

of a

ctio

n th

an 4

0µg

ipra

tropi

umw

ith n

o be

nefit

of a

ddin

g ip

ratro

pium

tosa

lmet

erol

. Sa

lmet

erol

shou

ld b

e co

nsid

ered

an a

ttrac

tive

alte

rnat

ive

to o

ther

bro

ncho

dila

-to

rs a

nd e

ndor

sed

as a

firs

t-lin

e ag

ent.

NO

TES:

FEV

1 val

ues w

ere

betw

een

16%

and

62%

of p

redi

cted

val

ues a

fter b

ronc

hodi

lato

rdr

ugs h

ad b

een

with

held

for 2

4 hr

s and

12

hrs,

resp

ectiv

ely;

des

ign

was

sing

le-b

lind,

bala

nced

, cro

ss-o

ver,

rand

omiz

ed tr

ial d

one

on fo

ur n

on-c

onse

cutiv

e da

ys

Wor

k G

roup

’s C

omm

ents

: sm

all p

atie

ntpo

pula

tion;

pat

ient

sele

ctio

n cr

iteria

not

de-

scrib

ed; n

ot d

rug

com

pany

fund

ed


www.icsi.org

��

Conclusion Grading Worksheet A – Chronic Obstructive Pulmonary Disease Annotation #11 (Pharmacological Management) Sixth Edition/January 2007

Aut

hor/

Yea

rD

esig

nTy

peC

lass

Qua

l-ity +

,–,ø

Popu

latio

n St

udie

d/Sa

mpl

e Si

zePr

imar

y O

utco

me

Mea

sure

(s)/R

esul

ts (e

.g.,

p-va

lue,

conf

iden

ce in

terv

al, r

elat

ive

risk,

odd

s rat

io, l

ikel

i-ho

od ra

tio, n

umbe

r nee

ded

to tr

eat)

Aut

hors

' Con

clus

ions

/W

ork

Gro

up's

Com

men

ts (i

talic

ized

)

Com

paris

on o

f the

effe

cts o

f sal

met

erol

and

ipra

tropi

um b

rom

ide

on e

xerc

ise p

erfo

rman

ce a

nd b

reat

hles

snes

s in

patie

nts w

ith st

able

chr

onic

obs

truct

ive

pulm

onar

y di

seas

e. R

espi

rM

ed 1

998;

92:1

116-

1121

.Pa

taka

s D,

And

read

is D

,M

avro

fridi

s E,

& A

rgyr

opou

-lo

u P

(199

8)

RC

TA

ø-1

5 pa

tient

s, st

able

CO

PD,

mea

n ag

e 64

.6 y

rs-In

clud

ed: F

EV1 <

65%

of p

re-

dict

ed, l

ess t

hen

20%

reve

rsib

il-ity

on

beta

-adr

ener

gic

inha

latio

n,di

ffusin

g ca

paci

ty o

f lun

g fo

rCO

≤65

% o

f pre

dict

ed n

orm

alva

lue

-Exc

lude

d: co

rona

ry h

eart

dis-

ease

, lef

t ven

tricu

lar d

ysfu

nc-

tion,

seve

re h

yper

tens

ion,

dis

-ea

se o

f maj

or o

rgan

syst

em th

ataf

fect

ed ex

erci

se p

erfo

rman

ce-3

stud

y da

ys, 2

4 hr

s apa

rt-T

hree

trea

tmen

ts:a.

6 p

uffs

pla

cebo

b. 6

puf

fs ip

ratro

pium

bro

mid

e(1

20µg

)c.

2 p

uffs

salm

eter

ol (5

0µg)

-Pul

mon

ary

func

tion

asse

ssed

befo

re tr

eatm

ent a

nd 3

0 m

in a

f-te

r; pr

ogre

ssiv

e in

crem

enta

ltre

adm

ill te

st a

fter f

unct

ion

test

-No

diffe

renc

es in

pul

mon

ary

func

tion

valu

es b

efor

ean

y of

the

treat

men

ts-F

VC

, FEV

1, an

d in

spira

tory

flow

at 5

0% F

VC

im-

prov

ed a

fter s

alm

eter

ol a

nd ip

ratro

pium

but

not

afte

rpl

aceb

o (p

<0.0

5 fo

r all

com

paris

ons t

o pl

aceb

o; n

odi

ffere

nce

betw

een

two

treat

men

ts)-R

estin

g ar

teria

l O2 s

atur

atio

n (S

aO2)

and

nadi

r SaO

2du

ring

exer

cise

afte

r ipr

atro

pium

or s

alm

eter

ol n

otdi

ffere

nt fr

om p

lace

bo; S

aO2 r

ecov

ery

time

shor

ter

afte

r bot

h ac

tive

treat

men

ts (v

s. pl

aceb

o) (b

oth

p<0.

05)

-Dist

ance

wal

ked

incr

ease

d af

ter i

prat

ropi

um a

ndsa

lmet

erol

(bot

h p<

0.01

); di

stan

ce w

alke

d w

ithbr

eath

less

ness

scor

e ze

ro in

crea

sed

afte

r sal

met

erol

(p<0

.05)

onl

y, d

istan

ce w

alke

d at

Bor

g br

eath

less

-ne

ss sc

ale

scor

e of

5 in

crea

sed

afte

r bot

h tre

atm

ents

(bot

h p<

0.05

); m

axim

um B

org

brea

thle

ssne

ss sc

ale

scor

e du

ring

exer

cise

did

not

impr

ove

signi

fican

tlyw

ith a

ctiv

e tre

atm

ent

-Res

t and

exe

rcise

hea

rt ra

te a

nd b

lood

pre

ssur

e va

l-ue

s wer

e no

t sig

nific

antly

diff

eren

t afte

r act

ive

treat

-m

ent (

vs. a

fter p

lace

bo)

