This Article Abstract Full Text (PDF) Online Supplement All Versions of this Article: 200703-456SOv1 176/6/532    most recent Alert me when this article is cited Alert me if a correction is posted Services Related articles in AJRCCM Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Rabe, K. F. Articles by Zielinski, J. Search for Related Content PubMed PubMed Citation Articles by Rabe, K. F. Articles by Zielinski, J.

Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease

GOLD Executive Summary

¹ Leiden University Medical Center, Pulmonology, Leiden, The Netherlands; ² Global Initiative for Chronic Obstructive Lung Disease, Gaithersburg, Maryland; ³ University of Texas Health Science Center, San Antonio, Texas; ⁴ National Heart and Lung Institute, London, United Kingdom; ⁵ Oregon Health and Science University, Portland, Oregon; ⁶ University Hospital Aintree, Liverpool, United Kingdom; ⁷ Asian Pacific Society of Respirology, Tokyo, Japan; ⁸ Woolcock Institute of Medical Research, North Sydney, Australia; ⁹ Hospital Clinic, Barcelona, Spain; ¹⁰ University of Nijmegen, Nijmegen, The Netherlands; and ¹¹ Institute of TB and Lung Diseases, Warsaw, Poland

Correspondence and requests for reprints should be addressed to Prof. Klaus F. Rabe, M.D., Ph.D., Leiden University Medical Center, Pulmonology, P.O. Box 9600, NL-2300 RC, Leiden, The Netherlands. E-mail: k.f.rabe{at}lumc.nl.

	ABSTRACT

TOP ABSTRACT CONTENTS INTRODUCTION 1. DEFINITION, CLASSIFICATION OF... 2. BURDEN OF COPD 3. THE FOUR COMPONENTS... 4. TRANSLATING GUIDELINE... REFERENCES

 
Chronic obstructive pulmonary disease (COPD) remains a major public health problem. It is the fourth leading cause of chronic morbidity and mortality in the United States, and is projected to rank fifth in 2020 in burden of disease worldwide, according to a study published by the World Bank/World Health Organization. Yet, COPD remains relatively unknown or ignored by the public as well as public health and government officials. In 1998, in an effort to bring more attention to COPD, its management, and its prevention, a committed group of scientists encouraged the U.S. National Heart, Lung, and Blood Institute and the World Health Organization to form the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Among the important objectives of GOLD are to increase awareness of COPD and to help the millions of people who suffer from this disease and die prematurely of it or its complications. The first step in the GOLD program was to prepare a consensus report, Global Strategy for the Diagnosis, Management, and Prevention of COPD, published in 2001. The present, newly revised document follows the same format as the original consensus report, but has been updated to reflect the many publications on COPD that have appeared. GOLD national leaders, a network of international experts, have initiated investigations of the causes and prevalence of COPD in their countries, and developed innovative approaches for the dissemination and implementation of COPD management guidelines. We appreciate the enormous amount of work the GOLD national leaders have done on behalf of their patients with COPD. Despite the achievements in the 5 years since the GOLD report was originally published, considerable additional work is ahead of us if we are to control this major public health problem. The GOLD initiative will continue to bring COPD to the attention of governments, public health officials, health care workers, and the general public, but a concerted effort by all involved in health care will be necessary.

Key Words: COPD • guidelines • human • chronic disease

	CONTENTS

TOP ABSTRACT CONTENTS INTRODUCTION 1. DEFINITION, CLASSIFICATION OF... 2. BURDEN OF COPD 3. THE FOUR COMPONENTS... 4. TRANSLATING GUIDELINE... REFERENCES

 
Introduction

Methodology and Summary of New Recommendations

Levels of Evidence

1. Definition, Classification of Severity, and Mechanisms of COPD

   Definition
   

   Spirometric Classification of Severity and Stages of COPD
   

   Pathology, Pathogenesis, and Pathophysiology
   

   
   
2. Burden of COPD

   Epidemiology

   Prevalence
   

   Morbidity
   

   Mortality
   

   
   

   Economic and Social Burden of COPD
   

   Risk Factors

   Genes
   

   Inhalational Exposures
   

   Sex
   

   Infection
   

   Socioeconomic Status
   

   
   

   
   
3. The Four Components of COPD Management

   Introduction
   

   Component 1: Assess and Monitor Disease

   Initial Diagnosis
   

   Ongoing Monitoring and Assessment
   

   
   

   Component 2: Reduce Risk Factors

   Smoking Prevention and Cessation
   

   Occupational Exposures
   

   Indoor and Outdoor Air Pollution
   

   
   

   Component 3: Manage Stable COPD

   Introduction
   

   Education
   

   Pharmacologic Treatments
   

   Nonpharmacologic Treatments
   

   Special Considerations
   

   
   

   Component 4: Manage Exacerbations

   Introduction
   

   Diagnosis and Assessment of Severity
   

   Home Management
   

   Hospital Management
   

   Hospital Discharge and Follow-up
   

   
   

   
   
4. Translating Guideline Recommendations to the Context of (Primary) Care

   Diagnosis

   Respiratory Symptoms
   

   
   

   Spirometry
   

   Comorbidities
   

   Reducing Exposure to Risk Factors
   

   Implementation of COPD Guidelines
   

   
   

	INTRODUCTION

TOP ABSTRACT CONTENTS INTRODUCTION 1. DEFINITION, CLASSIFICATION OF... 2. BURDEN OF COPD 3. THE FOUR COMPONENTS... 4. TRANSLATING GUIDELINE... REFERENCES

 
Chronic obstructive pulmonary disease (COPD) is a major cause of chronic morbidity and mortality throughout the world. Many people suffer from this disease for years and die prematurely of it or its complications. The goals of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) are 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 expanded level of research interest in this highly prevalent disease.

One strategy to help achieve the objectives of GOLD is to provide health care workers, health care authorities, and the general public with state-of-the-art information about COPD and specific recommendations on the most appropriate management and prevention strategies. The GOLD report, Global Strategy for the Diagnosis, Management, and Prevention of COPD, is based on the best-validated current concepts of COPD pathogenesis and the available evidence on the most appropriate management and prevention strategies. A major part of the GOLD report is devoted to the clinical management of COPD and presents a management plan with four components: (1) assess and monitor disease, (2) reduce risk factors, (3) manage stable COPD, and (4) manage exacerbations. A new section at the end of the document will assist readers in translating guideline recommendations to the context of (primary) care.

