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Guideline Summary
Guideline Title
Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease.
Bibliographic Source(s)
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Vancouver (WA): Global Initiative for Chronic Obstructive Lung Disease (GOLD); 2013. 80 p. [547 references]
Guideline Status

This is the current release of the guideline.

This guideline updates a previous version: Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Vancouver (WA): Global Initiative for Chronic Obstructive Lung Disease (GOLD); 2011. 78 p.

Scope

Disease/Condition(s)

Chronic obstructive pulmonary disease (COPD)

Guideline Category
Counseling
Diagnosis
Evaluation
Management
Prevention
Risk Assessment
Treatment
Clinical Specialty
Critical Care
Emergency Medicine
Family Practice
Internal Medicine
Nursing
Pathology
Physical Medicine and Rehabilitation
Preventive Medicine
Pulmonary Medicine
Sleep Medicine
Intended Users
Advanced Practice Nurses
Allied Health Personnel
Nurses
Physician Assistants
Physicians
Public Health Departments
Respiratory Care Practitioners
Guideline Objective(s)
  • To increase awareness of chronic obstructive pulmonary disease (COPD) and help the millions of people who suffer from this disease and die prematurely from it or its complications
  • To improve prevention and management of COPD through a concerted worldwide effort of people involved in all facets of health care and health care policy, and to encourage an greater research interest in this highly prevalent disease
  • To provide a new paradigm for treatment of stable COPD that is based on the best scientific evidence available
Target Population

Adults 19 years or older at risk for or with chronic obstructive pulmonary disease

Interventions and Practices Considered

Assessment/Diagnosis

  1. Assessment of risk factors
  2. Initial diagnosis:
    • Assessment of symptoms
    • Medical history
    • Physical examination
    • Measurement of airflow limitation (spirometry)
    • Assessment of chronic obstructive pulmonary disease (COPD) severity
    • Assessment of exacerbation risk
    • Assessment of comorbidities
    • Combined COPD assessment
    • Additional investigations including imaging, lung volumes and diffusing capacity, oximetry and arterial blood gas measurement, alpha-1 antitrypsin deficiency screening, exercise testing, composite scores
    • Differential diagnosis

Management/Treatment

  1. Management of stable COPD
    • Identification and reduction of risk factor exposure (tobacco smoke, occupational exposure, indoor and outdoor air pollution)
    • Non-pharmacologic treatment
      • Smoking cessation
      • Physical activity
      • Pulmonary rehabilitation
      • Vaccination (influenza and pneumococcal vaccine)
      • Oxygen therapy
      • Ventilatory support
      • Surgical treatment (lung volume reduction, lung transplantation, bullectomy)
      • Palliative care, end-of-life care, hospice care
    • Pharmacologic treatment
      • Bronchodilators (beta2-agonists, anticholinergics, theophylline, combination therapy)
      • Inhaled corticosteroids (oral corticosteroids not recommended for stable disease)
      • Phosphodiesterase-4 inhibitor (roflumilast)
      • Combination therapy
    • Monitoring and follow-up
  2. Management of exacerbations
    • Diagnosis and assessment of severity:
      • Medical history
      • Assessment of severity
      • Laboratory tests
    • Pharmacologic management:
      • Bronchodilator therapy
      • Corticosteroids
      • Antibiotics
    • Non-pharmacologic management:
      • Controlled oxygen therapy
      • Ventilatory support (noninvasive and invasive mechanical ventilation)
      • Adjunct therapies
      • Considerations for intensive care unit (ICU) admission
    • Discharge and follow-up
  3. Management of comorbidities
Major Outcomes Considered
  • Prevalence of chronic obstructive pulmonary disease (COPD)
  • Mortality
  • Morbidity
  • Exacerbation of symptoms
  • Quality of life
  • Cost of care

Methodology

Methods Used to Collect/Select the Evidence
Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
Description of Methods Used to Collect/Select the Evidence

The revised recommendations are based on publications that appeared on a PubMed (www.nlm.nih.gov External Web Site Policy) search in mid-December 2012 for the period July 1, 2011 through mid-December 2012. Posted on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) website along with the updated documents is a list of all the publications reviewed by the Committee.

To produce the updated documents a PubMed search is done using search fields established by the Committee: 1) COPD, All Fields, All Adult: 19+ years, only items with abstracts, Clinical Trial, Systematic Reviews, Human. The first search included publications for July 1–December 31, 2011 for review by the Committee during the American Thoracic Society (ATS) meeting in May 2012. The second search included publications for January 1–June 30 2012 for review by the Committee during the European Respiratory Society (ERS) meeting in September 2012. Publications that appeared June 30 through mid-December 2012 were considered by email ballot. Publications in peer review journals not captured by PubMed can be submitted to the Chair, GOLD Science Committee, providing an abstract and the full paper are submitted in (or translated into) English.

Number of Source Documents

For the 2013 update, between July 1, 2011 and December 30, 2012, 201 articles met the search criteria. Of the 201 articles reviewed, 30 of them (and an additional 13 from previous years) were identified to have an impact on the 2013 updated report.

Methods Used to Assess the Quality and Strength of the Evidence
Weighting According to a Rating Scheme (Scheme Given)
Rating Scheme for the Strength of the Evidence

Description of Levels of Evidence

Evidence Category Sources of Evidence Definition
A Randomized controlled trials (RCTs). Rich body of data. Evidence is from endpoints of well-designed RCTs that provide a consistent pattern of findings in the population for which the recommendation is made. Category A requires substantial numbers of studies involving substantial numbers of participants.
B Randomized controlled trials. Limited body of data. Evidence is from endpoints of intervention studies that include only a limited number of patients, posthoc or subgroup analysis of RCTs, or meta-analysis of RCTs. In general, Category B pertains when few randomized trials exist, they are small in size, they were undertaken in a population that differs from the target population of the recommendation, or the results are somewhat inconsistent.
C Nonrandomized trials. Observational studies. Evidence is from outcomes of uncontrolled or nonrandomized trials or from observational studies.
D Panel consensus judgment This category is used only in cases where the provision of some guidance was deemed valuable but the clinical literature addressing the subject was deemed insufficient to justify placement in one of the other categories. The Panel Consensus is based on clinical experience or knowledge that does not meet the above-listed criteria.
Methods Used to Analyze the Evidence
Review of Published Meta-Analyses
Systematic Review
Description of the Methods Used to Analyze the Evidence

All members of the Committee receive a summary of citations and all abstracts. Each abstract is assigned to at least two Committee members, although all members are offered the opportunity to provide an opinion on any abstract. Members evaluate the abstract or, up to her/his judgment, the full publication, by answering four specific written questions from a short questionnaire, and to indicate if the scientific data presented impacts on recommendations in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) report. If so, the member is asked to specifically identify modifications that should be made.

Levels of evidence are assigned to management recommendations where appropriate. Evidence levels are indicated in boldface type enclosed in parentheses after the relevant statement e.g., (Evidence A). The methodological issues concerning the use of evidence from meta-analyses were carefully considered. This evidence level scheme (see the "Rating Scheme for the Strength of the Evidence" field) has been used in previous GOLD reports, and was in use throughout the preparation of the guideline document.

Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations

The entire GOLD Science Committee meets twice yearly to discuss each publication that was considered by at least 1 member of the Committee to potentially have an impact on COPD management. The full Committee then reaches a consensus on whether to include it in the report, either as a reference supporting current recommendations, or to change the report. In the absence of consensus, disagreements are decided by an open vote of the full Committee. Recommendations by the Committee for use of any medication are based on the best evidence available from the literature and not on labeling directives from government regulators. The Committee does not make recommendations for therapies that have not been approved by at least one regulatory agency.

As an example of the workload of the Committee, for the 2013 update, between July 1, 2011 and December 30, 2012, 201 articles met the search criteria. Of the 201 articles reviewed, 30 of them (and an additional 13 from previous years) were identified to have an impact on the 2013 updated report either by: A) modifying, that is, changing the text or introducing a concept requiring a new recommendation to the report; B) confirming, that is, adding or replacing an existing reference; or C) requiring modification for clarification of the text.

Rating Scheme for the Strength of the Recommendations

Not applicable

Cost Analysis

The guideline developers reviewed published cost analyses.

Method of Guideline Validation
External Peer Review
Description of Method of Guideline Validation

Not stated

Recommendations

Major Recommendations

The levels of evidence (A-D) are defined at the end of the "Major Recommendations" field.

Definition and Overview

Key Points
  • Chronic obstructive pulmonary disease (COPD), a common preventable and treatable disease, is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. Exacerbations and comorbidities contribute to the overall severity in individual patients.
  • COPD is a leading cause of morbidity and mortality worldwide and results in an economic and social burden that is both substantial and increasing.
  • Inhaled cigarette smoke and other noxious particles such as smoke from biomass fuels cause lung inflammation, a normal response that appears to be modified in patients who develop COPD. This chronic inflammatory response may induce parenchymal tissue destruction (resulting in emphysema), and disrupt normal repair and defense mechanisms (resulting in small airway fibrosis). These pathological changes lead to air trapping and progressive airflow limitation, and in turn to breathlessness and other characteristic symptoms of COPD.

Diagnosis and Assessment

Key Points
  • A clinical diagnosis of COPD should be considered in any patient who has dyspnea, chronic cough or sputum production, and a history of exposure to risk factors for the disease.
  • Spirometry is required to make the diagnosis in this clinical context; the presence of a post-bronchodilator forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) <0.70 confirms the presence of persistent airflow limitation and thus of COPD.
  • The goals of COPD assessment are to determine the severity of the disease, including the severity of airflow limitation, the impact on the patient's health status, and the risk of future events (such as exacerbations, hospital admissions, or death), in order to guide therapy.
  • Comorbidities occur frequently in COPD patients, including cardiovascular disease, skeletal muscle dysfunction, metabolic syndrome, osteoporosis, depression, and lung cancer. Given that they can occur in patients with mild, moderate and severe airflow limitation and influence mortality and hospitalizations independently, comorbidities should be actively looked for, and treated appropriately if present.