-No

adve

rse

effe

cts a

fter s

alm

eter

ol, i

prat

ropi

um, o

rpl

aceb

o

-The

inha

led

adre

nerg

ic a

gent

salm

eter

ol,

whe

n gi

ven

in c

onve

ntio

nal d

oses

, pro

duce

ssi

gnifi

cant

impr

ovem

ents

in th

e ai

rflo

w o

b-str

uctio

n, in

the

reco

very

from

pos

t-exe

rcise

oxyh

emog

lobi

n de

satu

ratio

n, a

nd th

e dy

sp-

neic

sen

satio

n in

pat

ient

s w

ith C

OPD

. Th

eef

fect

s wer

e sim

ilar t

o th

ose

prod

uced

afte

rth

e in

hala

tion

of th

e an

ticho

liner

gic

agen

tip

ratro

pium

bro

mid

e.

NO

TES:

pat

ient

s wer

e as

ked

to n

ot ta

keth

eoph

yllin

e an

d an

ticho

liner

gic

com

poun

dsfo

r 48

hrs b

efor

e th

e stu

dy a

nd n

o in

hale

dbr

onch

odila

tors

on

the

mor

ning

of t

he st

udy

days

; des

ign

was

rand

omiz

ed, c

ross

-ove

r (it

was

not

stat

ed w

heth

er a

sses

smen

t was

blin

ded)

Wor

k G

roup

’s C

omm

ents

: sm

all p

atie

ntpo

pula

tion;

pat

ient

sele

ctio

n cr

iteria

not

de-

scrib

ed; n

ot d

rug

com

pany

fund

ed


www.icsi.org

��

Aut

hor/

Yea

rD

esig

nTy

peC

lass

Qua

l-ity +

,–,ø

Popu

latio

n St

udie

d/Sa

mpl

e Si

zePr

imar

y O

utco

me

Mea

sure

(s)/R

esul

ts (e

.g.,

p-va

lue,

conf

iden

ce in

terv

al, r

elat

ive

risk,

odd

s rat

io, l

ikel

i-ho

od ra

tio, n

umbe

r nee

ded

to tr

eat)

Aut

hors

' Con

clus

ions

/W

ork

Gro

up's

Com

men

ts (i

talic

ized

)

A c

ompa

rison

of t

he b

ronc

hodi

latin

g ef

fect

s of s

alm

eter

ol, s

albu

tam

ol [a

lbut

erol

], an

d ip

ratro

pium

bro

mid

e in

pat

ient

s with

chr

onic

obs

truct

ive

pulm

onar

y di

seas

e. P

ulm

Pha

rma-

col 1

995;

8:26

7-27

1.M

ater

a M

G,

Caz

zola

M,

Vin

cigi

erra

A,

et a

l. (1

995)

RC

TA

ø-1

6 m

ales

, mod

erat

e to

seve

reC

OPD

, age

s 62

-73

yrs

-Incl

uded

: cur

rent

or f

orm

erhe

avy

smok

er; c

hron

ic c

ough

with

or w

ithou

t spu

tum

, or

dysp

nea

whe

n w

alki

ng, o

r bot

h;no

cha

nge

in sy

mpt

om se

verit

yor

trea

tmen

t in

past

4 w

ks; n

osig

ns o

f res

pira

tory

trac

t inf

ec-

tion

in p

ast m

onth

or d

urin

gtri

al; n

ot ta

king

ora

l cor

ticos

ter-

oids

; FEV

1 bet

wee

n 15

-69%

of

pred

icte

d af

ter b

eta-

agon

ists

with

held

for 2

4 hr

s-E

xclu

ded:

hist

ory

of a

sthm

a, a

l-le

rgic

rhin

itis,

or a

topy

; tot

albl

ood

eosi

noph

il co

unt

>400

mm

3

-Fou

r tre

atm

ents

:a.

50µ

g sa

lmet

erol

hy-

drox

ynap

htho

ate

b. 2

00µg

sal

buta

mol

[alb

uter

ol]

sulp

hate

c. 4

0µg

ipra

tropi

um b

rom

ide

d. p

lace

bo

-No

diffe

renc

es b

etw

een

base

line

valu

es b

efor

e an

y of

the

treat

men

ts-A

t 15

min

afte

r inh

alat

ion

incr

ease

d FE

V1 o

f ≥15

%w

as o

bser

ved

for 8

of 1

6 af

ter a

lbut

erol

, 4 o

f 16

afte

rsa

lmet

erol

, and

7 o

f 16

afte

r ipr

atro

pium

-Mea

n pe

ak b

ronc

hodi

latio

n oc

curre

d 30

min

afte

ral

bute

rol (

rang

e 15

-120

min

), 3

hrs a

fter s

alm

eter

ol(r

ange

30-

360

min

), an

d 2

hrs a

fter i

prat

ropi

um(ra

nge

15-3

00 m

in)

-Cha

nge

from

bas

elin

e fo

r sal

met

erol

exc

eede

d th

atfo

r pla

cebo

(p<0

.05)

for 1

2 hr

s (vs

. 6 h

rs fo

rip

ratro

pium

and

3 h

rs fo

r alb

uter

ol);

sim

ilar p

atte

rnof

resp

onse

s fo

r FEV

1, FV

C, a

nd F

EF50

-Mea

n ar

ea u

nder

FEV

1 vs.

