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The Evidence Base for Management of Acute Exacerbations of COPD*: Clinical Practice Guideline, Part 1 FREE TO VIEW

Vincenza Snow, MD; Steven Lascher, DVM, MPH; Christel Mottur-Pilson, PhD; for the Joint Expert Panel on COPD of the American College of Chest Physicians and the American College of Physicians-American Society of Internal Medicine
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Affiliations: *From the American College of Physicians-American Society of Internal Medicine and the American College of Chest Physicians. This paper also appears in the Annals of Internal Medicine 2001; 134:595–599.,  A complete list of participants is given in the Appendix.

Correspondence to: Vincenza Snow, MD, American College of Physicians-American Society of Internal Medicine, 190 N. Independence Mall West, Philadelphia, PA 19106; e-mail: Vincenza@Mail.acponline.org

Chest. 2001;119(4):1185-1189. doi:10.1378/chest.119.4.1185
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The American College of Physicians-American Society of Internal Medicine (ACP-ASIM) and the American College of Chest Physicians (ACCP) developed this evidence-based clinical practice guideline in collaboration. A joint ACP-ASIM/ACCP expert panel examined the evidence and developed recommendations. The guideline and accompanying background article are primarily based on a systematic review compiled in an Agency for Health CareResearch and Quality evidence report prepared by the Evidence-Based Practice Center at Duke University.1 Our target audience is primary-care physicians and specialists who care for COPD patients. Although the majority of acute exacerbations of COPD (AE-COPD) take place and are treated on an outpatient basis, the research studies all focus on emergency department (ED) or inpatient settings. As a result, this guideline applies to exacerbations treated in those settings. The guideline presents the available evidence on the following:

1. Risk stratification for relapse, and 6-month mortality.

2. Diagnostic testing for AE-COPD.

3. Current treatment options for AE-COPD.

Currently in the United States, 16 million adults have COPD, accounting annually for 110,000 deaths, > 16 million office visits, 500,000 hospitalizations, and $18 billion in direct health-care costs. COPD is characterized by chronic airflow obstruction and episodic increases in dyspnea, cough, and sputum production that are commonly called“ exacerbations.” After an acute exacerbation, most patients experience a decrease in quality of life, transitory or permanent, and nearly half of patients discharged are readmitted to the hospital more than once in the following 6 months. Thus, one of the main treatment goals for COPD patients is to reduce the number and severity of exacerbations they experience each year.

There is no widely accepted definition of acute exacerbation of COPD, but most published definitions encompass some combination of three clinical findings: worsening dyspnea, increase in sputum purulence, and increase in sputum volume. A severity scale for acute exacerbations, developed by Anthonisen and colleagues,2 is based on these finding as well as others. Type 1 exacerbations (severe) have all three of the above symptoms; type 2 exacerbations (moderate) present with two; and type 3 exacerbations (mild) have one of these, plus at least one of the following: an upper-respiratory-tract infection in the past 5 days, fever without other apparent cause, increased wheezing, increased cough, or increase in respiratory rate or heart rate by 20% above baseline. We will use this scale when referring to severity in this guideline. Acute exacerbations can be triggered by tracheobronchial infections or environmental exposures, and patients often have associated clinical conditions, such as heart failure, extrapulmonary infections, and pulmonary embolism. Thus, acute exacerbation is mainly a clinical diagnosis.

Despite the importance of this disease, the review of the evidence brings to light the paucity of high-quality studies on this subject. Nevertheless, recommendations made in this guideline are based on the highest-quality evidence available at this time. While the“ highest”-quality studies available were often randomized controlled clinical trials, these were few in number and they tended to enroll small numbers of patients. The clinician must take this fact into consideration when basing management decisions on them.