GOLD is a partner organization in a program launched in March 2006 by the World Health Organization's Global Alliance Against Chronic Respiratory Diseases (GARD). Through the work of the GOLD committees, and in cooperation with GARD initiatives, progress toward better care for all patients with COPD should be substantial in the next decade.

Methodology and Summary of New Recommendations
After the release of the 2001 GOLD report, a science committee was formed and charged with keeping the GOLD documents up-to-date by reviewing published research, evaluating the impact of this research on the management recommendations in the GOLD documents, and posting yearly updates of these documents on the GOLD website (www.goldcopd.org). The methodology is described in each update (see, e.g., the 2005 update in Reference 3 and the APPENDIX in the online supplement).

In January 2005, the GOLD science committee initiated preparation of this revised 2006 document on the basis of the most current scientific literature. Multiple meetings were held, including several with GOLD national leaders to discuss concepts and new recommendations. Before its publications, several reviewers were invited to submit comments.

A summary of the issues presented in this report include the following:

1. Recognition that COPD is characterized by chronic airflow limitation and a range of pathologic changes in the lung, some significant extrapulmonary effects, and important comorbidities that may contribute to the severity of the disease in individual patients.
   
2. In the definition of COPD, the phrase "preventable and treatable" has been incorporated following the American Thoracic Society/European Respiratory Society recommendations to recognize the need to present a positive outlook for patients, to encourage the health care community to take a more active role in developing programs for COPD prevention, and to stimulate effective management programs to treat those with the disease.
   
3. The spirometric classification of severity of COPD now includes four stages: stage I, mild; stage II, moderate; stage III, severe; stage IV, very severe. A fifth category, "stage 0, at risk," that appeared in the 2001 report is no longer included as a stage of COPD, as there is incomplete evidence that the individuals who meet the definition of "at risk" (chronic cough and sputum production, normal spirometry) necessarily progress on to stage I. Nevertheless, the importance of the public health message that chronic cough and sputum are not normal is unchanged.
   
4. The spirometric classification of severity continues to recommend use of the fixed ratio post-bronchodilator FEV₁/FVC < 0.7 to define airflow limitation. Using the fixed ratio (FEV₁/FVC) is particularly problematic in patients with milder disease who are elderly because the normal process of aging affects lung volumes. Post-bronchodilator reference values in this population are urgently needed to avoid potential overdiagnosis.
   
5. Section 2, BURDEN OF COPD, provides references to published data from prevalence surveys to estimate that about 15 to 25% of adults aged 40 years and older may have airflow limitation classified as stage I mild COPD or higher and that the prevalence of COPD (stage I, mild COPD and higher) is appreciably higher in smokers and ex-smokers than in nonsmokers, in those over 40 years compared with those younger than 40, and higher in men than in women. The section also provides new data on COPD morbidity and mortality.
   
6. Cigarette smoke is the most commonly encountered risk factor for COPD and elimination of this risk factor is an important step toward prevention and control of COPD. However, other risk factors for COPD should be taken into account where possible, including occupational dusts and chemicals, and indoor air pollution from biomass cooking and heating in poorly ventilated dwellings—the latter especially among women in developing countries.
   
7. The section on pathology, pathogenesis, and pathophysiology, continues with the theme that inhaled cigarette smoke and other noxious particles cause lung inflammation, a normal response which appears to be amplified in patients who develop COPD. The section has been considerably updated and revised.
   
8. Management of COPD continues to be presented in four components: (1) assess and monitor disease, (2) reduce risk factors, (3) manage stable COPD, and (4) manage exacerbations. All components have been updated on the basis of recently published literature. Throughout it is emphasized that the overall approach to managing stable COPD should be individualized to address symptoms and improve quality of life.
   
9. In COMPONENT 4, MANAGE EXACERBATIONS, a COPD exacerbation is defined as "an event in the natural course of the disease characterized by a change in the patient's baseline dyspnea, cough, and/or sputum that is beyond normal day-to-day variations, is acute in onset, and may warrant a change in regular medication in a patient with underlying COPD."
   
10. It is widely recognized that a wide spectrum of health care providers is required to ensure that COPD is diagnosed accurately, and that individuals who have COPD are treated effectively. The identification of effective health care teams will depend on the local health care system, and much work remains to identify how best to build these health care teams. A section on COPD implementation programs and issues for clinical practice has been included but it remains a field that requires considerable attention.
    

Levels of Evidence
Levels of evidence are assigned to management recommendations where appropriate in subsections of section 3 that discuss COPD management, with the system used in previous GOLD reports (Table 1). Evidence levels are enclosed in parentheses after the relevant statement—for example, (Evidence A).

	1. DEFINITION, CLASSIFICATION OF SEVERITY, AND MECHANISMS OF COPD

TOP ABSTRACT CONTENTS INTRODUCTION 1. DEFINITION, CLASSIFICATION OF... 2. BURDEN OF COPD 3. THE FOUR COMPONENTS... 4. TRANSLATING GUIDELINE... REFERENCES

Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients. Its pulmonary component is characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases.

The chronic airflow limitation characteristic of COPD is caused by a mixture of small airway disease (obstructive bronchiolitis) and parenchymal destruction (emphysema), the relative contributions of which vary from person to person. Airflow limitation is best measured by spirometry, because this is the most widely available, reproducible test of lung function.

Because COPD often develops in longtime smokers in middle age, patients often have a variety of other diseases related to either smoking or aging (4). COPD itself also has significant extrapulmonary (systemic) effects that lead to comorbid conditions (5). Thus, COPD should be managed with careful attention also paid to comorbidities and their effect on the patient's quality of life. A careful differential diagnosis and comprehensive assessment of severity of comorbid conditions should be performed in every patient with chronic airflow limitation.

Spirometric Classification of Severity and Stages of COPD
For educational reasons, a simple spirometric classification of disease severity into four stages is recommended (Table 2). Spirometry is essential for diagnosis and provides a useful description of the severity of pathologic changes in COPD. Specific spirometric cut points (e.g., post-bronchodilator FEV₁/FVC ratio < 0.70 or FEV₁ < 80, 50, or 30% predicted) are used for purposes of simplicity; these cut points have not been clinically validated. A study in a random population sample found that the post-bronchodilator FEV₁/FVC exceeded 0.70 in all age groups, supporting the use of this fixed ratio (6). However, because the process of aging does affect lung volumes, the use of this fixed ratio may result in overdiagnosis of COPD in the elderly, especially in those with mild disease.