time

curv

e w

as la

rger

(p<0

.05)

afte

r sal

met

erol

than

for i

prat

ropi

um o

r al-

bute

rol;

area

und

er ip

ratro

pium

FEV

1 cur

ve w

asla

rger

(p<0

.05)

than

for a

lbut

erol

-On

aver

age,

salm

eter

ol c

ompa

res v

ery

fa-

vora

bly

with

ipra

tropi

um b

rom

ide

in te

rms

of e

ffec

ts o

n lu

ng fu

nctio

n at

clin

ical

ly re

c-om

men

ded

dose

s. S

alm

eter

ol h

as a

slow

eron

set o

f effe

ct b

ut a

long

er d

urat

ion

of a

ctio

nth

an ip

ratro

pium

and

alb

uter

ol, w

hich

, be-

caus

e of

pro

long

ed d

osin

g in

terv

als,

may

en-

hanc

e co

mpl

ianc

e. T

he in

divi

dual

resu

lts,

how

ever

, sho

wed

that

salm

eter

ol re

sulte

d in

the

best

impr

ovem

ent i

n FE

V1 f

or 8

pat

ient

sw

hile

ipra

tropi

um w

as b

est f

or th

e re

mai

ning

8. NO

TES:

des

ign

was

dou

ble-

blin

d, m

ultip

lecr

oss-

over

, ran

dom

ized

; pat

ient

s had

not

take

n an

y in

hale

d br

onch

odila

tor f

or a

t lea

st12

hou

rs a

nd o

ral t

heop

hylli

ne fo

r at l

east

24

hrs b

efor

e stu

dy; a

void

ed ca

ffein

ated

bev

er-

ages

and

smok

ing

befo

re a

nd d

urin

g in

vesti

-ga

tion

Wor

k G

roup

’s C

omm

ents

: st

udy

sugg

ests

supe

riorit

y of

salm

eter

ol a

s a sc

hedu

led

dose

agen

t; sm

all p

atie

nt p

opul

atio

n; p

atie

nt se

-le

ctio

n cr

iteria

not

des

crib

ed; n

ot d

rug

com

-pa

ny fu

nded



www.icsi.org

��

Aut

hor/

Yea

rD

esig

nTy

peC

lass

Qua

l-ity +

,–,ø

Popu

latio

n St

udie

d/Sa

mpl

e Si

zePr

imar

y O

utco

me

Mea

sure

(s)/R

esul

ts (e

.g.,

p-va

lue,

conf

iden

ce in

terv

al, r

elat

ive

risk,

odd

s rat

io, l

ikel

i-ho

od ra

tio, n

umbe

r nee

ded

to tr

eat)

Aut

hors

' Con

clus

ions

/W

ork

Gro

up's

Com

men

ts (i

talic

ized

)

Com

paris

on o

f neb

ulis

ed sa

lbut

amol

[alb

uter

ol] a

nd ip

ratro

pium

bro

mid

e w

ith sa

lbut

amol

alo

ne in

the

treat

men

t of c

hron

ic o

bstru

ctiv

e pu

lmon

ary

dise

ase.

Tho

rax

1995

;50:

834-

837.

Moa

yyed

i, P,

Con

glet

on J

,Pa

ge R

L,Pe

arso

n SB

,&

Mue

rs M

F(1

995)

RC

TA

–-P

atie

nts a

dmitt

ed a

s em

erge

n-ci

es w

ith a

cute

exa

cerb

atio

n of

CO

PD; 7

0 en

rolle

d, 6

2 su

itabl

efo

r ana

lysis

-Incl

uded

: no

t tak

ing

regu

lar

nebu

lized

bro

ncho

dila

tors

; ove

r45

yrs

; sm

okin

g hi

stor

y of

>10

pack

yrs

; FEV

1 <65

% p

redi

cted

,hi

story

of e

xerti

onal

dys

pnea

for

>3 y

rs-E

xclu

ded:

hist

ory

sugg

estiv

e of

asth

ma;

per

iphe

ral e

osin

ophi

ia>1

0%; >

20%

reve

rsib

ility

of

FEV

1 to

400µ

g sa

lbut

amol

[al-

bute

rol]

-Ran

dom

ized

to re

ceiv

e m

ebu-

lized

salb

utam

ol [a

lbut

erol

](5

mg)

4x/

day

or sa

lbut

amol

[al-

bute

rol]

(5m

g) p

lus i

prat

ropi

um(5

00µg

) 4x/

day

-Spi

rom

eter

val

ues b

efor

e tre

at-

men

t, da

ys 3

& 7

, the

n w

eekl

yan

d on

day

of d

ischa

rge;

dai

lysu

bjec

tive

sym

ptom

scor

e

-Alb

uter

ol (n

=33)

and

com

bina

tion

(n=2

9) g

roup

sw

ere

com

para

ble

at b

asel

ine

in a

ge, h

t, w

t, sm

okin

g,ar

teria

l O2 a

nd C

O2 t

ensi

ons,

FEV

1, an

d FV

C-L

engt

h of

stay

(10.

5 da

ys fo

r alb

uter

ol g

roup

and

11.8

day

s for

com

bina

tion

grou

p) a

nd d

ays o

n ne

bu-

lizer

s (8.

5 da

ys a

nd 8

.2 d

ays,

resp

ectiv

ely)

wer

eco

mpa

rabl

e as

wer

e da

ys o

n am

inop

hylli

ne a

nd a

nti-

biot

ics;

days

on

stero

ids d

iffer

ed w

ith fe

wer

day

s on

ster

oids

for a

lbut

erol

onl

y (0

.1 a

nd 0

.6, r

espe

ctiv

ely,

p=0.