Current practices for the diagnosis and management of AE-COPD are varied; some commonly used tests and therapies are not supported by evidence, while others are. The expert panel found enough evidence to make recommendations about the use of the following diagnostic and therapeutic modalities in AE-COPD: chest radiography, spirometry, bronchodilators, corticosteriods, antibiotics, oxygen, mucolytic agents, mucus clearing strategies, and noninvasive positive-pressure ventilation (NPPV). Indirect evidence shows that arterial blood gas measures are helpful in determining the present need for oxygen therapy and the potential need for mechanical ventilatory support. There was insufficient evidence to make recommendations regarding the use of pulse oximetry, sputum smear, and sputum culture.

Prediction of Outpatient Relapse

All the studies included for analysis were done in the ED, and relapse was defined as a return visit to the ED within 14 days of initial presentation. The ability to identify patients at high risk for relapse should help guide decisions about hospital admission and follow-up appointments. Several studies have confirmed what most clinicians know intuitively—that patients who have lower baseline FEV1, low Po2, high Pco2, low pH, and who receive more bronchodilator treatments while in the ED are more likely to relapse within 14 days of initial presentation. Unfortunately, none of the predictive models performs satisfactorily enough to justify uniform use in clinical practice.

Prediction of 6-Month Mortality

The Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments investigated the outcome of 180-day mortality, which was 33% in that cohort. Significant predictors of 180-day mortality were worse APACHE (acute physiology and chronic health evaluation) III score, lower body-mass index, older age, worse functional status 2 weeks before hospital admission, lower Po2/fraction of inspired oxygen ratio, history of congestive heart failure, lower serum albumin level, and presence of cor pulmonale. Other studies reported similar associations. Although, based on these studies, certain physiologic characteristics are associated with a higher likelihood of inpatient mortality, we conclude that there is currently no reliable method for identifying patients at high risk (> 90%) of inpatient or 6-month mortality. Therefore, these parameters should not influence decisions about instituting, continuing, or withdrawing life-sustaining therapies, but they should prompt a discussion regarding patient preferences for end-of-life care.

Diagnostic Testing: Chest Radiography and Spirometry

Three observational studies showed substantial rates of chest radiograph (CXR) abnormalities among patients admitted for AE-COPD. In one prospective study, which included asthma patients, 23.5% of the patients had a change in management prompted by their CXR result, mostly because of new infiltrates. Observational studies showed that spirometric assessment at the time of presentation, or during the course of treatment, is not useful in judging severity or guiding management of patients with AE-COPD. FEV1 measured at the time of an exacerbation showed no significant correlation with Po2 and only a weak, but statistically significant one, with Pco2. Peak expiratory flow rate is often used in the clinic to approximate FEV1. One study found a correlation between peak expiratory flow rate and FEV1. The clinical implication of this finding is not clear, because FEV1 is a poor predictor. Despite this fact, many studies use changes in FEV1 as the primary outcome, rather than other more clinically pertinent measures such as degree of dyspnea or sputum production and quality, probably because the latter are much more difficult to quantify and evaluate than FEV1.


Fourteen randomized trials show that inhaled short-actingβ 2-agonists, such as albuterol, and anticholinergic bronchodilators, such as ipratropium, are equally efficacious in the care of patients with acute exacerbations of COPD. They are also superior to all parenterally administered bronchodilators, including methylxanthines and sympathomimetic agents. Furthermore, there may be an additional benefit in some patients when a second inhaled bronchodilating agent is administered once the maximal dose of the initial one is reached. Several studies examined patients receiving a short-acting β2-agonist plus an anticholinergic bronchodilator. In general, patients in these studies had marginally shorter lengths of stay and proportionally larger increases in FEV1, but hospital admission rates were similar. Because anticholinergic bronchodilators are associated with fewer and milder side effects, it is advisable to start with them and then add a short-acting β2-agonist. Studies are equivocal on the addition of a methylxanthine, such as aminophylline, to inhaled bronchodilators. More importantly, the potentially serious side effects of the methylxanthines make their use more problematic. There is also some evidence that the efficacies of wet nebulization and dry aerosol delivery systems (metered-dose inhaler plus a spacer) are clinically equivalent. Thus, the choice of a specific delivery method should be determined on an individual basis, depending on the patient’s ability to use the different modalities.3