Stage I: mild COPD: Characterized by mild airflow limitation (FEV₁/FVC < 0.70, FEV₁ 80% predicted). Symptoms of chronic cough and sputum production may be present, but not always. At this stage, the individual is usually unaware that his or her lung function is abnormal.

Stage II: moderate COPD: Characterized by worsening airflow limitation (FEV₁/FVC < 0.70, 50% FEV₁ < 80% predicted), with shortness of breath typically developing on exertion and cough and sputum production sometimes also present. This is the stage at which patients typically seek medical attention because of chronic respiratory symptoms or an exacerbation of their disease.

Stage III: severe COPD: Characterized by further worsening of airflow limitation (FEV₁/FVC < 0.70, 30% FEV₁ < 50% predicted), greater shortness of breath, reduced exercise capacity, fatigue, and repeated exacerbations that almost always have an impact on patients' quality of life.

Stage IV: very severe COPD: Characterized by severe airflow limitation (FEV₁/FVC < 0.70, FEV₁ < 30% predicted or FEV₁ < 50% predicted plus the presence of chronic respiratory failure). Respiratory failure is defined as an arterial partial pressure of O₂ (Pa_O2) less than 8.0 kPa (60 mm Hg), with or without an arterial partial pressure of CO₂ (Pa_CO2) greater than 6.7 kPa (50 mm Hg) while breathing air at sea level. Respiratory failure may also lead to effects on the heart such as cor pulmonale (right heart failure). Clinical signs of cor pulmonale include elevation of the jugular venous pressure and pitting ankle edema. Patients may have stage IV COPD even if their FEV₁ is greater than 30% predicted, whenever these complications are present. At this stage, quality of life is very appreciably impaired and exacerbations may be life threatening.

Although asthma can usually be distinguished from COPD, in some individuals with chronic respiratory symptoms and fixed airflow limitation it remains difficult to differentiate the two diseases. In many developing countries, both pulmonary tuberculosis and COPD are common (7). In countries where tuberculosis is very common, respiratory abnormalities may be too readily attributed to this disease (8). Conversely, where the rate of tuberculosis is greatly diminished, the possible diagnosis of this disease is sometimes overlooked. Therefore, in all subjects with symptoms of COPD, a possible diagnosis of tuberculosis should be considered, especially in areas where this disease is known to be prevalent (9).

Pathology, Pathogenesis, and Pathophysiology
Pathologic changes characteristic of COPD are found in the proximal airways, peripheral airways, lung parenchyma, and pulmonary vasculature (10). The pathologic changes include chronic inflammation, with increased numbers of specific inflammatory cell types in different parts of the lung, and structural changes resulting from repeated injury and repair. In general, the inflammatory and structural changes in the airways increase with disease severity and persist on smoking cessation.

The inflammation in the respiratory tract of patients with COPD appears to be an amplification of the normal inflammatory response of the respiratory tract to chronic irritants such as cigarette smoke. The mechanisms for this amplification are not yet understood but may be genetically determined. Some patients develop COPD without smoking, but the nature of the inflammatory response in these patients is unknown (11). Lung inflammation is further amplified by oxidative stress and an excess of proteinases in the lung. Together, these mechanisms lead to the characteristic pathologic changes in COPD.

There is now a good understanding of how the underlying disease process in COPD leads to the characteristic physiologic abnormalities and symptoms. For example, decreased FEV₁ primarily results from inflammation and narrowing of peripheral airways and a dynamic airway collapse in more severe emphysema, whereas decreased gas transfer arises from the parenchymal destruction of emphysema. The extent of inflammation, fibrosis, and luminal exudates in small airways is correlated with the reduction in FEV₁ and FEV₁/FVC ratio, and probably with the accelerated decline in FEV₁ characteristic of COPD (4). Gas exchange abnormalities result in hypoxemia and hypercapnia, and have several mechanisms in COPD. In general, gas transfer worsens as the disease progresses. Mild to moderate pulmonary hypertension may develop late in the course of COPD and is due to hypoxic vasoconstriction of small pulmonary arteries. It is increasingly recognized that COPD involves several systemic features, particularly in patients with severe disease, and that these have a major impact on survival and comorbid diseases (12, 13).

	2. BURDEN OF COPD

TOP ABSTRACT CONTENTS INTRODUCTION 1. DEFINITION, CLASSIFICATION OF... 2. BURDEN OF COPD 3. THE FOUR COMPONENTS... 4. TRANSLATING GUIDELINE... REFERENCES

 
COPD prevalence, morbidity, and mortality vary across countries and across different groups within countries but, in general, are directly related to the prevalence of tobacco smoking, although, in many countries, air pollution resulting from the burning of wood and other biomass fuels has also been identified as a COPD risk factor. The prevalence and burden of COPD are projected to increase in the coming decades due to continued exposure to COPD risk factors and the changing age structure of the world's population.

Epidemiology
In the past, imprecise and variable definitions of COPD have made it difficult to quantify prevalence, morbidity, and mortality. Furthermore, the underrecognition and underdiagnosis of COPD lead to significant underreporting. The extent of the underreporting varies across countries and depends on the level of awareness and understanding of COPD among health professionals, the organization of health care services to cope with chronic diseases, and the availability of medications for the treatment of COPD (14).

Prevalence.
Many sources of variation can affect estimates of COPD prevalence, including sampling methods, response rates, quality control of spirometry, and whether spirometry is performed pre- or post-bronchodilator. Despite these complexities, data are emerging that enable some conclusions to be drawn regarding COPD prevalence. A prevalence study in Latin America (19), a systematic review and meta-analysis of studies performed in 28 countries between 1990 and 2004 (15), and an additional study from Japan (16) provide evidence that the prevalence of COPD (stage I, mild COPD and higher) is appreciably higher in smokers and ex-smokers compared with nonsmokers, in those older than 40 years compared with those younger than 40 years, and in men compared with women.

Morbidity.
Morbidity measures traditionally include physician visits, emergency department visits, and hospitalizations. Although COPD databases for these outcome parameters are less readily available and usually less reliable than mortality databases, the limited data available indicate that morbidity due to COPD increases with age and is greater in men than in women (17, 18). COPD in its early stages (stages I and II) is usually not recognized, diagnosed, or treated, and therefore may not be included as a diagnosis in a patient's medical record.

Morbidity from COPD may be affected by other comorbid chronic conditions (20) (e.g., musculoskeletal disease, diabetes mellitus) that are not directly related to COPD but nevertheless may have an impact on the patient's health status, or may interfere with COPD management. In patients with more advanced disease (stages III and IV), morbidity from COPD may be misattributed to another comorbid condition.