05)

-Cha

nges

in F

EV1 a

nd F

VC

val

ues w

ith re

spec

t to

base

line

at d

ay 3

, day

7, d

ay 1

4, a

nd d

ay o

f disc

harg

edi

d no

t diff

er b

etw

een

grou

ps (e

xcep

t FV

C da

y 3-

day1

, p=0

.05)

-No

diffe

renc

e in

subj

ectiv

e as

sess

men

t of i

mpr

ove-

men

t

-The

com

bina

tion

of a

lbut

erol

and

ipra

tro-

pium

bro

mid

e ap

pear

ed to

giv

e no

add

ition

albe

nefit

com

pare

d w

ith a

lbut

erol

alo

ne d

urin

gth

e ro

utin

e in

patie

nt tr

eatm

ent o

f an

acut

eex

acer

batio

n of

CO

PD.

NO

TES:

Of 7

0 en

rolle

d, 3

with

drew

, 2 w

ere

inel

igib

le (r

ever

sibi

lity

>20%

), 1

with

draw

nbe

caus

e of

new

ly d

iagn

osed

car

cino

ma,

2w

ithdr

awn

due

to si

de e

ffect

s; pa

tient

s wer

ebl

inde

d to

med

icat

ion

as w

ere

doct

ors w

hope

rform

ed sp

irom

eter

tests

; 3 d

eath

s dur

ing

adm

issi

on (1

in a

lbut

erol

gro

up, 2

in c

ombi

-na

tion

grou

p)

Wor

k G

roup

’s C

omm

ents

: pa

tient

sel

ectio

ncr

iteria

not

des

crib

ed; n

ot d

rug

com

pany

fund

ed; n

ot in

tent

ion-

to-tr

eat a

naly

sis; 1

1%lo

ss to

follo

w-u

p; a

pplic

atio

ns o

f the

se fi

nd-

ings

to a

gen

eral

, sta

ble

popu

latio

n sh

ould

be c

autio

ned

as th

e st

udy

was

don

e in

a se

t-tin

g of

acu

te e

xace

rbat

ion



www.icsi.org

��

Aut

hor/

Yea

rD

esig

nTy

peC

lass

Qua

l-ity +

,–,ø

Popu

latio

n St

udie

d/Sa

mpl

e Si

zePr

imar

y O

utco

me

Mea

sure

(s)/R

esul

ts (e

.g.,

p-va

lue,

conf

iden

ce in

terv

al, r

elat

ive

risk,

odd

s rat

io, l

ikel

i-ho

od ra

tio, n

umbe

r nee

ded

to tr

eat)

Aut

hors

' Con

clus

ions

/W

ork

Gro

up's

Com

men

ts (i

talic

ized

)

Exte

nded

ther

apy

with

ipra

tropi

um is

ass

ocia

ted

with

impr

oved

lung

func

tion

in p

atie

nts w

ith C

OPD

. C

hest

199

6;11

0:62

-70.

Renn

ard

SI,

Serb

y C

W,

Gha

four

i M,

John

son

PA,

& F

riedm

anM

(199

6)

Met

a-A

naly

-si

s

MN/A

-7 c

linic

al tr

ials

last

ing

at le

ast

90 d

ays c

ompa

ring

ipra

tropi

umw

ith a

β-a

goni

st (m

etap

rote

reno

lor

alb

uter

ol)

-Incl

uded

: di

agno

sis o

f CO

PD;

≥40

yrs

old;

sm

okin

g hi

stor

y≥1

0 pa

ck-y

rs; r

elat

ivel

y st

able

;FE

V1≤

65%

(5 tr

ials

) or ≤

75%

(2 tr

ials)

of p

redi

cted

; FEV

1<7

0% o

f FV

C-E

xclu

ded:

hist

ory

of a

sthm

a,al

lerg

ic rh

initi

s, or

ato

py; e

le-

vate

d bl

ood

eosi

noph

il co

unt;

>10

mg

pred

niso

ne/d

ay; u

se o

fcr

omol

yn so

dium

-2 tr

ials

requ

ired ≥1

5% im

-pr

ovem

ent i

n FE

V1 f

ollo

win

gis

opro

tere

nol i

nhal

atio

n-3

tria

ls ad

min

ister

ed d

rugs

by

nebu

lizer

, 4 b

y m

eter

ed-d

ose

in-

hale

r-B

asel

ine

lung

func

tion

befo

retre

atm

ent a

nd a

t 90

days

det

er-

min

ed a

fter w

ithho

ldin

g al

lbr

onch

odila

tors

for 1

2 ho

urs

-Tot

al o

f 1,8

36 p

atie

nts;

80%

of p

atie

nts i

n ip

ratro

-pi

um g

roup

(n=7

44) a

nd 7

7% o

f pat

ient

s in β-

agon

ist g

roup

s (n=

701)

com

plet

ed 3

mon

ths

-Gro

ups r

epor

ted

to b

e sim

ilar a

t bas

elin

e-P

oole

d da

ta fo

r cha

nges

from

bas

elin

e:Ip

ratro

pium

β-ag

onist

FEV

1, m

L28

(p<0

.01)

-1 (N

S)FV

C, m

L13

1 (p

<0.0

1)20

(NS)

Cha

nges

from

bas

elin

e fo

r β-a

goni

st g

roup

wer

e si

g-ni

fican

tly le

ss th

an fo

r ipr

atro

pium

gro

up (p

<0.0

5fo

r FEV

1, p<

0.01

for F

VC

)-9

0-da

y th

erap

y w

as a

ssoc

iate

d w

ith a

dec

reas

e in

num

ber o

f pat

ient

s who

resp

onde

d ac

utel

y (≥

15%

chan

ge in

FEV

1 & F

VC

) to

bron

chod

ilato

r; re

duc-

tion

in re

spon

sive

ness

was

gre

ater

for β

-ago

nist

grou

p (p

<0.0

01)