Diagnosis

Medical History

A detailed medical history of a new patient known or thought to have COPD should assess:

  • Patient's exposure to risk factors, such as smoking and occupational or environmental exposures
  • Past medical history, including asthma, allergy, sinusitis, or nasal polyps; respiratory infections in childhood; other respiratory diseases
  • Family history of COPD or other chronic respiratory disease
  • Pattern of symptom development: COPD typically develops in adult life and most patients are conscious of increased breathlessness, more frequent or prolonged "winter colds," and some social restriction for a number of years before seeking medical help
  • History of exacerbations or previous hospitalizations for respiratory disorder: Patients may be aware of periodic worsening of symptoms even if these episodes have not been identified as exacerbations of COPD
  • Presence of comorbidities, such as heart disease, osteoporosis, musculoskeletal disorders, and malignancies that may also contribute to restriction of activity
  • Impact of disease on patient's life, including limitation of activity, missed work and economic impact, effect on family routines, feelings of depression or anxiety, well-being and sexual activity
  • Social and family support available to the patient
  • Possibilities for reducing risk factors, especially smoking cessation

Physical Examination

Although an important part of patient care, a physical examination is rarely diagnostic in COPD. Physical signs of airflow limitation are usually not present until significant impairment of lung function has occurred, and their detection has a relatively low sensitivity and specificity. A number of physical signs may be present in COPD, but their absence does not exclude the diagnosis.

Spirometry

Spirometry is the most reproducible and objective measurement of airflow limitation available. Peak expiratory flow measurement alone cannot be reliably used as the only diagnostic test, despite its good sensitivity, because of its weak specificity. Good quality spirometric measurement is possible in any health care setting and all health care workers who care for COPD patients should have access to spirometry. A detailed discussion of some of the factors needed to achieve accurate test results can be found in the original guideline document.

Assessment of Disease

The goals of COPD assessment are to determine the severity of the disease, its impact on the patient's health status and the risk of future events (such as exacerbations, hospital admissions or death), in order to, eventually, guide therapy. To achieve these goals, COPD assessment must consider the following aspects of the disease separately:

  • Current level of patient's symptoms
  • Severity of the spirometric abnormality
  • Exacerbation risk
  • Presence of comorbidities

Assessment of Symptoms

There are several validated questionnaires to assess symptoms in patients with COPD. Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends the use of the Modified British Medical Research Council (mMRC) questionnaire or the COPD Assessment Test (CAT). The well-known mMRC questionnaire only assesses disability due to breathlessness; however, the COPD Assessment Test has a broader coverage of the impact of COPD on the patient's daily life and well-being.

Spirometric Assessment

The table below shows the classification of airflow limitation severity in COPD. Specific spirometric cut-points are used for purposes of simplicity. Spirometry should be performed after the administration of an adequate dose of a short-acting inhaled bronchodilator in order to minimize variability.

Classification of Severity of Airflow Limitation in COPD (Based on Post-Bronchodilator FEV1)
In patients with FEV1/FVC <0.70:
GOLD 1 Mild FEV1 ≥80% predicted
GOLD 2 Moderate 50% ≤FEV1 <80% predicted
GOLD 3 Severe 30% ≤FEV1 <50% predicted
GOLD 4 Very Severe FEV1 <30% predicted

FEV1, forced expiratory volume in 1 second

Assessment of Exacerbation Risk

An exacerbation of COPD is defined as an acute event characterized by a worsening of the patient's respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication. The rate at which exacerbations occur varies greatly between patients. The best predictor of having frequent exacerbations (2 or more exacerbations per year) is a history of previous treated events. In addition, worsening airflow limitation is associated with an increasing prevalence of exacerbations and risk of death.

Assessment of Comorbidities

Because COPD often develops in long-time smokers in middle age, patients frequently have a variety of other diseases related to either smoking or aging. COPD itself also has significant extrapulmonary (systemic) effects including weight loss, nutritional abnormalities and skeletal muscle dysfunction. The latter is characterized by both sarcopenia (loss of muscle cells) and abnormal function of the remaining cells. Its causes are likely multifactorial (inactivity, poor diet, inflammation, hypoxia) and it can contribute to exercise intolerance and poor health status in patients with COPD. Importantly, skeletal muscle dysfunction is a remediable source of exercise intolerance.

Comorbidities that occur frequently in COPD patients include cardiovascular disease, skeletal muscle dysfunction, metabolic syndrome, osteoporosis, depression and lung cancer. The existence of COPD may actually increase the risk for other diseases; this is particularly striking for COPD and lung cancer. Whether this association is due to common risk factors (e.g., smoking), involvement of susceptibility genes, or impaired clearance of carcinogens is not clear. Comorbidities can occur in patients with mild, moderate or severe airflow limitation, influence mortality and hospitalizations independently, and deserve specific treatment. Therefore, comorbidities should be looked for routinely, and treated appropriately, in any patient with COPD. The guidelines for the diagnosis, assessment of severity, and management of individual comorbidities in patients with COPD are the same as for all other patients. A more detailed description of the management of COPD and comorbidities is given in Chapter 6 of the original guideline document.

Combined COPD Assessment

An understanding of the impact of COPD on an individual patient combines the symptomatic assessment with the patient's spirometric classification and/or risk of exacerbations. This approach to combined assessment is illustrated in Figure 2.3 of the original guideline document.

Additional Investigations

The following additional investigations may be considered as part of the diagnosis and assessment of COPD (see the original guideline for detailed discussion of each investigation):

  • Imaging
  • Lung volumes and diffusing capacity
  • Oximetry and arterial blood gas measurement
  • Alpha-1 antitrypsin deficiency screening
  • Exercise testing
  • Composite scores

Differential Diagnosis

In some patients with chronic asthma, a clear distinction from COPD is not possible using current imaging and physiological testing techniques, and it is assumed that asthma and COPD coexist in these patients. In these cases, current management will include use of anti-inflammatory drugs and other treatments need to be individualized. Other potential diagnoses are usually easier to distinguish from COPD (see Table 2.7 in the original guideline document).

Therapeutic Options

Key Points
  • In patients who smoke, smoking cessation is very important. Pharmacotherapy and nicotine replacement reliably increase long-term smoking abstinence rates.
  • Appropriate pharmacologic therapy can reduce COPD symptoms, reduce the frequency and severity of exacerbations, and improve health status and exercise tolerance.
  • To date, none of the existing medications for COPD has been shown conclusively to modify the long-term decline in lung function.
  • Each pharmacological treatment regimen needs to be patient-specific, guided by severity of symptoms, risk of exacerbations, drug availability, and the patient's response.
  • Influenza and pneumococcal vaccination should be offered to every COPD patient; they appear to be more effective in older patients and those with more severe disease or cardiac comorbidity.
  • All patients who get short of breath when walking on their own pace on level ground should be offered rehabilitation; it can improve symptoms, quality of life, and physical and emotional participation in everyday activities.

Smoking Cessation

Smoking cessation is the intervention with the greatest capacity to influence the natural history of COPD. Evaluation of the smoking cessation component in a long term, multicenter study indicates that if effective resources and time are dedicated to smoking cessation, 25% long term quit rates can be achieved.

Recommendations for treating tobacco use and dependence are summarized in the table below:

Table. Treating Tobacco Use and Dependence: A Clinical Practice Guideline–Major Findings and Recommendations
  1. Tobacco dependence is a chronic condition that warrants repeated treatment until long-term or permanent abstinence is achieved.
  2. Effective treatments for tobacco dependence exist and all tobacco users should be offered these treatments.
  3. Clinicians and health care delivery systems must institutionalize the consistent identification, documentation, and treatment of every tobacco user at every visit.
  4. Brief smoking cessation counseling is effective and every tobacco user should be offered such advice at every contact with health care providers.
  5. There is a strong dose-response relation between the intensity of tobacco dependence counseling and its effectiveness.
  6. Three types of counseling have been found to be especially effective: practical counseling, social support as part of treatment, and social support arranged outside of treatment.
  7. First-line pharmacotherapies for tobacco dependence—varenicline, bupropion SR, nicotine gum, nicotine inhaler, nicotine nasal spray, and nicotine patch—are effective and at least one of these medications should be prescribed in the absence of contraindications.
  8. Tobacco dependence treatments are cost effective relative to other medical and disease prevention interventions.

A five-step program for intervention (see table below) provides a strategic framework helpful to health care providers interested in helping their patients stop smoking. Because tobacco dependence is a chronic disease, clinicians should recognize that relapse is common and reflects the chronic nature of dependence and addiction, not failure on the part of the clinician or the patient.

Table. Brief Strategies to Help the Patient Willing to Quit
  1. ASK: Systematically identify all tobacco users at every visit. Implement an office-wide system that ensures that, for EVERY patient at EVERY clinic visit, tobacco-use status is queried and documented.
  2. ADVISE: Strongly urge all tobacco users to quit. In a clear, strong, and personalized manner, urge every tobacco user to quit.
  3. ASSESS: Determine willingness to make a quit attempt. Ask every tobacco user if he or she is willing to make a quit attempt at this time (e.g., within the next 30 days).
  4. ASSIST: Aid the patient in quitting. Help the patient with a quit plan; provide practical counseling; provide intra-treatment social support; help the patient obtain extra-treatment social support; recommend use of approved pharmacotherapy except in special circumstances; provide supplementary materials.
  5. ARRANGE: Schedule follow-up contact. Schedule follow-up contact, either in person or via telephone.

Counseling delivered by physicians and other health professionals significantly increases quit rates over self-initiated strategies (Evidence A).

Pharmacologic Therapy for Stable COPD

Overview of the Medications

Pharmacologic therapy for COPD is used to reduce symptoms, reduce the frequency and severity of exacerbations, and improve health status and exercise tolerance. To date, none of the existing medications for COPD has been conclusively shown to modify the long-term decline in lung function when this is tested as a primary or secondary outcome in clinical trials. Post-hoc evidence of such an effect with long-acting bronchodilators and/or inhaled corticosteroids requires confirmation in specifically designed trials.

Each treatment regimen needs to be patient-specific as the relationship between severity of symptoms, airflow limitation, and severity of exacerbations will differ between patients.

Bronchodilators

Bronchodilator medications are given on either an as needed basis or a regular basis to prevent or reduce symptoms (Evidence A).

Table. Bronchodilators in Stable COPD
  • Bronchodilator medications are central to symptom management in COPD.
  • Inhaled therapy is preferred.
  • The choice between beta2-agonist, anticholinergic, theophylline, or combination therapy depends on availability and individual patient response in terms of symptom relief and side effects.
  • Bronchodilators are prescribed on an as-needed or on a regular basis to prevent or reduce symptoms.
  • Long-acting inhaled bronchodilators are convenient and more effective at producing maintained symptom relief than short-acting bronchodilators.
  • Combining bronchodilators of different pharmacological classes may improve efficacy and decrease the risk of side effects compared to increasing the dose of a single bronchodilator.