Mortality.
COPD is one of the most important causes of death in most countries. The Global Burden of Disease Study (2, 21, 22) has projected that COPD, which ranked sixth as the cause of death in 1990, will become the third leading cause of death worldwide by 2020. This increased mortality is driven by the expanding epidemic of smoking and the changing demographics in most countries, with more of the population living longer.

Economic and Social Burden of COPD
COPD is a costly disease. In developed countries, exacerbations of COPD account for the greatest burden on the health care system. In the European Union, the total direct costs of respiratory disease are estimated to be about 6% of the total health care budget, with COPD accounting for 56% (38.6 billion) of this cost of respiratory disease (23). In the United States in 2002, the direct costs of COPD were $18 billion and the indirect costs totaled $14.1 billion (1). Costs per patient will vary across countries because these costs depend on how health care is provided and paid (24). Not surprisingly, there is a striking direct relationship between the severity of COPD and the cost of care (25), and the distribution of costs changes as the disease progresses.

Risk Factors
Identification of cigarette smoking as the most commonly encountered risk factor for COPD has led to the incorporation of smoking cessation programs as a key element of COPD prevention, as well as an important intervention for patients who already have the disease. However, although smoking is the best-studied COPD risk factor, it is not the only one and there is consistent evidence from epidemiologic studies that nonsmokers may develop chronic airflow obstruction (26, 27) (Figure 1).

View larger version (33K): [in this window] [in a new window]   Figure 1. Chronic obstructive pulmonary disease risk is related to the total burden of inhaled particles.

Genetic association studies have implicated a variety of genes in COPD pathogenesis. However, the results of these genetic association studies have been largely inconsistent, and functional genetic variants influencing the development of COPD (other than ₁-antitrypsin deficiency) have not been definitively identified (30).

Inhalational exposures.
TOBACCO SMOKE.
Cigarette smokers have a higher prevalence of respiratory symptoms and lung function abnormalities, a greater annual rate of decline in FEV₁, and a greater COPD mortality rate than nonsmokers. Pipe and cigar smokers have greater COPD morbidity and mortality rates than nonsmokers, although their rates are lower than those for cigarette smokers (31). Other types of tobacco smoking popular in various countries are also risk factors for COPD (32, 33). Not all smokers develop clinically significant COPD, which suggests that genetic factors must modify each individual's risk (34). Passive exposure to cigarette smoke may also contribute to respiratory symptoms (35) and COPD (36) by increasing the lungs' total burden of inhaled particles and gases (37, 38). Smoking during pregnancy may also pose a risk for the fetus, by affecting lung growth and development in utero and possibly the priming of the immune system (39, 40).

OCCUPATIONAL DUSTS AND CHEMICALS.
Occupational exposures include organic and inorganic dusts and chemical agents and fumes. A statement published by the American Thoracic Society concluded that occupational exposures account for 10 to 20% of either symptoms or functional impairment consistent with COPD (41).

INDOOR AND OUTDOOR AIR POLLUTION.
The evidence that indoor pollution from biomass cooking and heating in poorly ventilated dwellings is an important risk factor for COPD (especially among women in developing countries) continues to grow (42–48), with case-control studies (47, 48) and other designed studies now available. High levels of urban air pollution are harmful to individuals with existing heart or lung disease, but the role of outdoor air pollution in causing COPD is unclear.

Sex.
Studies from developed countries (1, 49) show that the prevalence of the disease is now almost equal in men and women, probably reflecting the changing patterns of tobacco smoking. Some studies have suggested that women are more susceptible to the effects of tobacco smoke than men (50–52).

Infection.
A history of severe childhood respiratory infection has been associated with reduced lung function and increased respiratory symptoms in adulthood (53–55). However, susceptibility to viral infections may be related to another factor, such as low birth weight, that itself is related to COPD.

Socioeconomic status.
There is evidence that the risk of developing COPD is inversely related to socioeconomic status (56). It is not clear, however, whether this pattern reflects exposures to cigarette smoke, indoor and outdoor air pollutants, crowding, poor nutrition, or other factors that are related to low socioeconomic status (57, 58).

	3. THE FOUR COMPONENTS OF COPD MANAGEMENT

TOP ABSTRACT CONTENTS INTRODUCTION 1. DEFINITION, CLASSIFICATION OF... 2. BURDEN OF COPD 3. THE FOUR COMPONENTS... 4. TRANSLATING GUIDELINE... REFERENCES

 
Introduction
An effective COPD management plan includes four components: (1) assess and monitor disease, (2) reduce risk factors, (3) manage stable COPD, and (4) manage exacerbations. Although disease prevention is the ultimate goal, once COPD has been diagnosed, effective management should be aimed at the following goals:

• Relieve symptoms
  
• Prevent disease progression
  
• Improve exercise tolerance
  
• Improve health status
  
• Prevent and treat complications
  
• Prevent and treat exacerbations
  
• Reduce mortality
  

Patients should be identified as early in the course of the disease as possible, and certainly before the end stage of the illness when disability is substantial. Access to spirometry is key to the diagnosis of COPD and should be available to health care workers who care for patients with COPD. However, the benefits of community-based spirometric screening, of either the general population or smokers, are still unclear.

Educating patients, physicians, and the public to recognize that cough, sputum production, and especially breathlessness are not trivial symptoms is an essential aspect of the public health care of this disease.

Reduction of therapy once symptom control has been achieved is not normally possible in COPD. Further deterioration of lung function usually requires the progressive introduction of more treatments, both pharmacologic and nonpharmacologic, to attempt to limit the impact of these changes. Exacerbations of signs and symptoms, a hallmark of COPD, impair patients' quality of life and decrease their health status. Appropriate treatment and measures to prevent further exacerbations should be implemented as quickly as possible.

Component 1: Assess and Monitor Disease

KEY POINTS A clinical diagnosis of COPD should be considered in any patient who has dyspnea, chronic cough or sputum production, and/or a history of exposure to risk factors for the disease. The diagnosis should be confirmed by spirometry. For the diagnosis and assessment of COPD, spirometry is the gold standard because it is the most reproducible, standardized, and objective way of measuring airflow limitation. A post-bronchodilator FEV1/FVC < 0.70 confirms the presence of airflow limitation that is not fully reversible. Health care workers involved in the diagnosis and management of patients with COPD should have access to spirometry. Assessment of COPD severity is based on the patient's level of symptoms, the severity of the spirometric abnormality, and the presence of complications. Measurement of arterial blood gas tensions should be considered in all patients with FEV1 < 50% predicted or clinical signs suggestive of respiratory failure or right heart failure. COPD is usually a progressive disease and 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. Comorbidities are common in COPD and should be actively identified. Comorbidities often complicate the management of COPD, and vice versa.