-Cur

rent

smok

ers i

mpr

oved

sim

ilarly

whe

n tre

ated

with

ipra

tropi

um a

nd β

-ago

nists

; ex-

smok

ers s

how

edgr

eate

r im

prov

emen

t whe

n tre

ated

with

ipra

tropi

uman

d m

inim

al im

prov

emen

t or w

orse

ning

whe

ntre

ated

with

β-a

goni

sts (n

o p-

valu

es re

porte

d)-S

ympt

om sc

ores

unc

hang

ed fo

r the

ove

rall

study

grou

p; im

prov

emen

t in

shor

tnes

s of b

reat

h no

ted

for

ex-s

mok

ers t

reat

ed w

ith ip

ratro

pium

(p=0

.005

); qu

al-

ity o

f life

scor

es im

prov

ed sl

ight

ly fo

r the

ent

iregr

oup;

gre

ater

impr

ovem

ent i

n qu

ality

of l

ife fo

r ex-

smok

ers t

reat

ed w

ith ip

ratro

pium

(p=0

.000

3)

-Nin

ety-

day

adm

inist

ratio

n of

ipra

tropi

um re

-su

lted

in im

prov

emen

ts in

bas

elin

e lu

ngfu

nctio

n (F

EV1 &

FV

C) a

nd a

cute

resp

onse

to b

ronc

hodi

lato

r the

rapy

. Ef

fect

s on

sym

p-to

ms a

nd q

ualit

y of

life

wer

e sm

all,

cons

is-

tent

with

sm

all c

hang

es in

lung

func

tion.

Patie

nts t

reat

ed w

ith β

-ago

nists

exp

erie

nced

min

imal

cha

nges

in b

asel

ine

lung

func

tion

and

lung

func

tion

afte

r sho

rt-te

rm a

dmin

istra

-tio

n of

bro

ncho

dila

tor d

ecre

ased

ove

r tim

e.

NO

TES:

the

incl

uded

tria

ls w

ere

part

of d

rug

deve

lopm

ent p

rogr

ams c

ondu

cted

by

one

phar

mac

eutic

al c

ompa

ny; c

ontin

ued

use

ofst

able

dos

es o

f the

ophy

lline

, inh

aled

ster

oids

,or

ora

l ste

roid

s (≤1

0 m

g/da

y) w

as a

llow

ed;

regu

lar u

se o

f inh

aled

bro

ncho

dila

tors

oth

erth

an st

udy

drug

was

not

per

mitt

ed; i

ncre

ase

in o

r add

ition

of o

ral s

tero

ids w

as a

llow

edbu

t lim

ited

to 2

per

iods

of ≤

5 da

ys; r

esid

ual

bron

chod

ilato

r effe

cts m

ay h

ave

been

pre

sent

desp

ite w

ithho

ldin

g fo

r 12

hour

s

Wor

k G

roup

’s C

omm

ents

: th

e in

clud

ed tr

i-al

s wer

e al

l fun

ded

by B

oehr

inge

r Ing

elhe

imPh

arm

aceu

tical

s, th

e m

aker

of i

prat

ropi

um



www.icsi.org

�7

Aut

hor/

Yea

rD

esig

nTy

peC

lass

Qua

l-ity +

,–,ø

Popu

latio

n St

udie

d/Sa

mpl

e Si

zePr

imar

y O

utco

me

Mea

sure

(s)/R

esul

ts (e

.g.,

p-va

lue,

conf

iden

ce in

terv

al, r

elat

ive

risk,

odd

s rat

io, l

ikel

i-ho

od ra

tio, n

umbe

r nee

ded

to tr

eat)

Aut

hors

' Con

clus

ions

/W

ork

Gro

up's

Com

men

ts (i

talic

ized

)

A c

ompa

rison

of t

he b

ronc

hodi

latin

g ef

fect

s of a

bet

a-2

adre

nerg

ic a

gent

(alb

uter

ol) a

nd a

n an

ticho

liner

gic

agen

t (ip

ratro

pium

bro

mid

e) g

iven

by

aero

sol a

lone

or i

n se

quen

ce.

NEn

gl J

Med

198

6;31

5:73

5-73

9.Ea

ston

PA

,Ja

due

C,D

hing

ra S

, &A

ntho

nise

nN

R (1

986)

RC

TA

–-1

1 pa

tient

s w

ith C

OPD

; mea

nag

e 70

yea

rs (r

ange

59-

79)

-Incl

uded

: clin

ical

dia

gnos

is of

chro

nic

bron

chiti

s, em

phys

ema

or b

oth;

his

tory

of c

igar

ette

smok

ing;

evi

denc

e of

seve

re a

ir-flo

w o

bstru

ctio

n (F

EV1<

1.5L

and

need

for l

ong-

term

bro

n-ch

odila

tor t

hera

py)

-Exc

lude

d: h

istor

y su

gges

tive

ofas

thm

a; e

osin

ophi

lia; e

xace

rba-

tion

of a

irflo

w o

bstru

ctio

n or

any

chan

ge in

med

icat

ions

inpr

eced

ing

2 m

onth

s-4

pro

toco

ls:

a. 4

00µg

alb

uter

ol +

200

µg a

t15

min

+ 2

00µg

at 3

0 m

in +

80µg

ipra

tropi

um a

t 90

min

b. s

ame

with

pla

cebo

at 9

0 m

inc.