Beta2-agonists

The principal action of beta2-agonists is to relax airway smooth muscle by stimulating beta2- adrenergic receptors, which increases cyclic adenosine monophosphate (AMP) and produces functional antagonism to bronchoconstriction. The bronchodilator effects of short-acting beta2-agonists usually wear off within 4 to 6 hours. Regular and as-needed use of short-acting beta2-agonists improve FEV1 and symptoms (Evidence B). The use of high doses of short-acting beta2-agonists on an as-needed basis in patients already treated with long-acting bronchodilators is not supported by evidence, may be limited by side effects, and cannot be recommended. For single-dose, as-needed use in COPD, there appears to be no advantage in using levalbuterol over conventional bronchodilators.

Long-acting inhaled beta2-agonists show duration of action of 12 or more hours. Formoterol and salmeterol significantly improve FEV1 and lung volumes, dyspnea, health-related quality of life and exacerbation rate (Evidence A), but have no effect on mortality and rate of decline of lung function. Salmeterol reduces the rate of hospitalization (Evidence B). Indacaterol is a once daily beta2-agonists with a duration of action of 24 hours. The bronchodilator effect is significantly greater than that of formoterol and salmeterol, and similar to tiotropium (Evidence A). Indacaterol has significant effects on breathlessness, health status and exacerbation rate (Evidence B). Its safety profile is similar to placebo; in clinical trials a significant number of patients (24% vs. 7%) experienced cough following the inhalation of indacaterol.

Anticholinergics

The most important effect in COPD patients of anticholinergic medications, such as ipratropium, oxitropium and tiotropium bromide, appears to be blockage of acetylcholine's effect on muscarinic receptors. Current short-acting drugs block M2 and M3 receptors and modify transmission at the pre-ganglionic junction, although these effects appear less important in COPD. The long-acting anticholinergic tiotropium has a pharmacokinetic selectivity for the M3 and M1 receptors. The bronchodilating effect of short-acting inhaled anticholinergics lasts longer than that of short-acting beta2-agonists, with some bronchodilator effect generally apparent up to 8 hours after administration. Tiotropium has duration of action of more than 24 hours. Tiotropium reduces exacerbations and related hospitalizations, improves symptoms and health status (Evidence A), and improves the effectiveness of pulmonary rehabilitation (Evidence B).

Methylxanthines

Theophylline is less effective and less well tolerated than inhaled long-acting bronchodilators and is not recommended if those drugs are available and affordable. However, there is evidence for a modest bronchodilator effect compared with placebo in stable COPD (Evidence A). There is also some evidence of symptomatic benefit compared to placebo. Addition of theophylline to salmeterol produced a greater improvement in FEV1 and breathlessness than salmeterol alone (Evidence B). Low-dose theophylline reduces exacerbations but does not improve post-bronchodilator lung function (Evidence B).

Combination Bronchodilator Therapy

Combining bronchodilators with different mechanisms and durations of action may increase the degree of bronchodilation for equivalent or lesser side effects. For example, a combination of a short-acting beta2-agonist and an anticholinergic produces greater and more sustained improvements in FEV1 than either drug alone and does not produce evidence of tachyphylaxis over 90 days of treatment. The combination of a beta2-agonist, an anticholinergic, and/or theophylline may produce additional improvements in lung function and health status. Short-term combination therapy using formoterol and tiotropium has been shown to have a bigger impact on FEV1 than the single components (Evidence B). Combinations of short-acting beta2-agonists and anticholinergics are also superior compared to either medication alone in improving FEV1 and symptoms (Evidence B).

Corticosteroids

Regular treatment with inhaled corticosteroids improves symptoms, lung function, and quality of life, and reduces the frequency of exacerbations in COPD patients with an FEV1 <60% predicted (Evidence A). Withdrawal from treatment with inhaled corticosteroids may lead to exacerbations in some patients. Regular treatment with inhaled corticosteroids does not modify the long-term decline of FEV1 nor mortality in patients with COPD (Evidence A).

Combination Inhaled Corticosteroid/Bronchodilator Therapy

An inhaled corticosteroid combined with a long-acting beta2-agonist is more effective than the individual components in improving lung function and health status and reducing exacerbations in patients with moderate (Evidence B) to very severe COPD (Evidence A). A large prospective clinical trial failed to demonstrate a statistically significant effect of combination therapy on mortality, but a subsequent meta-analysis found that combination therapy may reduce mortality with a number needed to treat (NNT) of 36 (Evidence B). Combination therapy is associated with an increased risk of pneumonia, but no other significant side effect (Evidence A). The addition of a long-acting beta2-agonist/inhaled corticosteroid combination to tiotropium improves lung function and quality of life and may further reduce exacerbations (Evidence B) but more studies of triple therapy are needed.

Oral Corticosteroids

In view of the well-known toxicity of long-term treatment with oral corticosteroids, prospective studies on the long-term effects of these drugs in COPD are limited.

Phosphodiesterase-4 Inhibitors

The principal action of phosphodiesterase-4 inhibitors is to reduce inflammation by inhibiting of the breakdown of intracellular cyclic AMP. It is a once daily oral medication with no direct bronchodilator activity, although it has been shown to improve FEV1 in patients treated with salmeterol or tiotropium. Roflumilast reduces moderate and severe exacerbations treated with corticosteroids by 15-20% in patients with chronic bronchitis, severe to very severe COPD, and a history of exacerbations (Evidence A). The effects on lung function are also seen when roflumilast is added to long-acting bronchodilators (Evidence A). There are no direct comparison or add-on studies of roflumilast and inhaled corticosteroids. Phosphodiesterase-4 inhibitors should always be used in combination with at least one long-acting bronchodilator.

Other Pharmacologic Treatments

Vaccines

Influenza vaccination can reduce serious illness (such as lower respiratory tract infections requiring hospitalization) and death in COPD patients (Evidence A). Vaccines containing killed or live, inactivated viruses are recommended as they are more effective in elderly patients with COPD. The strains are adjusted each year for appropriate effectiveness and should be given once each year. Pneumococcal polysaccharide vaccine is recommended for COPD patients 65 years and older, and also in younger patients with significant comorbid conditions such as cardiac disease. In addition, this vaccine has been shown to reduce the incidence of community-acquired pneumonia in COPD patients younger than age 65 with an FEV1 <40% predicted (Evidence B).

Alpha-1 Antitrypsin Augmentation Therapy

Young patients with severe hereditary alpha-1 antitrypsin deficiency and established emphysema may be candidates for alpha-1 antitrypsin augmentation therapy (Evidence C). However, this therapy is very expensive, is not available in most countries, and is not recommended for patients with COPD that is unrelated to alpha-1 antitrypsin deficiency.

Antibiotics

In older studies prophylactic, continuous use of antibiotics was shown to have no effect on the frequency of exacerbations in COPD, and a study that examined the efficacy of chemoprophylaxis undertaken in winter months over a period of 5 years concluded that there was no benefit. Although recent studies have shown some effects of antibiotics on exacerbation rate, the role of this treatment is unclear. A recent trial of daily azithromycin showed efficacy on exacerbation end-points; however, treatment is not recommended because of an unfavorable balance between benefits and side effects. Thus, the use of antibiotics, other than for treating infectious exacerbations of COPD and other bacterial infections, is currently not indicated (Evidence B).

Mucolytic (Mucokinetic, Mucoregulator) and Antioxidant Agents (Ambroxol, Erdosteine, Carbocysteine, Iodinated Glycerol)

The regular use of mucolytics in COPD has been evaluated in a number of long-term studies with controversial results. Although a few patients with viscous sputum may benefit from mucolytics, the overall benefits seem to be very small; the widespread use of these agents cannot be recommended at present (Evidence D). Drugs like N-acetylcysteine may have antioxidant effects, leading to speculation that these medications could have a role in the treatment of patients with recurrent exacerbations (Evidence B). There is some evidence that in COPD patients not receiving inhaled corticosteroids, treatment with mucolytics such as carbocysteine and N-acetylcysteine may reduce exacerbations (Evidence B) although a Cochrane review showed little or no effect on the overall quality of life.

Immunoregulators (Immunostimulators, Immunomodulators)

Studies using an immunoregulator in COPD report a decrease in the severity and frequency of exacerbations. However, additional studies to examine the long-term effects of this therapy are required; at present, its regular use cannot be recommended.

Antitussives

Cough, although sometimes a troublesome symptom in COPD, has a significant protective role. The regular use of antitussives is not recommended in stable COPD (Evidence D).

Vasodilators

The belief that pulmonary hypertension in COPD is associated with a poorer prognosis has provoked many attempts to reduce right ventricular afterload, increase cardiac output, and improve oxygen delivery and tissue oxygenation. Many agents have been evaluated, including inhaled nitric oxide, but the results have been uniformly disappointing. In patients with COPD, in whom hypoxemia is caused primarily by ventilation-perfusion mismatching rather than by increased intrapulmonary shunt (as in noncardiogenic pulmonary edema), inhaled nitric oxide can worsen gas exchange because of altered hypoxic regulation of ventilation-perfusion balance. Therefore, based on the available evidence, nitric oxide is contraindicated in stable COPD. Likewise, guidelines on the treatment of pulmonary hypertension do not recommend the use of endothelium-modulating agents for the treatment of pulmonary hypertension associated with COPD until data on their safety and efficacy in this condition are available.

Narcotics (Morphine)

Oral and parenteral opioids are effective for treating dyspnea in COPD patients with very severe disease. There is insufficient data to conclude whether nebulized opioids are effective. However, some clinical studies suggest that morphine used to control dyspnea may have serious adverse effects and its benefits may be limited to a few sensitive subjects.

Others

Nedocromil and leukotriene modifiers have not been adequately tested in COPD patients and cannot be recommended. There was no evidence of benefit—and some evidence of harm (malignancy and pneumonia)—from an anti-tumor necrosis factor-alpha antibody (infliximab) tested in moderate to severe COPD. There is no evidence for the effectiveness of herbal medicines in treating COPD and other alternative healing methods (e.g., acupuncture and homeopathy) have not been adequately tested.

Non-Pharmacologic Therapies

Rehabilitation

Benefits of Pulmonary Rehabilitation in COPD
  • Improves exercise capacity (Evidence A)
  • Reduces the perceived intensity of breathlessness (Evidence A)
  • Improves health-related quality of life (Evidence A)
  • Reduces the number of hospitalizations and days in the hospital (Evidence A)
  • Reduces anxiety and depression associated with COPD (Evidence A)
  • Strength and endurance training of the upper limbs improves arm function (Evidence B).
  • Benefits extend well beyond the immediate period of training (Evidence B).
  • Improves survival (Evidence B)
  • Respiratory muscle training can be beneficial, especially when combined with general exercise training (Evidence C)
  • Improves recovery after hospitalization for an exacerbation (Evidence A)
  • Enhances the effect of long-acting bronchodilators (Evidence B)

Components of Pulmonary Rehabilitation Programs

The components of pulmonary rehabilitation vary widely but a comprehensive programs includes exercise training, smoking cessation, nutrition counseling, and education.