 

Initial diagnosis.
A clinical diagnosis of COPD should be considered in any patient who has dyspnea, chronic cough or sputum production, and/or a history of exposure to risk factors for the disease (Table 3). The diagnosis should be confirmed by spirometry.

MEDICAL HISTORY.
A detailed medical history of a new patient known or believed to have COPD should assess the following:

• Exposure to risk factors
  
• 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
  
• History of exacerbations or previous hospitalizations for respiratory disorder
  
• Presence of comorbidities, such as heart disease, malignancies, osteoporosis, and muscloskeletal disorders, which may also contribute to restriction of activity (62)
  
• Appropriateness of current medical treatments
  
• 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
  
• 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 (63, 64), and their detection has a relatively low sensitivity and specificity.

MEASUREMENT OF AIRFLOW LIMITATION (SPIROMETRY).
Spirometry should be undertaken in all patients who may have COPD. Spirometry should measure the volume of air forcibly exhaled from the point of maximal inspiration (FVC) and the volume of air exhaled during the first second of this maneuver (FEV₁), and the ratio of these two measurements (FEV₁/FVC) should be calculated. Spirometry measurements are evaluated by comparison with reference values (65) based on age, height, sex, and race (use appropriate reference values; e.g., see Reference 65). Patients with COPD typically show a decrease in both FEV₁ and FVC. The presence of airflow limitation is defined by a post-bronchodilator FEV₁/FVC < 0.70. This approach is pragmatic in view of the fact that universally applicable reference values for FEV₁ and FVC are not available. Where possible, values should be compared with age-related normal values to avoid overdiagnosis of COPD in the elderly (66). Using the fixed ratio (FEV₁/FVC) is particularly problematic in patients with milder COPD who are elderly because the normal process of aging affects lung volumes.

ASSESSMENT OF COPD SEVERITY.
Assessment of COPD severity is based on the patient's level of symptoms, the severity of the spirometric abnormality (Table 2), and the presence of complications such as respiratory failure, right heart failure, weight loss, and arterial hypoxemia.

ADDITIONAL INVESTIGATIONS.
For patients diagnosed with stage II, moderate, COPD and beyond, the following additional investigations may be considered.

   Bronchodilator reversibility testing.
Despite earlier hopes, neither bronchodilator nor oral glucocorticosteroid reversibility testing predicts disease progression, whether judged by decline in FEV₁, deterioration of health status, or frequency of exacerbations (67, 68) in patients with a clinical diagnosis of COPD and abnormal spirometry (68). In some cases (e.g., a patient with an atypical history such as asthma in childhood and regular night waking with cough or wheeze), a clinician may wish to perform a bronchodilator and/or glucocorticosteroid reversibility test.

   Chest X-ray.
An abnormal chest X-ray is seldom diagnostic in COPD unless obvious bullous disease is present, but it is valuable in excluding alternative diagnoses and establishing the presence of significant comorbidities, such as cardiac failure. Computed tomography (CT) of the chest is not routinely recommended. However, when there is doubt about the diagnosis of COPD, high-resolution CT scanning might help in the differential diagnosis. In addition, if a surgical procedure such as lung volume reduction is contemplated, a chest CT scan is necessary because the distribution of emphysema is one of the most important determinants of surgical suitability (69).

   Arterial blood gas measurement.
In advanced COPD, measurement of arterial blood gases while the patient is breathing air is important. This test should be performed in stable patients with FEV₁ < 50% predicted or with clinical signs suggestive of respiratory failure or right heart failure.

   ₁-Antitrypsin deficiency screening.
In patients of Caucasian descent who develop COPD at a young age (< 45 yr) or who have a strong family history of the disease, it may be valuable to identify coexisting ₁-antitrypsin deficiency. This could lead to family screening or appropriate counseling.

DIFFERENTIAL DIAGNOSIS.
In some patients with chronic asthma, a clear distinction from COPD is not possible using current imaging and physiologic testing techniques, and it is assumed that asthma and COPD coexist in these patients. In these cases, current management is similar to that of asthma. Other potential diagnoses are usually easier to distinguish from COPD (Table 4).

Follow-up visits should include a physical examination and discussion of symptoms, particularly any new or worsening symptoms. Spirometry should be performed if there is a substantial increase in symptoms or a complication. The development of respiratory failure is indicated by a Pa_O2 < 8.0 kPa (60 mm Hg) with or without Pa_CO2 > 6.7 kPa (50 mm Hg) in arterial blood gas measurements made while breathing air at sea level. Measurement of pulmonary arterial pressure is not recommended in clinical practice as it does not add practical information beyond that obtained from a knowledge of Pa_O2.

MONITOR PHARMACOTHERAPY AND OTHER MEDICAL TREATMENT.
To adjust therapy appropriately as the disease progresses, each follow-up visit should include a discussion of the current therapeutic regimen. Dosages of various medications, adherence to the regimen, inhaler technique, effectiveness of the current regime at controlling symptoms, and side effects of treatment should be monitored.

MONITOR EXACERBATION HISTORY.
Frequency, severity, and likely causes of exacerbations should be evaluated. Increased sputum volume, acutely worsening dyspnea, and the presence of purulent sputum should be noted. Severity can be estimated by the increased need for bronchodilator medication or glucocorticosteroids and by the need for antibiotic treatment. Hospitalizations should be documented, including the facility, duration of stay, and any use of critical care or intubation.

MONITOR COMORBIDITIES.
Comorbidities are common in COPD and may become harder to manage when COPD is present, either because COPD adds to the total level of disability or because COPD therapy adversely affects the comorbid disorder. Until more integrated guidance about disease management for specific comorbid problems becomes available, the focus should be on identification and management of these individual problems.

Component 2: Reduce Risk Factors

KEY POINTS Reduction of total personal exposure to tobacco smoke, occupational dusts and chemicals, and indoor and outdoor air pollutants are important goals to prevent the onset and progression of COPD. Smoking cessation is the single most effective—and cost-effective—intervention in most people to reduce the risk of developing COPD and stop its progression (Evidence A). Comprehensive tobacco control policies and programs with clear, consistent, and repeated nonsmoking messages should be delivered through every feasible channel. Efforts to reduce smoking through public health initiatives should also focus on passive smoking to minimize risks for nonsmokers. Many occupationally induced respiratory disorders can be reduced or controlled through a variety of strategies aimed at reducing the burden of inhaled particles and gases. Reducing the risk from indoor and outdoor air pollution is feasible and requires a combination of public policy and protective steps taken by individual patients.