80µ

g ip

ratro

pium

+ 4

0µg

at30

min

+ 2

00µg

alb

uter

ol a

t12

0 m

ind.

sam

e w

ith p

lace

bo a

t 120

min

-Spi

rom

etry

at b

asel

ine,

bef

ore

2nd in

hala

nt, a

fter 2

nd in

hala

nt-B

linde

d ou

tcom

e as

sess

men

t

-Mea

n sm

okin

g hi

stor

y of

56

pack

-yea

rs-B

asel

ine

FEV

1 val

ues c

ompa

rabl

e be

fore

all

prot

o-co

ls (a

s wer

e ot

her m

easu

res)

-Mea

n ch

ange

s in

FEV

1 in

resp

onse

to a

lbut

erol

alon

e an

d to

ipra

tropi

um a

lone

wer

e no

t sig

nific

antly

diffe

rent

; effe

ct o

f add

ing

a se

cond

age

nt d

id n

ot d

iffer

from

that

of p

lace

bo-P

atte

rn o

f mea

n ch

ange

s in

spec

ific

airw

ay c

ondu

c-ta

nce

was

the

sam

e as

for F

EV1

-Sim

ilar l

esse

ning

of h

yper

infla

tion

with

eith

erag

ent a

lone

; neg

ligib

le a

dditi

onal

cha

nge

whe

n ei

ther

agen

t was

inha

led

seco

nd-N

o sid

e ef

fect

s rep

orte

d by

any

pat

ient

; no

evid

ence

of tr

emor

and

no

incr

ease

in h

eart

rate

ove

r bas

elin

edu

ring

any

prot

ocol

-Alb

uter

ol a

nd ip

ratro

pium

bro

mid

e ar

e eq

ui-

pote

nt in

max

imal

dos

es; t

he a

dditi

on o

fip

ratro

pium

to a

hig

h do

se o

f alb

uter

ol is

of

no p

ract

ical

val

ue.

NO

TES:

des

ign

was

rand

omiz

ed, d

oubl

e-bl

ind,

cro

ss-o

ver d

one

on 4

con

secu

tive

days

;pa

tient

s allo

wed

to c

ontin

ue o

ral m

edic

atio

nsin

clud

ing

theo

phyl

lines

at u

sual

dos

age

and

times

; aer

osol

bro

ncho

dila

tors

wer

e di

scon

-tin

ued

6 hr

s bef

ore

start

of e

ach

prot

ocol

;w

hen

used

as t

he in

itial

age

nt th

e do

sage

ex-

ceed

ed th

at re

com

men

ded

by m

anuf

actu

rer

for s

ingl

e-do

se b

ut c

umul

ativ

e am

ount

giv

enw

as n

ot g

reat

er th

an re

com

men

ded

daily

max

imum

Wor

k G

roup

’s C

omm

ents

: 8

puffs

of a

l-bu

tero

l was

wel

l-tol

erat

ed w

ithou

t sid

e ef

-fe

cts a

nd p

rovi

ded

up to

45%

impr

ovem

ent

in F

EV1;

smal

l pat

ient

pop

ulat

ion;

not

dru

gco

mpa

ny fu

nded



www.icsi.org

��

Aut

hor/

Yea

rD

esig

nTy

peC

lass

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l-ity +

,–,ø

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latio

n St

udie

d/Sa

mpl

e Si

zePr

imar

y O

utco

me

Mea

sure

(s)/R

esul

ts (e

.g.,

p-va

lue,

conf

iden

ce in

terv

al, r

elat

ive

risk,

odd

s rat

io, l

ikel

i-ho

od ra

tio, n

umbe

r nee

ded

to tr

eat)

Aut

hors

' Con

clus

ions

/W

ork

Gro

up's

Com

men

ts (i

talic

ized

)

Is a

n an

ticho

liner

gic

agen

t sup

erio

r to

a ß 2

- ago

nist

in im

prov

ing

dysp

nea

and

exer

cise

lim

itatio

n in

CO

PD?

Che

st 1

995;

108:

730-

735.

Blo

sser

SA

,M

axw

ell S

L,Re

eves

-Hoc

heM

K, L

ocal

ioA

R, &

Zw

il-lic

h C

W(1

995)

RC

TA

–-V

olun

teer

s with

CO

PD (A

TScr

iteria

)-In

clud

ed:

FEV

1 <55

% o

f pre

-di

cted

; >15

% im

prov

emen

t ove

rba

selin

e fo

llow

ing

albu

tero

l and

ipra

tropi

um; a

ble

to w

alk

for 1

2m

in; a

ble

to w

ithho

ld in

hale

dbr

onch

odila

tors

(6-1

2 hr

s) p

rior

to v

isits

; the

ophy

lline

leve

lsw

ithin

5%

of b

asel

ine

durin

gstu

dy; c

ortic

oste

roid

dos

e un

-ch

ange

d 1

mon

th p

rior a

nd d

ur-

ing

stud

y-E

xclu

ded:

uns

tabl

e an

gina

,C

HF,

nar

row

-ang

le g

lauc

oma,

BPH

-Tw

o 7-

day

treat

men

t pha

ses (

2pu

ffs 4

x/da

y of

alb

uter

ol o

rip

ratro

pium

) with

7-d

ay w

asho

utbe

twee

n

-Of 2

7 vo

lunt

eers

, 19

wer

e el

igib

le a

nd 1

5 co

mpl

eted

the

stud

y; a

ges r

ange

d fr

om 5

3 to

72

yrs

-12-

min

ute

wal

k di

stanc

e af

ter 1

wk

of tr

eatm

ent w

asno

t sig

nific

antly

diff

eren

t (75

5.7m

for i

prat

ropi

umvs

. 751

.0 m

for a

lbut

erol

); bo

th im

prov

ed s

igni

fi-ca

ntly

ove

r bas

elin

e (p≤0

.01)

; no

diffe

renc

e be

twee

nw

eek

1 an

d w

eek

2 re

gard

less

of t

reat

men

t-M

ean

dysp

nea

afte

r 12-

min

wal

k di

d no

t diff

er fr

omba

selin

e af

ter 1

wk

of ip

ratro

pium

but

was

diff

eren

taf

ter 1

wk

of a

lbut

erol

(p=0

.02)