Exercise Training

Exercise tolerance can be assessed by either bicycle ergometry or treadmill exercise with the measurement of a number of physiological variables, including maximum oxygen consumption, maximum heart rate, and maximum work performed. A less complex approach is to use a self-paced, timed walking test (e.g., 6-minute walking distance). These tests require at least one practice session before data can be interpreted. Shuttle walking tests offer a compromise: they provide more complete information than an entirely self-paced test, but are simpler to perform than a treadmill test.

The following points summarize current knowledge of considerations important in choosing patients for pulmonary rehabilitation:

Functional Status

Benefits have been seen in patients with a wide range of disability, although those who are chair-bound appear less likely to respond even to home visiting programs (Evidence B).

Severity of Dyspnea

Stratification by breathlessness intensity using the mMRC questionnaire may be helpful in selecting patients most likely to benefit from rehabilitation. Those with mMRC grade 4 dyspnea may not benefit (Evidence B).

Motivation

Selecting highly motivated participants is especially important in the case of outpatient programs.

Smoking Status

There is no evidence that smokers will benefit less than nonsmokers, although some suggest that continuing smokers are less likely to complete pulmonary rehabilitation programs than nonsmokers (Evidence B).

Education

Most pulmonary rehabilitation programs include an educational component. The topics that seem most appropriate for an education program include: smoking cessation; basic information about COPD; general approach to therapy and specific aspects of medical treatment; self-management skills; strategies to help minimize dyspnea; advice about when to seek help; decision-making during exacerbations; and advance directives and end-of-life issues.

The intensity and content of these educational messages should vary depending on the severity of the patient's disease, although the specific contributions of education to the improvements seen after pulmonary rehabilitation remain unclear. Studies indicate that patient education alone does not improve exercise performance or lung function, but it can play a role in improving skills, ability to cope with illness, and health status. These outcomes are not traditionally measured in clinical trials, but they may be most important in COPD where even pharmacologic interventions generally confer only a small benefit in terms of lung function.

Patients with severe COPD often express the desire to discuss end-of-life care with clinicians, but these conversations rarely occur in clinical practice. Simple, structured approaches to facilitate these conversations may help to improve the occurrence and quality of communication from the patients' perspective. In particular, patients with a chronic life-limiting illness like COPD should be informed that, should they become critically ill, they or their family members may be in a position where they would need to decide whether a) a course of intensive care is likely to achieve their personal goals of care, and b) they are willing to accept the burdens of such treatment. Communication about end-of-life care and advance care planning gives patients the opportunity to make informed decisions about the kind of care they want and ensure that their family and clinicians understand their values, goals, and perspectives. Clinicians should develop and implement methods to help patients and their families to make informed choices that are consistent with patients' values. Such methods have the potential to improve the quality of care and simultaneously may contribute to efforts to reduce health care costs by ensuring patients receive care consistent with their goals and values.

Assessment and Follow-up

Baseline and outcome assessments of each participant in a pulmonary rehabilitation program should be made to quantify individual gains and target areas for improvement. Assessments should include:

  • Detailed history and physical examination
  • Measurement of post-bronchodilator spirometry
  • Assessment of exercise capacity
  • Measurement of health status and impact of breathlessness (e.g., COPD Assessment Test [CAT] and mMRC scales)
  • Assessment of inspiratory and expiratory muscle strength and lower limb strength (e.g., quadriceps) in patients who suffer from muscle wasting

Nutrition Counseling

Nutritional state is an important determinant of symptoms, disability, and prognosis in COPD; being either overweight or underweight can be a problem.

Present evidence suggests that nutritional supplementation alone may not be a sufficient strategy. Increased calorie intake is best accompanied by exercise regimes that have a nonspecific anabolic action, and there is some evidence this also helps even in those patients without severe nutritional depletion.

Other Treatments

Oxygen Therapy

The long-term administration of oxygen (>15 hours per day) to patients with chronic respiratory failure has been shown to increase survival in patients with severe resting hypoxemia (Evidence B). Long-term oxygen therapy is indicated for patients who have:

  • Partial pressure of arterial oxygen (PaO2 ) at or below 7.3 kPa (55 mmHg) or percentage of available hemoglobin that is saturated with oxygen (SaO2) at or below 88%, with or without hypercapnia confirmed twice over a three week period (Evidence B); or
  • PaO2 between 7.3 kPa (55 mmHg) and 8.0 kPa (60 mmHg), or SaO2 of 88%, if there is evidence of pulmonary hypertension, peripheral edema suggesting congestive cardiac failure, or polycythemia (hematocrit >55%) (Evidence D).

A decision about the use of long-term oxygen should be based on the resting PaO2 or saturation values repeated twice over three weeks in the stable patient. Current data do not support the use of ambulatory oxygen in patient populations that do not meet the above criteria.

Although air travel is safe for most patients with chronic respiratory failure who are on long-term oxygen therapy, patients should ideally be able to maintain an in-flight PaO2 of at least 6.7 kPa (50 mmHg). Studies indicate that this can be achieved in those with moderate to severe hypoxemia at sea level by supplementary oxygen at 3 L/min by nasal cannulae or 31% by Venturi facemask. Those with a resting PaO2 at sea level >9.3 kPa (70 mmHg) are likely to be safe to fly without supplementary oxygen, although it is important to emphasize that a resting PaO2 >9.3 kPa (70 mmHg) at sea level does not exclude the development of severe hypoxemia when traveling by air (Evidence C). Careful consideration should be given to any comorbidity that may impair oxygen delivery to tissues (e.g., cardiac impairment, anemia). Also, walking along the aisle may profoundly aggravate hypoxemia.

Ventilatory Support

Non-invasive ventilation (NIV) is increasingly used in patients with stable very severe COPD. The combination of NIV with long-term oxygen therapy may be of some use in a selected subset of patients, particularly in those with pronounced daytime hypercapnia. It may improve survival but does not improve quality of life. However, in patients with both COPD and obstructive sleep apnea there are clear benefits from continuous positive airway pressure (CPAP) in both survival and risk of hospital admission.

Surgical Treatments

Lung Volume Reduction Surgery (LVRS)

LVRS is a surgical procedure in which parts of the lung are resected to reduce hyperinflation, making respiratory muscles more effective pressure generators by improving their mechanical efficiency (as measured by length/tension relationship, curvature of the diaphragm, and area of apposition). In addition, LVRS increases the elastic recoil pressure of the lung and thus improves expiratory flow rates and reduces exacerbations. The advantage of surgery over medical therapy is more significant among patients with predominantly upper-lobe emphysema and low exercise capacity prior to treatment. A prospective economic analysis indicated that LVRS is costly relative to health-care programs not including surgery. In contrast to medical treatment, LVRS has been demonstrated to result in improved survival (54% vs. 39.7%) in severe emphysema patients with upper lobe emphysema and low post-rehabilitation exercise capacity (Evidence A). In similar patients with high post pulmonary rehabilitation exercise capacity no difference in survival was noted after LVRS, although health-related quality of life and exercise capacity improved. LVRS has been demonstrated to result in higher mortality than medical management in severe emphysema patients with an FEV1 ≤20% predicted and either homogeneous emphysema on high resolution computed tomography or a diffusing capacity of the lung for carbon monoxide (DLCO) ≤20% predicted.

Bronchoscopic Lung Volume Reduction (BLVR)

In a post-hoc analysis, BLVR in COPD patients with severe airflow limitation (FEV1 15%-45% predicted), heterogeneous emphysema on computed tomography (CT) scan, and hyperinflation (total lung capacity [TLC] >100% and residual volume [RV] >150% predicted) has been demonstrated to result in modest improvements in lung function, exercise tolerance, and symptoms at the cost of more frequent exacerbations of COPD, pneumonia, and hemoptysis after implantation. Additional data are required to define the optimal technique and patient population.

Lung Transplantation

In appropriately selected patients with very severe COPD, lung transplantation has been shown to improve quality of life and functional capacity. The common complications seen in COPD patients after lung transplantation, apart from post-operative mortality, are acute rejection, bronchiolitis obliterans, opportunistic infections such as cytomegalovirus (CMV), fungal (Candida, Aspergillus, Cryptococcus, Pneumocystis) or bacterial (Pseudomonas, Staphylococcus species) infections, and lymphoproliferative disease. Lung transplantation is limited by the shortage of donor organs and costs. Criteria for referral for lung transplantation include COPD with a Body mass index, Obstruction, Dyspnea, and Exercise (BODE) index exceeding 5. Recommended criteria for listing include a BODE index of 7-10 and at least one of the following: history of exacerbation associated with acute hypercapnia (PaCO2 >6.7 kPa [50 mmHg]); pulmonary hypertension, cor pulmonale, or both despite oxygen therapy; and FEV1 <20% predicted with either DLCO <20% predicted or homogenous distribution of emphysema (Evidence C).

Bullectomy

Bullectomy is an older surgical procedure for bullous emphysema. Removal of a large bulla that does not contribute to gas exchange decompresses the adjacent lung parenchyma. Pulmonary hypertension, hypercapnia, and severe emphysema are not absolute contraindications for bullectomy.

Palliative Care, End-of-life Care, and Hospice Care

The disease trajectory in COPD is usually marked by a gradual decline in health status and increasing symptoms, punctuated by acute exacerbations that are associated with an increased risk of dying. Although mortality following hospitalization for an acute exacerbation of COPD is falling, it still varies between 23% and 80%. Progressive respiratory failure, cardiovascular diseases, malignancies and other diseases are the primary cause of death in patients with COPD hospitalized for an exacerbation. For all these reasons, palliative care, end-of-life care, and hospice care are important components of the care of patients with advanced COPD.

Palliative care is the broadest term and incorporates (but is not limited to) both end-of-life care (care for those who are actively dying) as well as hospice care (a model for delivery of end-of-life care for patients who are terminally ill and predicted to have less than 6 months to live). The goal of palliative care is to prevent and relieve suffering, and to support the best possible quality of life for patients and their families, regardless of the stage of disease or the need for other therapies. Therefore, palliative care is an important component in the management of all patients with advanced COPD and should begin at the time of the diagnosis of a chronic life-limiting illness such as COPD; yet patients with COPD are less likely to receive such services than patients with lung cancer. Palliative care expands traditional disease-model medical treatment to increase the focus on the goals of enhancing quality of life, optimizing function, helping with decision making about end-of-life care, providing emotional and spiritual support to patients and their families. Increasingly, palliative care teams are available for consultation for hospitalized patients and such teams are rapidly increasing in numbers and capacity. Availability for outpatient palliative care consultation is less common, but has been shown to improve quality of life, reduce symptoms and even prolong survival for some patients, such as those with advanced lung cancer. Clinicians caring for patients with COPD should help identify patients who could benefit from palliative care services and identify available palliative care resources within their community for these patients.