 

Smoking prevention and cessation.
Comprehensive tobacco control policies and programs with clear, consistent, and repeated nonsmoking messages should be delivered through every feasible channel, including health care providers, community activities, and schools, and radio, television, and print media. Legislation to establish smoke-free schools, public facilities, and work environments should be developed and implemented by government officials and public health workers, and encouraged by the public.

SMOKING CESSATION INTERVENTION PROCESS.
Smoking cessation is the single most effective—and cost-effective—way to reduce exposure to COPD risk factors. All smokers—including those who may be at risk for COPD as well as those who already have the disease—should be offered the most intensive smoking cessation intervention feasible. Even a brief (3 min) period of counseling to urge a smoker to quit results in smoking cessation rates of 5 to 10% (70). At the very least, this should be done for every smoker at every health care provider visit (70, 71).

Guidelines for smoking cessation entitled "Treating Tobacco Use and Dependence: A Clinical Practice Guideline" were published by the U.S. Public Health Service (72) and recommend a five-step program for intervention (Table 5), which provides a strategic framework helpful to health care providers interested in helping their patients stop smoking (72–75).

The antidepressants bupropion (78) and nortriptyline have also been shown to increase long-term quit rates (76, 77, 79), but should always be used as one element in a supportive intervention program rather than on their own. The effectiveness of the antihypertensive drug clonidine is limited by side effects (77). Varenicline, a nicotinic acetylcholine receptor partial agonist that aids smoking cessation by relieving nicotine withdrawal symptoms and reducing the rewarding properties of nicotine, has been demonstrated to be safe and efficacious (80–82). Special consideration should be given before using pharmacotherapy in the following selected populations: people with medical contraindications, light smokers (<10 cigarettes/d), and pregnant and adolescent smokers.

Occupational exposures.
Although it is not known how many individuals are at risk of developing respiratory disease from occupational exposures in either developing or developed countries, many occupationally induced respiratory disorders can be reduced or controlled through a variety of strategies aimed at reducing the burden of inhaled particles and gases (83–85).

The main emphasis should be on primary prevention, which is best achieved by the elimination or reduction of exposures to various substances in the workplace. Secondary prevention, achieved through surveillance and early case detection, is also of great importance.

Indoor and outdoor air pollution.
Individuals experience diverse indoor and outdoor environments throughout the day, each of which has its own unique set of air contaminants and particulates that cause adverse effects on lung function (86). Although outdoor and indoor air pollution are generally considered separately, the concept of total personal exposure may be more relevant for COPD. Reducing the risk from indoor and outdoor air pollution is feasible and requires a combination of public policy and protective steps taken by individual patients. At the national level, achieving a set level of air quality standards should be a high priority; this goal will normally require legislative action. Reduction of exposure to smoke from biomass fuel, particularly among women and children, is a crucial goal to reduce the prevalence of COPD worldwide. Although efficient nonpolluting cooking stoves have been developed, their adoption has been slow due to social customs and cost.

The health care provider should consider COPD risk factors, including smoking history, family history, exposure to indoor/outdoor pollution, and socioeconomic status, for each individual patient. Those who are at high risk should avoid vigorous exercise outdoors during pollution episodes. Persons with advanced COPD should monitor public announcements of air quality and be aware that staying indoors when air quality is poor may help reduce their symptoms. If various solid fuels are used for cooking and heating, adequate ventilation should be encouraged. Under most circumstances, vigorous attempts should be made to reduce exposure through reducing workplace emissions and improving ventilation measures, rather than simply using respiratory protection to reduce the risks of ambient air pollution. Air cleaners have not been shown to have health benefits, whether directed at pollutants generated by indoor sources or at those brought in with outdoor air.

Component 3: Manage Stable COPD

KEY POINTS The overall approach to managing stable COPD should be individualized to address symptoms and improve quality of life. For patients with COPD, health education plays an important role in smoking cessation (Evidence A) and can also play a role in improving skills, ability to cope with illness, and health status. None of the existing medications for COPD have been shown to modify the long-term decline in lung function that is the hallmark of this disease (Evidence A). Therefore, pharmacotherapy for COPD is used to decrease symptoms and/or complications. Bronchodilator medications are central to the symptomatic management of COPD (Evidence A). They are given on an as-needed basis or on a regular basis to prevent or reduce symptoms and exacerbations. The principal bronchodilator treatments are 2-agonists, anticholinergics, and methylxanthines used singly or in combination (Evidence A). Regular treatment with long-acting bronchodilators is more effective and convenient than treatment with short-acting bronchodilators (Evidence A). The addition of regular treatment with inhaled glucocorticosteroids to bronchodilator treatment is appropriate for symptomatic patients with COPD with an FEV1 < 50% predicted (stage III, severe COPD, and stage IV, very severe COPD) and repeated exacerbations (Evidence A). Chronic treatment with systemic glucocorticosteroids should be avoided because of an unfavorable benefit-to-risk ratio (Evidence A). In patients with COPD, influenza vaccines can reduce serious illness (Evidence A). Pneumococcal polysaccharide vaccine is recommended for patients with COPD who are 65 years and older and for patients with COPD who are younger than age 65 with an FEV1 < 40% predicted (Evidence B). All patients with COPD benefit from exercise training programs, improving with respect to both exercise tolerance and symptoms of dyspnea and fatigue (Evidence A). The long-term administration of oxygen (> 15 h/d) to patients with chronic respiratory failure has been shown to increase survival (Evidence A).

 

Introduction.
The overall approach to managing stable COPD should be characterized by an increase in treatment, depending on the severity of the disease and the clinical status of the patient. Management of COPD is based on an individualized assessment of disease severity and response to various therapies. The classification of severity of stable COPD incorporates an individualized assessment of disease severity and therapeutic response into the management strategy. The severity of airflow limitation provides a general guide to the use of some treatments, but the selection of therapy is predominantly determined by the patient's symptoms and clinical presentation. Treatment also depends on the patient's educational level and willingness to apply the recommended management, on cultural and local practice conditions, and on the availability of medications.