; dys

pnea

scor

edda

ily, o

xyge

n co

st, a

nd m

ean

num

ber o

f res

cue

“puf

fs”

did

not d

iffer

bet

wee

n th

e 2

treat

men

t gro

ups;

signi

fican

tly m

ore

resc

ue “

puffs

” du

ring

was

hout

wee

k th

an a

lbut

erol

wee

k (p

=0.0

03) o

r ipr

atro

pium

wee

k (p

=0.0

1)-M

ean

FEV

1 afte

r wee

k of

alb

uter

ol w

as n

ot d

iffer

ent

from

bas

elin

e FE

V1 n

or fr

om F

EV1 a

fter a

wee

k of

ipra

tropi

um; F

EV1 a

fter i

prat

ropi

um w

as im

prov

edov

er b

asel

ine

(p=0

.03)

-7 su

bjec

ts pr

efer

red

albu

tero

l, 7

pref

erre

d ip

ratro

-pi

um, a

nd 1

had

no

pref

eren

ce-I

n a

mul

tivar

iate

ana

lysi

s the

re w

as n

o si

gnifi

cant

diffe

renc

e be

twee

n ov

eral

l effe

cts o

f the

2 d

rugs

-The

re w

ere

no si

gnifi

cant

mea

sura

ble

diffe

r-en

ces i

n ex

erci

se a

bilit

y or

exe

rtion

al d

ysp-

nea

in su

bjec

ts w

ith se

vere

stab

le C

OPD

in-

halin

g sta

ndar

d do

ses o

f eith

er a

lbut

erol

or

ipra

tropi

um fo

r 1 w

eek.

NO

TES:

stu

dy d

esig

n w

as d

oubl

e-bl

inde

dtw

o-pe

riod

cros

sove

r; m

etap

rote

reno

l allo

wed

durin

g tre

atm

ent a

nd w

asho

ut p

hase

s; m

edi-

catio

n ca

niste

rs w

eigh

ed a

t end

of 7

-day

perio

d to

qua

ntita

te u

se; p

atie

nts w

ere

re-

porte

d to

be

“gen

eral

ly c

ompl

iant

”; m

ulti-

varia

te a

naly

sis w

as u

sed

to a

ccou

nt fo

r cor

-re

latio

n am

ong

mea

sure

men

ts of

dist

ance

wal

ked,

dys

pnea

on

wal

king

, pea

k flo

w, a

ndFE

V1 w

ithin

subj

ects

and

for t

he se

quen

ce o

fad

min

istra

tion

of d

rugs

Wor

k G

roup

’s C

omm

ents

: sm

all p

atie

ntpo

pula

tion

ther

efor

e m

ay n

ot h

ave

suffi

cien

tst

atis

tical

pow

er to

det

ect s

igni

fican

t diff

er-

ence

s; n

ot in

tent

ion-

to-tr

eat a

naly

sis;

no

base

line

com

pari

sons

; fun

ded

by G

laxo

, the

mak

ers o

f alb

uter

ol



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rD

esig

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latio

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udie

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mpl

e Si

zePr

imar

y O

utco

me

Mea

sure

(s)/R

esul

ts (e

.g.,

p-va

lue,

conf

iden

ce in

terv

al, r

elat

ive

risk,

odd

s rat

io, l

ikel

i-ho

od ra

tio, n

umbe

r nee

ded

to tr

eat)

Aut

hors

' Con

clus

ions

/W

ork

Gro

up's

Com

men

ts (i

talic

ized

)

The

com

bina

tion

of ip

ratro

pium

and

alb

uter

ol o

ptim

izes

pul

mon

ary

func

tion

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for a

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if th

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pare

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Pha

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aker

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�0

This section provides resources, strategies and measurement specifications for use in closing the gap between current clinical practice and the recommendations set forth in the guideline.

The subdivisions of this section are:

• Priority Aims and Suggested Measures

- Measurement Specifications

• Key Implementation Recommendations

• Knowledge Products and Resources

• Other Resources Available


Support for Implementation:


Copyright © 2007 by Institute for Clinical Systems Improvement


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�1

Priority Aims and Suggested Measures

1. Increase the quality and use of spirometry testing in the diagnosis of patients with COPD.

Possible measure for accomplishing this aim:

a. Percentage of spirometry tests performed that meet the ATS Statement of Standardization of Spirom-etry.

b. Percentage of patients with a diagnosis of COPD who received routine spirometry testing at the time of diagnosis.

2. Increase the number of patients with COPD who receive information on the options for tobacco cessa-tion and information on the risks of continued smoking.

Possible measures for accomplishing this aim:

a. Percentage of patients with COPD whose physician inquired about smoking cessation (if patient a smoker) at every visit.

b. Percentage of patients with COPD who have documented assessment of readiness to attempt tobacco cessation.

c. Percentage of patients with COPD who receive a prescription for medication to aid smoking cessa-tion.

d. Percentage of patients who have a smoking cessation intervention.

e. Percentage of patients with COPD who quit (100% quit-rate goal).

f. Percentage of patients with COPD who are non-tobacco users.

3. Reduce COPD exacerbation requiring emergency department (ED) evaluation or hospital admission.


a. Number of ED encounters for patients with COPD in a one-month period.

b. Number of hospital admissions for patients with COPD in a one-month period.

c. Number of patients with two or more hospitalizations within a 12-month period.

4. Increase the appropriate use of pharmacotherapy prescribed for patients with COPD.


a. Percentage of patients with COPD who received an influenza vaccine in the previous 12 months.

b. Percentage of patients with COPD who have received a pneumococcal vaccine.

c. Percentage of patients with COPD who are hypoxemic and meet criteria for long-term home oxygen who are prescribed oxygen.

d. Percentage of patients with severe COPD who have been assessed for the need for long-term oxygen.

e. Percentage of patients who have moderate to severe COPD who have a prescription for regular use of a scheduled bronchodilator.