For patients with the most advanced and terminal illness, hospice services may provide additional benefit. Hospice services often focus on patients with severe disability or symptom burden and may provide these services within the patient's home or in hospice beds in dedicated hospice units or other institutions such as hospitals or nursing homes. The National Hospice and Palliative Care Organization (http://www.nhpco.org External Web Site Policy) provides guidance for selecting patients with non-cancer diseases like COPD for access to hospice services (for example, disabling dyspnea at rest that is poorly responsive to bronchodilators and progression of advanced disease demonstrated by increasing hospitalizations or emergency department visits). These guidelines discuss the difficulties in accurately predicting the prognosis of patients with advanced COPD, but recognize the appropriateness of providing hospice services for some of these patients.

Management of Stable COPD

Key Points
  • Identification and reduction of exposure to risk factors are important steps in the prevention and treatment of COPD. All individuals who smoke should be encouraged to quit.
  • The level of FEV1 is an inadequate descriptor of the impact of the disease on patients and for this reason individualized assessment of symptoms and future risk of exacerbation should also be incorporated into the management strategy for stable COPD.
  • Pharmacologic therapy is used to reduce symptoms, reduce frequency and severity of exacerbations, and improve health status and exercise tolerance. Existing medications for COPD have not been conclusively shown to modify the long-term decline in lung function that is the hallmark of this disease.
  • For both beta2-agonists and anticholinergics, long-acting formulations are preferred over short-acting formulations. Based on efficacy and side effects, inhaled bronchodilators are preferred over oral bronchodilators.
  • Long-term treatment with inhaled corticosteroids added to long-acting bronchodilators is recommended for patients at high risk of exacerbations.
  • Long-term monotherapy with oral or inhaled corticosteroids is not recommended in COPD.
  • The phosphodiesterase-4 inhibitor roflumilast may be useful to reduce exacerbations for patients with FEV1 <50% predicted, chronic bronchitis, and frequent exacerbations.
  • Influenza vaccines can reduce the risk of serious illness (such as hospitalization due to lower respiratory tract infections) and death in COPD patients.
  • Currently, the use of antibiotics is not indicated in COPD, other than for treating infectious exacerbations of COPD and other bacterial infections.
  • All COPD patients with breathlessness when walking at their own pace on level ground appear to benefit from rehabilitation and maintenance of physical activity, improving their exercise tolerance and quality of life, and reducing symptoms of dyspnea and fatigue.

Introduction

Once COPD has been diagnosed, effective management should be based on an individualized assessment of disease in order to reduce both current symptoms and future risks (see table below). These goals should be reached with minimal side effects from treatment, a particular challenge in COPD patients because they commonly have comorbidities that also need to be carefully identified and treated.

Table. Goals for Treatment of Stable COPD
Relive symptoms Reduce symptoms
Improve exercise tolerance
Improve health status
and
Prevent disease progression Reduce risk
Prevent and treat exacerbations
Reduce mortality

It is crucial for patients with COPD to understand the nature of their disease, the risk factors for its progression, and their role and that of their health care workers in achieving optimal management and health outcomes. The type of health care workers seen, and the frequency of visits, will depend on the health care system. Ongoing monitoring should ensure that the goals of treatment are being met and should include continuous evaluation of exposure to risk factors and monitoring of disease progression, the effect of treatment and possible adverse effects, exacerbation history, and comorbidities. In addition, patients should receive general advice on healthy living, including diet and the fact that physical exercise is safe and encouraged for people with COPD.

Identification and reduction of exposure to risk factors are important in the treatment and prevention of COPD. Since cigarette smoking is the most commonly encountered and easily identifiable risk factor, smoking cessation should be encouraged for all individuals who smoke. Reduction of total personal exposure to occupational dusts, fumes, and gases and to indoor and outdoor air pollutants may be more difficult but should be attempted.

Identify and Reduce Exposure to Risk factors

Tobacco Smoke

Smoking cessation is the key intervention for all COPD patients who continue to smoke (Evidence A). Health care providers are important to the delivery of smoking cessation messages and interventions and should encourage all patients who smoke to quit, even when patients visit a health care provider for reasons unrelated to COPD or breathing problems.

Occupational Exposures

Although studies as yet have not been done to demonstrate whether interventions to reduce occupational exposures also reduce the burden of COPD, it seems common sense to advise patients to avoid continued exposures to potential aggravants, if possible (Evidence D).

Indoor and Outdoor Air Pollution

Reducing the risk from indoor and outdoor air pollution is feasible and requires a combination of public policy, local and national resources, cultural changes, and protective steps taken by individual patients. Reduction of exposure to smoke from biomass fuel, particularly among women and children, is a crucial goal to reduce the prevalence of COPD worldwide. Efficient ventilation, non-polluting cooking stoves, use of flues, and similar interventions are feasible and should be recommended (Evidence B).

Treatment of Stable COPD

In previous versions of the GOLD report, COPD treatment recommendations were based on spirometry only. This is in keeping with the fact that most of the clinical trial evidence about treatment efficacy in COPD is oriented around baseline FEV1. However, FEV1 alone is a poor descriptor of disease status and for this reason the treatment strategy for stable COPD should also consider an individual patient's symptoms and future risk of exacerbations. This individualized assessment is summarized in Table 4.2 of the original guideline document.

Non-Pharmacologic Treatment

Smoking Cessation

Smoking cessation should be considered the most important intervention for all COPD patients who smoke regardless of the level of disease severity.

Physical Activity

Physical activity is recommended for all patients with COPD. There is very little COPD-specific evidence to support recommendations for physical activity other than studies of pulmonary rehabilitation (the physical exercise component is believed to provide the most benefit). However, given the overall population benefits of physical exercise and its role in primary and secondary prevention of cardiovascular disease, it seems intuitively correct to recommend daily physical activity.

Rehabilitation

Although more information is needed on criteria for patient selection for pulmonary rehabilitation programs, all COPD patients appear to benefit from rehabilitation and maintenance of physical activity, improving their exercise tolerance and experiencing decreased dyspnea and fatigue (Evidence A). Several studies have documented an effect of pulmonary rehabilitation in patients with breathlessness, usually mMRC >1, and following acute exacerbations. Data suggest that these benefits can be sustained even after a single pulmonary rehabilitation program. Benefit does wane after a rehabilitation program ends, but if exercise training is maintained at home the patient's health status remains above pre-rehabilitation levels (Evidence B).

Vaccination

Decisions about vaccination in COPD patients depend on local policies, availability, and affordability.

Pharmacologic Treatment

Pharmacologic therapy in COPD is used to reduce symptoms, reduce the frequency and severity of exacerbations, and improve health status and exercise tolerance. Existing medications for COPD have not been conclusively shown to modify the long-term decline in lung function that is the hallmark of this disease.

The classes of medications commonly used in treating COPD are shown in Table 3.3 in the original guideline document and a detailed description of the effects of these medications is given in Chapter 3 in the original guideline document. The choice within each class depends on the availability of medication and the patient's response. A proposed model for initial pharmacological management of COPD according to the individualized assessment of symptoms and exacerbation risk is shown in Table 4.4 in the original guideline document.

See the original guideline document for more information on patient classifications group A to D.

Table 4.4 in the original guideline document provides a summary of initial pharmacologic management of COPD for each patient group.

Bronchodilators

  • For both beta2-agonists and anticholinergics, long-acting formulations are preferred over short-acting formulations (Evidence A).
  • The combined use of short- or long-acting beta2-agonists and anticholinergics may be considered if symptoms are not improved with single agents (Evidence B).
  • Based on efficacy and side effects inhaled bronchodilators are preferred over oral bronchodilators (Evidence A).
  • Based on evidence of relatively low efficacy and more side effects, treatment with theophylline is not recommended unless other long-term treatment bronchodilators are unavailable or unaffordable (Evidence B).

Corticosteroids and Phosphodiesterase-4 Inhibitors

  • There is no evidence to recommend a short-term therapeutic trial with oral corticosteroids in patients with COPD to identify those who will respond to inhaled corticosteroids or other medications.
  • Long-term treatment with inhaled corticosteroids is recommended for patients with severe and very severe COPD and frequent exacerbations that are not adequately controlled by long-acting bronchodilators (Evidence A).
  • Long-term monotherapy with oral corticosteroids is not recommended in COPD (Evidence A).
  • Long-term monotherapy with inhaled corticosteroids is not recommended in COPD because it is less effective than the combination of inhaled corticosteroids with long-acting beta2-agonists (Evidence A).
  • Long-term treatment containing inhaled corticosteroids should not be prescribed outside their indications, due to the risk of pneumonia and the possibility of an increased risk of fractures following long-term exposure.
  • The phosphodiesterase-4 inhibitor roflumilast may also be used to reduce exacerbations for patients with chronic bronchitis, severe and very severe COPD, and frequent exacerbations that are not adequately controlled by long acting bronchodilators (Evidence B).

Monitoring and Follow-up

Routine follow-up is essential in COPD. Lung function can be expected to worsen over time, even with the best available care. Symptoms and objective measures of airflow limitation should be monitored to determine when to modify therapy and to identify any complications that may develop. As at the initial assessment, follow-up visits should include a discussion of symptoms, particularly any new or worsening symptoms, and a physical examination.

See the original guideline document for a more detailed discussion of the evidence for monitoring disease progression and the development of complications.

Management of Exacerbations

Key Points
  • An exacerbation of COPD is an acute event characterized by a worsening of the patient's respiratory symptoms that is beyond normal day-to day variations and leads to a change in medication.
  • Exacerbations of COPD can be precipitated by several factors. The most common causes appear to be viral upper respiratory tract infections and infection of the tracheobronchial tree.
  • The diagnosis of an exacerbation relies exclusively on the clinical presentation of the patient complaining of an acute change of symptoms (baseline dyspnea, cough, and/or sputum production) that is beyond normal day-to-day variation.
  • The goal of treatment in COPD exacerbations is to minimize the impact of the current exacerbation and to prevent the development of subsequent exacerbations.
  • Short-acting inhaled beta2-agonists with or without short-acting anticholinergics are usually the preferred bronchodilators for treatment of an exacerbation.
  • Systemic corticosteroids and antibiotics can shorten recovery time, improve lung function (FEV1) and arterial hypoxemia (PaO2), and reduce the risk of early relapse, treatment failure, and length of hospital stay.
  • COPD exacerbations can often be prevented. Smoking cessation, influenza and pneumococcal vaccination, knowledge of current therapy including inhaler technique, and treatment with long-acting inhaled bronchodilators, with or without inhaled corticosteroids, and treatment with a phosphodiesterase-4 inhibitor are all interventions that reduce the number of exacerbations and hospitalizations.