Six randomized, placebo-controlled trials showed that for patients hospitalized with AE-COPD, systemic corticosteroids administered for up to 2 weeks are helpful. There was a great deal of variability in the dosage, length of treatment, administration, and setting among the studies evaluated. In the largest trial (the Systemic Corticosteroids in Chronic Obstructive Pulmonary Disease Exacerbations trial), patients received either a 2-week or an 8-week course. The 2-week course consisted of 3 days of treatment with IV methylprednisolone (125 mg IV q6h), followed by oral prednisone for 2 weeks (60 mg on days 4 to 7; 40 mg on days 8 to 11; 20 mg on days 12 to 15). There was no significant difference in outcome between the 2-week and 8-week courses. The difference in FEV1 between the glucocorticoid group and placebo group was statistically significant for the first 3 days of treatment and not significant after 2 weeks. The most common adverse effect associated with systemic corticosteroids was hyperglycemia, with two thirds of these cases occurring in patients with known diabetes mellitus. There is no evidence as to whether hyperglycemia is more severe in longer courses of treatment. Inhaled steroids are not appropriate in the treatment of AE-COPD.


Eleven randomized, placebo-controlled trials have shown that antibiotic treatment is beneficial in selected patients with AE-COPD. In particular, the studies show that patients with more severe exacerbations (type I) are more likely to experience benefit than those with less severe ones. Severity was assessed using either clinical judgment or using the criteria developed by Anthonisen et al.2 Typical administration periods in the studies range from 3 to 14 days, with tetracyclines, amoxicillin, and trimethoprim-sulfamethoxazole as the most commonly used antibiotics. Although most of these studies were done before the emergence of multidrug-resistant organisms, these randomized placebo-controlled trials show only a minimal benefit to antibiotic treatment in the more severe exacerbations. Based on these data and the emergence over time of more resistant organisms, in particular Streptococcus pneumoniae, it has become common practice to use more broad-spectrum antibiotics in AE-COPD. To date, though, there are no randomized, placebo-controlled trials proving the superiority of the newer broad-spectrum antibiotics in AE-COPD.

Oxygen Therapy

There is ample evidence that oxygen therapy provides important benefits to inpatients with AE-COPD and hypoxemia. The major concern with the administration of this therapy is the risk of resultant hypercarbia and respiratory failure. In three observational studies, oxygen administration (fraction of inspired oxygen ranged from 24 to 28%) in patients with AE-COPD resulted in hypercarbia in the majority of patients. It appears from these studies that the relationship between pH and Po2 at the time of presentation is a good predictor of the risk for hypercarbia and subsequent failure. This relationship was translated into a discriminant function for predicting respiratory failure (see Figure 1 of background article). Although this model is not widely used, it does underscore that patients who present with altered gas exchange are at greatest risk of developing respiratory failure.

Mucolytic Agents and Mucus Clearance Strategies

Mucolytic agents have not been shown to be effective at shortening the course or improving outcomes of patients in five randomized trials. Three randomized trials showed that mechanical percussion of the chest as applied by a physical/respiratory therapist is ineffective, ie, no increase in FEV1 in patients with AE-COPD. In fact, one study showed a decrease in FEV1 after chest physical therapy.


NPPV is frequently used in the inpatient management of AE-COPD patients. It serves not only to improve ventilation and lower Pco2 levels but, in many instances, as a means of avoiding intubation. Five randomized controlled trials and five observational studies have confirmed that in the study populations, NPPV was a beneficial support strategy and it decreased the likelihood of respiratory failure requiring invasive mechanical ventilation. There are also some data that NPPV might improve survival of patients with AE-COPD. Weakening these conclusions are study design issues such as the unclear selection criteria for patients receiving this therapy, and the uncertain number of patients screened but excluded from these trials. Further studies are needed to provide information on which patients would benefit most from this intervention.