Education.
Although patient education is generally regarded as an essential component of care for any chronic disease, assessment of the value of education in COPD may be difficult because of the relatively long time required to achieve improvements in objective measurements of lung function. Patient education alone does not improve exercise performance or lung function (87–90) (Evidence B), but it can play a role in improving skills, ability to cope with illness, and health status (91). Patient education regarding smoking cessation has the greatest capacity to influence the natural history of COPD (Evidence A). Education also improves patient response to exacerbations (92, 93) (Evidence B). Prospective end-of-life discussions can lead to understanding of advance directives and effective therapeutic decisions at the end of life (94) (Evidence B).

Ideally, educational messages should be incorporated into all aspects of care for COPD and may take place in many settings: consultations with physicians or other health care workers, home-care or outreach programs, and comprehensive pulmonary rehabilitation programs. Education should be tailored to the needs and environment of the individual patient, interactive, directed at improving quality of life, simple to follow, practical, and appropriate to the intellectual and social skills of the patient and the caregivers. The topics that seem most appropriate for an education program include the following: smoking cessation; basic information about COPD and pathophysiology of the disease, general approach to therapy and specific aspects of medical treatment, self-management skills, strategies to help minimize dyspnea, advice about when to seek help, self-management and decision making during exacerbations, and advance directives and end-of-life issues.

Pharmacologic treatments.
Pharmacologic therapy is used to prevent and control symptoms (Figure 2), reduce the frequency and severity of exacerbations, improve health status, and improve exercise tolerance. None of the existing medications (Table 6) for COPD have been shown to modify the long-term decline in lung function that is the hallmark of this disease (51, 95–97) (Evidence A). However, this should not preclude efforts to use medications to control symptoms.

View larger version (33K): [in this window] [in a new window]   Figure 2. Therapy at each stage of chronic obstructive pulmonary disease (COPD). Post-bronchodilator FEV1 is recommended for the diagnosis and assessment of severity of COPD.

Regular treatment with long-acting bronchodilators is more effective and convenient than treatment with short-acting bronchodilators (106–109) (Evidence A). Regular use of a long-acting ₂-agonist (107) or a short- or long-acting anticholinergic improves health status (106–108). Treatment with a long-acting inhaled anticholinergic drug reduces the rate of COPD exacerbations (110) and improves the effectiveness of pulmonary rehabilitation (111). Theophylline is effective in COPD, but, due to its potential toxicity, inhaled bronchodilators are preferred when available. All studies that have shown efficacy of theophylline in COPD were done with slow-release preparations.

Combining bronchodilators with different mechanisms and durations of action may increase the degree of bronchodilation for equivalent or lesser side effects. A combination of a short-acting ₂-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 (112–114) (Evidence A).

The combination of a ₂-agonist, an anticholinergic, and/or theophylline may produce additional improvements in lung function (112–118) and health status (112, 119). Increasing the number of drugs usually increases costs, and an equivalent benefit may occur by increasing the dose of one bronchodilator when side effects are not a limiting factor. Detailed assessments of this approach have not been performed.

Dose–response relationships using the FEV₁ as the outcome are relatively flat with all classes of bronchodilators (98–101). Toxicity is also dose related. Increasing the dose of either a ₂-agonist or an anticholinergic by an order of magnitude, especially when given by a wet nebulizer, appears to provide subjective benefit in acute episodes (120) (Evidence B) but is not necessarily helpful in stable disease (121) (Evidence C).

When treatment is given by the inhaled route, attention to effective drug delivery and training in inhaler technique are essential. The choice of inhaler device will depend on availability, cost, the prescribing physician, and the skills and ability of the patient. Patients with COPD may have more problems in effective coordination and find it harder to use a simple metered-dose inhaler than do healthy volunteers or younger patients with asthma. It is essential to ensure that inhaler technique is correct and to recheck this at each visit.

GLUCOCORTICOSTEROIDS.
Regular treatment with inhaled glucocorticosteroids does not modify the long-term decline of FEV₁ in patients with COPD (95–97, 122). However, regular treatment with inhaled glucocorticosteroids is appropriate for symptomatic patients with COPD with an FEV₁ < 50% predicted (stages III and IV) and repeated exacerbations (e.g., three in the last 3 yr) (123–126) (Evidence A). This treatment has been shown to reduce the frequency of exacerbations and thus improve health status (127) (Evidence A), and withdrawal from treatment with inhaled glucocorticosteroids can lead to exacerbations in some patients (128). Reanalysis of pooled data from several longer studies of inhaled glucocorticosteroids in COPD suggests that this treatment reduces all-cause mortality (129), but this conclusion requires confirmation in prospective studies before leading to a change in current treatment recommendations. An inhaled glucocorticosteroid combined with a long-acting ₂-agonist is more effective than the individual components (123, 125, 126, 130, 131) (Evidence A). The dose–response relationships and long-term safety of inhaled glucocorticosteroids in COPD are not known.

Long-term treatment with oral glucocorticosteroids is not recommended in COPD (Evidence A). A side effect of long-term treatment with systemic glucocorticosteroids is steroid myopathy (132–134), which contributes to muscle weakness, decreased functionality, and respiratory failure in subjects with advanced COPD.

OTHER PHARMACOLOGIC TREATMENTS.
   Vaccines.
Influenza vaccines can reduce serious illness (135) and death in patients with COPD by approximately 50% (136, 137) (Evidence A). Vaccines containing killed or live, inactivated viruses are recommended (138) because they are more effective in elderly patients with COPD (139). The strains are adjusted each year for appropriate effectiveness and should be given once each year (140). Pneumococcal polysaccharide vaccine is recommended for patients with COPD who are 65 years and older (141, 142). In addition, this vaccine has been shown to reduce the incidence of community-acquired pneumonia in patients with COPD who are younger than 65 years with an FEV₁ < 40% predicted (143) (Evidence B).

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

   Antibiotics.
Prophylactic, continuous use of antibiotics has been shown to have no effect on the frequency of exacerbations in COPD (144–146), and a study that examined the efficacy of chemoprophylaxis undertaken in the winter months over a period of 5 years concluded that there was no benefit (147). There is no current evidence that the use of antibiotics, other than for treating infectious exacerbations of COPD and other bacterial infections, is helpful (148, 149) (Evidence A).

   Mucolytic (mucokinetic, mucoregulator) 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 (150–152). Although a few patients with viscous sputum may benefit from mucolytics (153, 154), the overall benefits seem to be very small, and the widespread use of these agents cannot be recommended at present (Evidence D).