Diagnosis

Currently, the diagnosis of an exacerbation relies exclusively on the clinical presentation of the patient complaining of an acute change of symptoms (baseline dyspnea, cough, and/or sputum production) that is beyond normal day-to-day variation. In the future, a biomarker or panel of biomarkers that allows a more precise etiologic diagnosis would be desirable.

Assessment

The assessment of an exacerbation is based on the patient's medical history and clinical signs of severity (see tables below) and some laboratory tests, if available.

Table. Assessment of COPD Exacerbations: Medical History
  • Severity of COPD based on degree of airflow limitation
  • Duration of worsening or new symptoms
  • Number of previous episodes (total/hospitalizations)
  • Comorbidities
  • Present treatment regimen
  • Previous use of mechanical ventilation

 

Table. Assessment of COPD Exacerbations: Signs of Severity
  • Use of accessory respiratory muscles
  • Paradoxical chest wall movements
  • Worsening or new onset central cyanosis
  • Development of peripheral edema
  • Hemodynamic instability
  • Deteriorated mental status

The following tests may be considered to assess the severity of an exacerbation:

  • Pulse oximetry is useful for tracking and/or adjusting supplemental oxygen therapy. The measurement of arterial blood gases is vital if the coexistence of acute or acute-on-chronic respiratory failure is suspected (PaO2 <8.0 kPa [60 mmHg] with or without PaCO2 >6.7 kPa [50 mmHg] breathing ambient air). Assessment of the acid-base status is necessary before initiating mechanical ventilation.
  • Chest radiographs are useful in excluding alternative diagnoses.
  • An electrocardiogram (ECG) may aid in the diagnosis of coexisting cardiac problems.
  • Whole blood count may identify polycythemia (hematocrit >55%), anemia, or leukocytosis.
  • The presence of purulent sputum during an exacerbation can be sufficient indication for starting empirical antibiotic treatment. Hemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis are the most common bacterial pathogens involved in an exacerbation; in GOLD 3 and GOLD 4 patients Pseudomonas aeruginosa becomes important. If an infectious exacerbation does not respond to the initial antibiotic treatment, a sputum culture and an antibiotic sensitivity test should be performed.
  • Biochemical test abnormalities including electrolyte disturbances and hyperglycemia can be associated with exacerbations. However, these abnormalities can also be due to associated comorbidities.

Spirometry is not recommended during an exacerbation because it can be difficult to perform and measurements are not accurate enough.

Treatment Options

Treatment Setting

The goals of treatment for COPD exacerbations are to minimize the impact of the current exacerbation and prevent the development of subsequent exacerbations. Depending on the severity of an exacerbation and/or the severity of the underlying disease, an exacerbation can be managed in an outpatient or inpatient setting. More than 80% of exacerbations can be managed on an outpatient basis with pharmacologic therapies including bronchodilators, corticosteroids, and antibiotics.

The table below shows the indications for hospital assessment and potential admission of a patient with a COPD exacerbation. When a patient comes to the emergency department the first actions are to provide supplemental oxygen therapy and to determine whether the exacerbation is life-threatening (see Table 5.4 in the original guideline). If so, the patient should be admitted to the intensive care unit (ICU) immediately. Otherwise, the patient may be managed in the emergency department or hospital as detailed in Table 5.5 of the original guideline document. In addition to pharmacologic therapy, hospital management of exacerbations includes respiratory support (oxygen therapy, ventilation).

Table. Potential Indications for Hospital Assessment or Admission*
  • Marked increase in intensity of symptoms, such as sudden development of resting dyspnea
  • Severe underlying COPD
  • Onset of new physical signs (e.g., cyanosis, peripheral edema)
  • Failure of an exacerbation to respond to initial medical management
  • Presence of serious comorbidities (e.g., heart failure or newly occurring arrhythmias)
  • Frequent exacerbations
  • Older age
  • Insufficient home support

*Local resources need to be considered.

Pharmacologic Treatment

The three classes of medications most commonly used for exacerbations of COPD are bronchodilators, corticosteroids, and antibiotics.

Short-acting Bronchodilators

Although there are no controlled trials, short-acting inhaled beta2-agonists with or without short-acting anticholinergics are usually the preferred bronchodilators for treatment of an exacerbation (Evidence C). There are no clinical studies that have evaluated the use of inhaled long-acting bronchodilators (either beta2-agonists or anticholinergics) with or without inhaled corticosteroids during an exacerbation. A systematic review of the route of delivery of short-acting bronchodilators found no significant differences in FEV1 between metered-dose inhalers (with or without a spacer device) and nebulizers, although the latter can be more convenient for sicker patients. Intravenous methylxanthines (theophylline or aminophylline) are considered second-line therapy, only to be used in selected cases when there is insufficient response to short-acting bronchodilators (Evidence B). Side effects of methylxanthines are significant and their beneficial effects in terms of lung function and clinical endpoints are modest and inconsistent.

Corticosteroids

Data from studies in secondary health care indicate that systemic corticosteroids in COPD exacerbations shorten recovery time, improve lung function (FEV1) and arterial hypoxemia (PaO2) (Evidence A), and reduce the risk of early relapse, treatment failure, and length of hospital stay. A dose of 30-40 mg prednisolone per day for 10-14 days is recommended (Evidence D), although there are insufficient data to provide firm conclusions concerning the optimal duration of corticosteroid therapy of acute exacerbations of COPD. Therapy with oral prednisolone is preferable. Nebulized budesonide alone may be an alternative (although more expensive) to oral corticosteroids in the treatment of exacerbations.

Antibiotics

Although the infectious agents in COPD exacerbations can be viral or bacterial the use of antibiotics in exacerbations remains controversial. The uncertainties originate from studies that did not differentiate between bronchitis (acute or chronic) and COPD exacerbations, studies without placebo control, and/or studies without chest X-rays in which it was unclear if patients had signs of pneumonia. There is evidence supporting the use of antibiotics in exacerbations when patients have clinical signs of a bacterial infection, e.g., increase in sputum purulence. A systematic review of the very few available placebo-controlled studies has shown that antibiotics reduce the risk of short-term mortality by 77%, treatment failure by 53% and sputum purulence by 44%. This review supports antibiotics for only moderately or severely ill patients with COPD exacerbations with increased cough and sputum purulence. In outpatients, sputum cultures are not feasible as they take too long (at least 2 days) and frequently do not give reliable results for technical reasons, i.e., more than 4 hours elapse between expectoration of sputum and analysis in the microbiology lab. Procalcitonin III, a marker that is specific for bacterial infections, may be of value in the decision to use antibiotics, but this test is expensive and thus not widely established. A study in COPD patients with exacerbations requiring mechanical ventilation (invasive or noninvasive) indicated that not giving antibiotics was associated with increased mortality and a greater incidence of secondary nosocomial pneumonia.

In summary, antibiotics should be given to patients with exacerbations of COPD who have three cardinal symptoms – increase in dyspnea, sputum volume, and sputum purulence (Evidence B); have two of the cardinal symptoms, if increased purulence of sputum is one of the two symptoms (Evidence C); or require mechanical ventilation (invasive or noninvasive) (Evidence B). The recommended length of antibiotic therapy is usually 5-10 days (Evidence D).

The choice of the antibiotic should be based on the local bacterial resistance pattern. Usually initial empirical treatment is an aminopenicillin with or without clavulanic acid, macrolide, or tetracycline. In patients with frequent exacerbations, severe airflow limitation and/or exacerbations requiring mechanical ventilation, cultures from sputum or other materials from the lung should be performed, as gram-negative bacteria (e.g., Pseudomonas species) or resistant pathogens that are not sensitive to the above-mentioned antibiotics may be present. The route of administration (oral or intravenous) depends on the ability of the patient to eat and the pharmacokinetics of the antibiotic, although preferably antibiotics are given orally. Improvements in dyspnea and sputum purulence suggest clinical success.

Adjunct Therapies

Depending on the clinical condition of the patient, an appropriate fluid balance with special attention to the administration of diuretics, anticoagulants, treatment of comorbidities and nutritional aspects should be considered. At all times, health care providers should strongly enforce stringent measures against active cigarette smoking.

Respiratory Support

Oxygen Therapy

This is a key component of hospital treatment of an exacerbation. Supplemental oxygen should be titrated to improve the patient's hypoxemia with a target saturation of 88%-92%. Once oxygen is started, arterial blood gases should be checked 30-60 minutes later to ensure satisfactory oxygenation without carbon dioxide retention or acidosis. Venturi masks (high-flow devices) offer more accurate and controlled delivery of oxygen than do nasal prongs but are less likely to be tolerated by the patient.

Ventilatory Support

Some patients need immediate admission to an intensive care unit (ICU) (see table below for a list of criteria for ICU admission). Admission of patients with severe exacerbations to intermediate or special respiratory care units may be appropriate if personnel, skills, and equipment exist to identify and manage acute respiratory failure successfully.

Ventilatory support in an exacerbation can be provided by either noninvasive (by nasal or facial mask) or invasive ventilation (by oro-tracheal tube or tracheostomy). Respiratory stimulants are not recommended for acute respiratory failure.

Table. Indications for ICU Admission*
  • Severe dyspnea that responds inadequately to initial emergency therapy
  • Changes in mental status (confusion, lethargy, coma)
  • Persistent or worsening hypoxemia (PaO2 <5.3 kPa, 40 mmHg) and/or severe/worsening respiratory acidosis (pH <7.25) despite supplemental oxygen and noninvasive ventilation
  • Need for invasive mechanical ventilation
  • Hemodynamic instability—need for vasopressors

*Local resources need to be considered.

Noninvasive Mechanical Ventilation (NIV)

The use of NIV has increased significantly over time among patients hospitalized for acute exacerbations of COPD. NIV has been studied in randomized controlled trials showing a success rate of 80%-85%. NIV has been shown to improve acute respiratory acidosis (increases pH and decreases PaCO2), decrease respiratory rate, work of breathing, severity of breathlessness, complications such as ventilator associated pneumonia, and length of hospital stay (Evidence A). More importantly, mortality and intubation rates are reduced by this intervention (Evidence A).