Recommendation 1

An admission CXR may be useful because it has been shown that up to 23% of patients admitted to the hospital had changes in management related to their CXR findings. Chest radiography in the patient visiting the ED may also useful. To date, there is no evidence for or against the utility of chest radiography in the office setting.

Recommendation 2

For patients being hospitalized with AE-COPD, spirometry should not be used to diagnose an exacerbation nor to assess its severity.

Recommendation 3

Inhaled anticholinergic bronchodilators or inhaled short-actingβ 2-agonists are beneficial in the treatment of patients presenting to the hospital with AE-COPD. Because the inhaled anticholinergic bronchodilators have fewer and more benign side effects, consider these agents first. Only once the initial bronchodilator is at maximum dose is there benefit to adding a second inhaled bronchodilator.

Recommendation 4

In the treatment of patients presenting to the hospital with a moderate or severe AE-COPD, the following therapeutic options are beneficial: (1) systemic corticosteroids administered for up to 2 weeks, in patients who are not receiving long-term treatment with oral steroids; (2) NPPV administered under the supervision of a trained physician; (3) oxygen administration, with caution, in hypoxemic patients.

Recommendation 5

In patients with severe AE-COPD, initial narrow-spectrum antibiotics are reasonable first-line agents. The superiority of newer, broader-spectrum antibiotics is not established. (The agents favored in the randomized, placebo-controlled trials include amoxicillin, trimethoprim-sulfamethoxazole, and tetracycline. Most of these studies were done before the emergence of multidrug-resistant organisms, in particular S pneumoniae. To date, however, there are no randomized placebo-controlled trials proving the superiority of the newer, broader-spectrum antibiotics in AE-COPD. The trials also did not include nursing-home residents or patients with recent hospitalizations.

Recommendation 6

In the treatment of patients with AE-COPD, the following therapeutic options are not beneficial (and may be harmful): mucolytic medications, chest physiotherapy, methylxanthine bronchodilators.

Recommendation 7

Currently, there are no reliable methods of risk stratification for relapse or inpatient mortality.

Recommendation 8

Future research should include efforts to develop a reproducible, transportable definition of “acute exacerbation” in order to provide more consistent and transparent inclusion/exclusion criteria for clinical trials studying this entity. There is a great need, in this age of antibiotic-resistant organisms, for randomized, placebo-controlled trials of the newer broad-spectrum antibiotics. More in-depth research into therapeutics and management would greatly benefit patients with COPD, as well as the recognition that nonphysiologic outcomes such as symptomatology, quality of life, and interval before subsequent relapse are all clinically important.

Notice: Clinical practice guidelines are “guides” only and may not apply to all patients and all clinical situations. Thus, they are not intended to override clinicians’ judgment. All ACP-ASIM clinical practice guidelines are considered automatically withdrawn, or invalid, 5 years after publication, or once an update has been issued.