   Antioxidant agents.
Antioxidants, in particular N-acetylcysteine, have been reported in small studies to reduce the frequency of exacerbations, leading to speculation that these medications could have a role in the treatment of patients with recurrent exacerbations (155–158) (Evidence B). However, a large randomized controlled trial found no effect of N-acetylcysteine on the frequency of exacerbations, except in patients not treated with inhaled glucocorticosteroids (159).

   Immunoregulators (immunostimulators, immunomodulators).
Studies using an immunoregulator in COPD show a decrease in the severity and frequency of exacerbations (160, 161). However, additional studies to examine the long-term effects of this therapy are required before its regular use can be recommended (162).

   Antitussives.
Cough, although sometimes a troublesome symptom in COPD, has a significant protective role (163). Thus, the regular use of antitussives is not recommended in stable COPD (Evidence D).

   Vasodilators.
In patients with COPD, inhaled nitric oxide can worsen gas exchange because of altered hypoxic regulation of ventilation–perfusion balance (164, 165). Therefore, based on the available evidence, nitric oxide is not indicated in stable COPD.

   Narcotics (morphine).
Oral and parenteral opioids are effective for treating dyspnea in patients with advanced COPD disease. There are insufficient data to conclude whether nebulized opioids are effective (166). 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 (167–171).

   Others.
Nedocromil, leukotriene modifiers, and alternative healing methods (e.g., herbal medicine, acupunture, homeopathy) have not been adequately tested in patients with COPD and thus cannot be recommended at this time.

Nonpharmacologic treatments.
REHABILITATION.
The principal goals of pulmonary rehabilitation are to reduce symptoms, improve quality of life, and increase physical and emotional participation in everyday activities. To accomplish these goals, pulmonary rehabilitation covers a range of nonpulmonary problems that may not be adequately addressed by medical therapy for COPD. Such problems, which especially affect patients with stages II through IV COPD, include exercise deconditioning, relative social isolation, altered mood states (especially depression), muscle wasting, and weight loss.

Although more information is needed on criteria for patient selection for pulmonary rehabilitation programs, patients with COPD at all stages of disease appear to benefit from exercise training programs, improving with respect to both exercise tolerance and symptoms of dyspnea and fatigue (172) (Evidence A). Data suggest that these benefits can be sustained even after a single pulmonary rehabilitation program (173–175). 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). To date, there is no consensus on whether repeated rehabilitation courses enable patients to sustain the benefits gained through the initial course. Benefits have been reported from rehabilitation programs conducted in inpatient, outpatient, and home settings (176–178).

Ideally, pulmonary rehabilitation should involve several types of health professionals. The components of pulmonary rehabilitation vary widely from program to program, but a comprehensive pulmonary rehabilitation program includes exercise training, nutrition counseling, and education. 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 the following:

• Detailed history and physical examination
  
• Measurement of spirometry before and after use of a bronchodilator drug
  
• Assessment of exercise capacity
  
• Measurement of health status and impact of breathlessness
  
• Assessment of inspiratory and expiratory muscle strength and lower limb strength (e.g., quadriceps) in patients who suffer from muscle wasting
  

The first two assessments are important for establishing entry suitability and baseline status but are not used in outcome assessment. The last three assessments are baseline and outcome measures.

OXYGEN THERAPY
The long-term administration of oxygen (> 15 h/d) to patients with chronic respiratory failure has been shown to increase survival (179, 180). It can also have a beneficial impact on hemodynamics, hematologic characteristics, exercise capacity, lung mechanics, and mental state (181).

Long-term oxygen therapy is generally introduced in patients with stage IV COPD, who have

• Pa_O2 at or below 7.3 kPa (55 mm Hg) or Sa_O2 at or below 88%, with or without hypercapnia (Evidence B), or
  
• Pa_O2 between 7.3 kPa (55 mm Hg) and 8.0 kPa (60 mm Hg), or Sa_O2 of 88%, if there is evidence of pulmonary hypertension, peripheral edema suggesting congestive cardiac failure, or polycythemia (hematocrit > 55%) (Evidence D).
  

The primary goal of oxygen therapy is to increase the baseline Pa_O2 to at least 8.0 kPa (60 mm Hg) at sea level and rest, and/or produce an Sa_O2 of at least 90%, which will preserve vital organ function by ensuring adequate delivery of oxygen. A decision about the use of long-term oxygen should be based on the waking Pa_O2 values. The prescription should always include the source of supplemental oxygen (gas or liquid), method of delivery, duration of use, and flow rate at rest, during exercise, and during sleep.

VENTILATORY SUPPORT.
Although long-term noninvasive positive-pressure ventilation (NIPPV) cannot be recommended for the routine treatment of patients with chronic respiratory failure due to COPD, the combination of NIPPV with long-term oxygen therapy may be of some use in a selected subset of patients, particularly in those with pronounced daytime hypercapnia (182).

SURGICAL TREATMENTS.
   Bullectomy.
In carefully selected patients, this procedure is effective in reducing dyspnea and improving lung function (183) (Evidence C). A thoracic CT scan, arterial blood gas measurement, and comprehensive respiratory function tests are essential before making a decision regarding suitability for resection of a bulla.

   Lung volume reduction surgery.
A large multicenter study of 1,200 patients comparing lung volume reduction surgery with medical treatment has shown that after 4.3 years, patients with upper lobe emphysema and low exercise capacity who received the surgery had a greater survival rate than similar patients who received medical therapy (54 vs. 39.7%) (184). In addition, the surgery patients experienced greater improvements in their maximal work capacity and their health-related quality of life. The advantage of surgery over medical therapy was less significant among patients who had other emphysema distribution or high exercise capacity before treatment. Although the results of this study showed some very positive results of surgery in a select group of patients (69, 184), lung volume reduction surgery is an expensive palliative surgical procedure and can be recommended only in carefully selected patients.

   Lung transplantation.
In appropriately selected patients with very advanced COPD, lung transplantation has been shown to improve quality of life and functional capacity (185–188) (Evidence C). Criteria for referral for lung transplantation include FEV₁ < 35% predicted, Pa_O2 < 7.3–8.0 kPa (55–60 mm Hg), Pa_CO2 > 6.7 kPa (50 mm Hg), and secondary pulmonary hypertension (189, 190).

Special considerations.
SURGERY IN COPD.
Postoperative pulmonary complications are as important and common as postoperative cardiac complications and, consequently, are a key component of the increased risk posed by surgery in patients with COPD. The principal potential factors contributing to the risk include smoking, poor general health status, age, obesity, and COPD severity. A comprehensive definition of postoperative pulmonar