Table. Indications for Noninvasive Mechanical Ventilation
At least one of the following:
  • Respiratory acidosis (arterial pH ≤7.35 and/or PaCO2 ≥6.0 kPa, 45mm Hg)
  • Severe dyspnea with clinical signs suggestive of respiratory muscle fatigue, increased work of breathing, or both, such as use of respiratory accessory muscles, paradoxical motion of the abdomen, or retraction of the intercostal spaces

Invasive Mechanical Ventilation

The indications for initiating invasive mechanical ventilation during an exacerbation are shown in the table below and include failure of an initial trial of NIV. As experience is being gained with the generalized clinical use of NIV in COPD, several indications for invasive mechanical ventilation are being successfully treated with NIV, and in all but a few situations there is nothing to be lost by a trial of noninvasive ventilation.

Table. Indications for Invasive Mechanical Ventilation
  • Unable to tolerate NIV or NIV failure
  • Respiratory or cardiac arrest
  • Respiratory pauses with loss of consciousness or gasping for air
  • Diminished consciousness, psychomotor agitation inadequately controlled by sedation
  • Massive aspiration
  • Persistent inability to remove respiratory secretions
  • Heart rate <50 min-1 with loss of alertness
  • Severe hemodynamic instability without response to fluids and vasoactive drugs
  • Severe ventricular arrhythmias
  • Life-threatening hypoxemia in patients unable to tolerate NIV

See the original guideline document for a discussion of other measures that can be used in the hospital.

Hospital Discharge and Follow-up

Insufficient clinical data exist to establish the optimal duration of hospitalization in individual patients with an exacerbation of COPD, although units with more respiratory consultants and better organized care have lower mortality and reduced length of hospital stay following admission for an exacerbation. In the hospital prior to discharge, patients should start long-acting bronchodilators, either beta2-agonists and/or anticholinergics with or without inhaled corticosteroids. Consensus and limited data support the discharge criteria listed in the following table.

Table. Discharge Criteria
  • Able to use long acting bronchodilators, either beta2-agonists and/or anticholinergics with or without inhaled corticosteroids
  • Inhaled short-acting beta2-agonist therapy is required no more frequently than every 4 hrs
  • Patient, if previously ambulatory, is able to walk across room
  • Patient is able to eat and sleep without frequent awakening by dyspnea
  • Patient has been clinically stable for 12-24 hrs
  • Arterial blood gases have been stable for 12-24 hrs
  • Patient (or home caregiver) fully understands correct use of medications
  • Follow-up and home care arrangements have been completed (e.g., visiting nurse, oxygen delivery, meal provisions)
  • Patient, family, and physician are confident that the patient can manage successfully at home

A checklist of items to assess at time of discharge and items to assess at follow-up 4 to 6 weeks after discharge from the hospital are shown in the tables below. Thereafter, follow-up is the same as for stable COPD: supervise smoking cessation, monitor the effectiveness of each medication, and monitor changes in spirometric parameters. Prior hospital admission, oral corticosteroids, use of long-term oxygen therapy, poor health-related quality of life, and lack of routine physical activity have been found to be predictive of readmission.

Table. Checklist of Items to Assess at Time of Discharge from Hospital
  • Assurance of effective home maintenance pharmacotherapy regimen
  • Reassessment of inhaler technique
  • Education regarding role of maintenance regimen
  • Instruction regarding completion of steroid therapy and antibiotics, if prescribed
  • Assess need for long-term oxygen therapy
  • Assure follow-up visit in 4-6 weeks
  • Provide a management plan for comorbidities and their follow-up

 

Table. Items to Assess at Follow-Up Visit 4-6 Weeks After Discharge from Hospital
  • Ability to cope in usual environment
  • Measurement of FEV1
  • Reassessment of inhaler technique
  • Understanding of recommended treatment regimen
  • Reassess need for long-term oxygen therapy and/or home nebulizer
  • Capacity to do physical activity and activities of daily living
  • CAT or mMRC
  • Status of comorbidities

Home visits by a community nurse may permit earlier discharge of patients hospitalized with an exacerbation without increasing readmission rates. Use of a written action plan increases appropriate therapeutic interventions for an exacerbation, an effect that does not decrease health-care resource utilization (Evidence B) but may shorten recovery time.

For patients who are hypoxemic during an exacerbation, arterial blood gases and/or pulse oximetry should be evaluated prior to hospital discharge and in the following 3 months. If the patient remains hypoxemic, long-term supplemental oxygen therapy may be required.

Home Management of Exacerbations

The risk of dying from an exacerbation of COPD is closely related to the development of respiratory acidosis, the presence of significant comorbidities, and the need for ventilatory support. Patients lacking these features are not at high risk of dying. Four randomized clinical trials have shown that nurse-administered home care (also known as "hospital-at-home" care) represents an effective and practical alternative to hospitalization in selected patients with exacerbations of COPD without acidotic respiratory failure (Evidence A). However, the exact criteria for this approach as opposed to hospital treatment remain uncertain and will vary by health care setting. Treatment recommendations are the same for hospitalized patients. Supported self-management had no effect on time to first readmission or death with COPD.

Prevention of COPD Exacerbations

COPD exacerbations can often be prevented. Smoking cessation, influenza and pneumococcal vaccines, knowledge of current therapy including inhaler technique, and treatment with long-acting inhaled bronchodilators, with or without inhaled corticosteroids, and possibly phosphodiesterase-4 inhibitors, are all therapies that reduce the number of exacerbations and hospitalizations. Early outpatient pulmonary rehabilitation after hospitalization for an exacerbation is safe and results in clinically significant improvements in exercise capacity and health status at 3 months. Patients should be encouraged to maintain physical activity, and anxiety, depression and social problems should be discussed. Principal caregivers should be identified if the patient has a significant persisting disability.

COPD and Comorbidities

Key Points
  • COPD often coexists with other diseases (comorbidities) that may have a significant impact on prognosis.
  • In general, the presence of comorbidities should not alter COPD treatment and comorbidities should be treated as if the patient did not have COPD.
  • Cardiovascular disease is a major comorbidity in COPD and probably both the most frequent and most important disease coexisting with COPD.
  • Osteoporosis and depression are also major comorbidities in COPD, are often under-diagnosed, and are associated with poor health status and prognosis.
  • Lung cancer is frequently seen in patients with COPD and has been found to be the most frequent cause of death in patients with mild COPD.

Refer to the original guideline for a discussion of treatment of COPD with comorbid cardiovascular disease, osteoporosis, anxiety and depression, lung cancer, infections, metabolic syndrome, and diabetes.

Definitions:

Evidence Category Sources of Evidence Definition
A Randomized controlled trials (RCTs). Rich body of data. Evidence is from endpoints of well-designed RCTs that provide a consistent pattern of findings in the population for which the recommendation is made. Category A requires substantial numbers of studies involving substantial numbers of participants.
B Randomized controlled trials. Limited body of data. Evidence is from endpoints of intervention studies that include only a limited number of patients, posthoc or subgroup analysis of RCTs, or meta-analysis of RCTs. In general, Category B pertains when few randomized trials exist, they are small in size, they were undertaken in a population that differs from the target population of the recommendation, or the results are somewhat inconsistent.
C Nonrandomized trials. Observational studies. Evidence is from outcomes of uncontrolled or nonrandomized trials or from observational studies.
D Panel consensus judgment This category is used only in cases where the provision of some guidance was deemed valuable but the clinical literature addressing the subject was deemed insufficient to justify placement in one of the other categories. The Panel Consensus is based on clinical experience or knowledge that does not meet the above-listed criteria.
Clinical Algorithm(s)

None provided

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The type of supporting evidence is specifically stated for selected recommendations (see the "Major Recommendations" field).

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

Appropriate diagnosis, management, and prevention of chronic obstructive pulmonary disease (COPD)

Potential Harms
  • Nicotine replacement products: Continuous chewing of nicotine gum produces secretions that are swallowed rather than absorbed through the buccal mucosa, results in little absorption, and can cause nausea. Acidic beverages, particularly coffee, juices, and soft drinks, interfere with the absorption of nicotine.
  • Beta2-agonists: Stimulation of beta2-adrenergic receptors can produce resting sinus tachycardia and has the potential to precipitate cardiac rhythm disturbances in susceptible patients, although these seem to have remarkably few clinical implications. Exaggerated somatic tremor is troublesome in some older patients treated with higher doses of beta2-agonists, whatever the route of administration, and this limits the dose that can be tolerated. Although hypokalemia can occur, especially when treatment is combined with thiazide diuretics, and oxygen consumption can be increased under resting conditions, these metabolic effects show tachyphylaxis unlike the bronchodilator actions. Mild falls in the partial pressure of arterial oxygen (PaO2) can occur after administration of both short-and long-acting beta2-agonists but the clinical significance of these changes is doubtful. Despite the concerns raised some years ago related to beta2-agonists in the management of asthma, further detailed study has found no association between beta2-agonist use and an accelerated loss of lung function or increased mortality in chronic obstructive pulmonary disease (COPD).
  • Anticholinergics: Anticholinergic drugs are poorly absorbed, which limits the troublesome systemic effects seen with atropine. Extensive use of this class of inhaled agents in a wide range of doses and clinical settings has shown them to be very safe. The main side effect is dryness of the mouth. Twenty-one days of inhaled tiotropium, 18 mcg/day as a dry powder, does not retard mucus clearance from the lungs. Although occasional prostatic symptoms have been reported, there are no data to prove a true causal relationship. Some patients using ipratropium report a bitter, metallic taste. An unexpected small increase in cardiovascular events in COPD patients regularly treated with ipratropium bromide has been reported and requires further investigation. Tiotropium delivered via the Respimat soft mist inhaler has been shown to be associated with a significantly increased risk of mortality compared with placebo. Caution is urged until further studies designed to compare delivery devices and doses are reported. Use of solutions with a facemask has been reported to precipitate acute glaucoma, probably by a direct effect of the solution on the eye.
  • Methylxanthines: Toxicity is dose-related, a particular problem with the xanthine derivatives because their therapeutic ratio is small and most of the benefit occurs only when near-toxic doses are given. Methylxanthines are nonspecific inhibitors of all phosphodiesterase enzyme subsets, which explains their wide range of toxic effects. Problems include the development of atrial and ventricular arrhythmias (which can prove fatal) and grand mal convulsions (which can occur irrespective of prior epileptic history). Other side effects include headaches, insomnia, nausea, and heartburn, and these may occur within the therapeutic range of serum theophylline. These medications also have significant interactions with commonly used medications such as digitalis, Coumadin, etc. Unlike the other bronchodilator classes, xanthine derivatives may involve a risk of overdose (either intentional or accidental).
  • Inhaled corticosteroids: Inhaled corticosteroid use is associated with higher prevalence of oral candidiasis, hoarse voice, and skin bruising. Treatment with inhaled corticosteroids is associated with an increased risk of pneumonia. While long-term treatment with triamcinolone acetonide is associated with an increased risk of reduced bone density, the evidence with other inhaled corticosteroids is controversial. One long-term study showed no effect of budesonide on bone density and fracture rate, and treatment over a three-year period with 500 mcg bid fluticasone propionate alone or in combination with salmeterol was not associated with decreased bone mineral density in a population of COPD patients with high prevalence of osteoporosis.
  • Oral corticosteroids: Oral corticosteroids have numerous side effects. An important side effect of long-term treatment of COPD with systemic corticosteroids is steroid myopathy, which contributes to muscle weakness, decreased functionality, and respiratory failure in subjects with very severe COPD.
  • Phosphodiesterase-4 inhibitors: Phosphodiesterase-4 inhibitors have more adverse effects than inhaled medications for COPD. The most frequent adverse effects are nausea, reduced appetite, abdominal pain, diarrhea, sleep disturbances, and headache. Adverse effects led to increased withdrawal in clinical trials from the group receiving roflumilast. Adverse effects seem to occur early during treatment, are reversible, and diminish over time with continued treatment. In controlled studies an average unexplained weight loss of 2 kg has been seen and weight monitoring during treatment is advised as well as avoiding treatment with roflumilast in underweight patients. Roflumilast should also be used with caution in patients with depression. Roflumilast and theophylline should not be given together.
  • Narcotics (morphine): Some clinical studies suggest that morphine used to control dyspnea may have serious adverse effects and its benefits may be limited to a few sensitive subjects.
  • Weaning or discontinuation from mechanical ventilation: Weaning can be particularly difficult and hazardous in patients with COPD. The most influential determinant of mechanical ventilatory dependency in these patients is the balance between the respiratory load and the capacity of the respiratory muscles to cope with this load. By contrast, pulmonary gas exchange by itself is not a major difficulty in patients with COPD. Weaning patients from the ventilator can be a very difficult and prolonged process and the best method (pressure support or a T-piece trial) remains a matter of debate.
  • Lung transplantation: The common complications seen in COPD patients after lung transplantation, apart from post-operative mortality, are acute rejection, bronchiolitis obliterans, opportunistic infections such as cytomegalovirus, fungal (Candida, Aspergillus, Cryptococcus, Pneumocystis) or bacterial (Pseudomonas, Staphylococcus species) infections, and lymphoproliferative disease.