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�2

5. Increase patients' education and management skills with COPD.


a. Percentage of patients with moderate or severe COPD who have been referred to a pulmonary rehabilitation or exercise program.

b. Percentage of patients with COPD instructed on the use of inhaler with spacer technique and with documentation that inhaler technique was observed by a doctor, nurse or other health care profes-sional.

c. Percentage of patients with COPD who express satisfaction with the supporting information about COPD and the level of their own participation in care.

d. Percentage of patients with COPD who have discussed health care directives (or advanced direc-tives) and goals of care with their health care professional.

6. Increase the number of patients with COPD presenting with an acute exacerbation who have an oxymetric evaluation.


a. Percentage of patients presenting with a COPD exacerbation having an oxymetric evaluation.

b. Percentage of patients with COPD who have an O2 saturation less than 88%, positive history of hypercapnia, questionable accuracy of oximetry, somnolence or other evidence of impending respi-ratory failure, who receive an ABG.

Chronic Obstructive Pulmonary Disease Priority Aims and Suggested Measures Sixth Edition/January 2007


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��

Measurement Specifications

Possible Success Measure #2aPercentage of patients with COPD whose physician inquired about smoking cessation (if patient a smoker) at every visit.

Population DefinitionPatients with COPD who have any indication on their charts that they are users of tobacco who presented to the clinic within a designated time period.

Data of Interest# of patients with documentation that the physician asked

about tobacco status and/or readiness to quit

Total # of patients with COPD who are smokers

Numerator/Denominator DefinitionsNumerator: Any indication in the chart that the physician asked about a change in smoking status and/or

readiness to quit.

Denominator: Patients with a diagnosis of chronic bronchitis: (491.8, 491.20, or 491.21) or asthma with COPD (493.2) or chronic emphysema (491.20) who have an indication in their charts that they are users of tobacco who present for a clinic visit within the reporting month.

Method/Source of Data CollectionIdentify patients with a clinic visit in the reporting month who meet the inclusion criteria. Data may be collected by medical record review.

Time Frame Pertaining to Data CollectionRandomly selected cases may be reviewed monthly.

Chronic Obstructive Pulmonary Disease Priority Aims and Suggested Measures Sixth Edition/January 2007


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Key Implementation Recommendations

The following system changes were identified by the guideline work group as key strategies for health care systems to incorporate in support of the implementation of this guideline.

1. A model of patient education should be established in the clinics based upon individual learning needs assessments and including coordinated plans jointly developed by educators, patients and their families. Patient education should include core learning and needs objectives based upon individual needs.

2. Include COPD patients in a system of patient visit planning for establishing tobacco status at each visit and advice to quit if appropriate, as well as appropriate pharmacotherapy and assessment of hypox-emia.

Knowledge Products and Resources

Criteria for Selecting ResourcesThe following resources were selected by the Chronic Obstructive Pulmonary Disease guideline work group as additional resources for providers and/or patients. The following criteria were considered in selecting these resources.

• The site contains information specific to the topic of the guideline.

• The content is supported by evidence-based research.

• The content includes the source/author and contact information.

• The content clearly states revision dates or the date the information was published.

• The content is clear about potential biases, noting conflict of interest and/or disclaimers as appropriate.

Resources Available to ICSI Members OnlyThe following materials are available to ICSI members only. Also available is a wide variety of other knowledge products, including tool kits on CQI processes and Rapid Cycling that can be helpful. To obtain copies of these or other Knowledge Products, go to http://www.icsi.org/knowledge.

To access these materials on the Web site, you must be logged in as an ICSI member.

Educational Resources• Pneumovax algorithm for (re)vaccination of persons with chronic disease or at high risk of infec-

tion



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Title/Description Audience Author/Organization Web Sites/Order InformationComprehensive websites for respira-tory care professionals with links to a site tailored to COPD patients and their families. Includes information about the disease, symptoms, treat-ment and support.

Patients and professionals

American Association for Respiratory Care

Professional focus:http://www.aarc.orgPatient focus:http://www.aarc.org/klein

Primarily provides support for patients with COPD and other lung diseases, rather than a source of medi-cal information. Includes a variety of resources on lung diseases compiled from many sources.

Patients American Lung Association (Minnesota Chapter)

http://www.alamn.org

Comprehensive Web site for COPD. Includes definition, diagnosis, risk factors, pathology. Also includes the management of stable COPD and acute exacerbation. Smoking cessa-tion, pharmacological therapy, pul-monary rehab, nutrition and surgical options information is also presented.

Patients and professionals

American Thoracic Society

http://www.thoracic.org/COPD

Guidelines for professionals in the diagnosis and treatment of COPD. Resources include pocket guides, patient guides, workshop reports, teaching and educational materials and newsletter.

Professionals and patients

Global Initiative for Chronic Obstructive Lung Disease

http://www.goldcopd.com

Health information on various diseases and conditions.

Patients Mayo Clinic http://www.mayohealth.org

Patient education resources based on current practice guidelines and stan-dards of care.

Patients Krames http://www.krames.com

Provides information on conferences, products and resources for nurses on all aspects of end-of-life care. Most resources available for a fee.

Nurses who provide end-of-life care

American Association of Colleges of Nursing; End-of-Life Nursing Education Consortium Project

http://www.aacn.nche.edu/elnec/ index.htm

Evidence-based clinical practice guidelines

Professionals American College of Chest Physicians

http://www.chestnet.org

Other Resources Available