Contraindications

Contraindications
  • Nicotine replacement therapy: Medical contraindications to nicotine replacement therapy include unstable coronary artery disease, untreated peptic ulcer disease, and recent myocardial infarction or stroke.
  • Vasodilators: In patients with COPD, in whom hypoxemia is caused primarily by ventilation-perfusion mismatching rather than by increased intrapulmonary shunt (as in noncardiogenic pulmonary edema), inhaled nitric oxide can worsen gas exchange because of altered hypoxic regulation of ventilation-perfusion balance. Therefore, based on the available evidence, nitric oxide is contraindicated in stable COPD.

Qualifying Statements

Qualifying Statements

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) report is not intended to be a comprehensive textbook on chronic obstructive pulmonary disease (COPD), but rather to summarize the current state of the field.

Implementation of the Guideline

Description of Implementation Strategy

An implementation strategy was not provided.

Implementation Tools
Chart Documentation/Checklists/Forms
Foreign Language Translations
Patient Resources
Pocket Guide/Reference Cards
Quick Reference Guides/Physician Guides
Resources
Slide Presentation
For information about availability, see the Availability of Companion Documents and Patient Resources fields below.

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need
End of Life Care
Living with Illness
Staying Healthy
IOM Domain
Effectiveness
Patient-centeredness

Identifying Information and Availability

Bibliographic Source(s)
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Vancouver (WA): Global Initiative for Chronic Obstructive Lung Disease (GOLD); 2013. 80 p. [547 references]
Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released
2001 (revised 2013)
Guideline Developer(s)
Global Initiative for Chronic Obstructive Lung Disease - Disease Specific Society
Source(s) of Funding

Unrestricted educational grants from Almirall, AstraZeneca, Boehringer-Ingelheim, Chiesi, Forest Laboratories, GlaxoSmithKline, Groupo Ferrer, Merck Sharp & Dohme, Mylan, Nonin Medical, Novartis, Pearl Therapeutics, Pfizer, Quintiles, and Takeda enabled development of this report.

Guideline Committee

Global Initiative for Chronic Obstructive Lung Disease (GOLD) Science Committee

Composition of Group That Authored the Guideline

Science Committee Members: Jørgen Vestbo, MD (Chair), Hvidovre University Hospital, Hvidovre, Denmark and University of Manchester, Manchester, England, UK; Alvar G. Agusti, MD, Thorax Institute, Hospital Clinic, Univ. Barcelona, Ciberes, Barcelona, Spain; Antonio Anzueto, MD, University of Texas Health Science Center, San Antonio, Texas, USA; Peter J. Barnes, MD, National Heart and Lung Institute, London, England, UK; Marc Decramer, MD, Katholieke Universiteit Leuven, Leuven, Belgium; Leonardo M. Fabbri, MD, University of Modena & Reggio Emilia, Modena, Italy; Paul Jones, MD, St George's Hospital Medical School, London, England, UK; Fernando Martinez, MD, University of Michigan School of Medicine, Ann Arbor, Michigan, USA; Masaharu Nishimura, MD, Hokkaido University School of Medicine, Sapporo, Japan; Nicholas Roche, MD, Hôtel-Dieu, Paris, France; Roberto Rodriguez-Roisin, MD, Thorax Institute, Hospital Clinic, Univ. Barcelona, Barcelona, Spain; Donald Sin, MD, St. Paul's Hospital, Vancouver, Canada; Robert Stockley, MD, University Hospital, Birmingham, UK; Claus Vogelmeier, MD, University of Giessen and Marburg, Marburg, Germany

Financial Disclosures/Conflicts of Interest

Disclosure forms for Global Initiative for Chronic Obstructive Lung Disease (GOLD) Committees are posted on the GOLD Web site External Web Site Policy.

Guideline Status

This is the current release of the guideline.

This guideline updates a previous version: Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Vancouver (WA): Global Initiative for Chronic Obstructive Lung Disease (GOLD); 2011. 78 p.

Guideline Availability
Availability of Companion Documents

The following are available:

  • Pocket guide to COPD diagnosis, management, and prevention. Vancouver (WA): Global Initiative for Chronic Obstructive Lung Disease; 2013. 32 p.
  • At-a-glance outpatient management reference for chronic obstructive pulmonary disease. Vancouver (WA): Global Initiative for Chronic Obstructive Lung Disease; 2013. 8 p.
  • Spirometry for health care providers. Vancouver (WA): Global Initiative for Chronic Obstructive Lung Disease; 2010. 14 p.
  • Spirometry for health care providers: quick guide. Vancouver (WA): Global Initiative for Chronic Obstructive Lung Disease; 2010. 2 p.
  • GOLD teaching slide set. Vancouver (WA): Global Initiative for Chronic Obstructive Lung Disease; 2013 Feb. 117 p. Also available in Italian.
  • Spirometry slide set. Vancouver (WA): Global Initiative for Chronic Obstructive Lung Disease; 2010. 61 p.
  • Instructions for inhaler and spacer use. Vancouver (WA): Global Initiative for Chronic Obstructive Lung Disease; 2007. 28 p.

Electronic copies: Available from the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Web site External Web Site Policy.

The original guideline document External Web Site Policy contains the Modified Medical Research Council Questionnaire for assessing the severity of breathlessness.

Patient Resources

The following is available:

Please note: This patient information is intended to provide health professionals with information to share with their patients to help them better understand their health and their diagnosed disorders. By providing access to this patient information, it is not the intention of NGC to provide specific medical advice for particular patients. Rather we urge patients and their representatives to review this material and then to consult with a licensed health professional for evaluation of treatment options suitable for them as well as for diagnosis and answers to their personal medical questions. This patient information has been derived and prepared from a guideline for health care professionals included on NGC by the authors or publishers of that original guideline. The patient information is not reviewed by NGC to establish whether or not it accurately reflects the original guideline's content.

NGC Status

This summary was completed by ECRI on May 22, 2001. This summary was updated by ECRI on August 18, 2004, and on October 5, 2005. This summary was updated by ECRI on December 5, 2005 following the U.S. Food and Drug Administration (FDA) advisory on long-acting beta2-adrenergic agonists (LABA). This summary was updated by ECRI on January 27, 2006 following the U.S. Food and Drug Administration (FDA) advisory on Ketek (telithromycin). This summary was updated by ECRI on February 21, 2006 following the U.S. Food and Drug Administration (FDA) advisory on Tequin (gatifloxacin). This summary was updated by ECRI on July 3, 2006 following the updated U.S. Food and Drug Administration (FDA) advisory on Ketek (telithromycin). This NGC summary was updated again on January 29, 2007. This summary was updated by ECRI on March 6, 2007 following the updated FDA advisory on Ketek (telithromycin). This summary was updated by ECRI Institute on June 22, 2007 following the U.S. Food and Drug Administration (FDA) advisory on heparin sodium injection. This summary was updated by ECRI Institute on November 9, 2007, following the U.S. Food and Drug Administration advisory on Antidepressant drugs. This summary was updated by ECRI Institute on April 18, 2008. This NGC summary was updated by ECRI Institute on December 26, 2008 following the FDA advisory on Innohep (tinzaparin). This summary was updated by ECRI Institute on May 12, 2009. This summary was updated by ECRI Institute on July 20, 2009 following the U.S. Food and Drug Administration advisory on Varenicline and Bupropion. This summary was updated by ECRI Institute on April 13, 2010. This summary was updated by ECRI Institute on July 27, 2010 following the FDA drug safety communication on Heparin. This NGC summary was updated by ECRI Institute on June 17, 2011. This NGC summary was updated by ECRI Institute on August 1, 2012. The updated information was verified by the guideline developer on August 24, 2012. This summary was updated by ECRI Institute on January 14, 2013 following the revised U.S. Food and Drug Administration advisory on Chantix (varenicline). This summary was updated by ECRI Institute on April 23, 2013. The updated information was verified by the guideline developer on April 30, 2013.

Copyright Statement

The material in this document is from the Global Strategy for the Diagnosis, Management, and Prevention of COPD, 2013 and is protected by copyright. Printing and/or distribution requires prior approval from the Global Initiative for Chronic Lung Disease (GOLD) – http://www.goldcopd.org External Web Site Policy.

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