Joint ACCP/ACP-ASIM Expert Panel

Peter Almenoff, MD (VA), Pulmonary Critical Care, VA Medical Center, Kansas City, MO; Paul G. Auwaerter, MD (ACP-ASIM), Division of General Internal Medicine and Infectious Disease, Johns Hopkins School of Medicine, Lutherville, MD; Sidney Braman, MD, FCCP (ATS), Rhode Island Hospital, Providence, RI; Bart Celli, MD, FCCP (ACCP), St. Elizabeth Medical Center, Boston, MA; Alan Fein, MD (Co-Chair, ACCP), North Shore University Hospital, Manhasset, NY; Stan Fiel, MD, FCCP (ACCP), MCP-Hahnemann University, Philadelphia, PA; David Hudgel, MD (ACCP), Case Western Reserve University, Cleveland, OH; Stephanie Levine, MD (ACCP), Audie Murphy VA Hospital, San Antonio, TX; Michael Mandel, MD, FCCP (ACP-ASIM), New Rochelle, NY; Sean Tunis, MD, MSc, (Co-Chair, ACP-ASIM), Johns Hopkins School of Medicine, Baltimore, MD; Peter Bach, MD (ACCP, author), Memorial Sloan Kettering Cancer Center, New York, NY; Steve Lascher, DVM, MPH (ACP-ASIM), Scientific Policy Department, ACP-ASIM, Philadelphia, PA; Douglas C. McCrory, MD, MHSc (Duke EPC), Duke Center for Clinical Health Policy Research, Durham, NC; Christel Mottur-Pilson, PhD (ACP-ASIM), Director, Scientific Policy Department, ACP-ASIM, Philadelphia, PA; Sydney Parker, PhD (ACCP), Vice President, Health and Science Policy, ACCP, Northbrook, IL; Vincenza Snow, MD (ACP-ASIM), Scientific Policy Department, ACP-ASIM, Philadelphia, PA.

ACP-ASIM Clinical Efficacy Assessment Subcommittee

David Dale, MD, Chair; Patricia Barry, MD, MPH; William Golden, MD; Robert McCartney, MD; Keith Michl, MD; Stephen Pauker, MD; Allan Ronald, MD; Sean Tunis, MD, MSc; Kevin Weiss, MD; Preston Winters, MD; John Whyte, MD, MPH.

ACCP Health and Science Policy Committee

Gene Colice, MD, FCCP, Chair; Russel Acevedo, MD, FCCP; Robert Baughman, MD, FCCP; Michael Baumann, MD, FCCP; Joann Blessing-Moore, MD, FCCP; Richard Dart, MD, FCCP; James Fink, MD, FCCP; Susan Harding, MD, FCCP; Alan Lisbon, MD, FCCP; George Mallory, MD, FCCP; Peter McKeown, MD, FCCP; Edward Oppenheimer, MD, FCCP; David Schroeder, MD, FCCP; Gerard Silvestri, MD, FCCP; Dorsett Smith, MD, FCCP.

Abbreviations: ACCP = American College of Chest Physicians; ACP-ASIM = American College of Physicians-American Society of Internal Medicine; AE-COPD = acute exacerbations of COPD; CXR = chest radiograph; ED = emergency department; NPPV = noninvasive positive-pressure ventilation

Disclaimer: The authors of this article are responsible for its contents, including any clinical or treatment recommendations. No statement in this article should be construed as an official position of the Agency for Healthcare Research and Quality or the US Department of Health and Human Services.

McCrory DC, Brolon CB, Gray RN, et al. Management of acute exacerbations of chronic obstructive pulmonary disease. Evidence report/technology assessment No. 19. (Prepared by Duke University under contract No. 290-97-0014.) Rockville, MD: Agency for Health Care Policy and Research (in press); Publication No. 01-E003.
Anthonisen, NR, Manfreda, J, Warren, CPW, et al Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease.Ann Intern Med1987;106,196-204. [PubMed]
Turner, MO, Patel, A, Ginsberg, S, et al Bronchodilator delivery in acute airflow obstruction: a meta-analysis.Arch Intern Med1997;157,1736-1744. [CrossRef] [PubMed]




McCrory DC, Brolon CB, Gray RN, et al. Management of acute exacerbations of chronic obstructive pulmonary disease. Evidence report/technology assessment No. 19. (Prepared by Duke University under contract No. 290-97-0014.) Rockville, MD: Agency for Health Care Policy and Research (in press); Publication No. 01-E003.
Anthonisen, NR, Manfreda, J, Warren, CPW, et al Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease.Ann Intern Med1987;106,196-204. [PubMed]
Turner, MO, Patel, A, Ginsberg, S, et al Bronchodilator delivery in acute airflow obstruction: a meta-analysis.Arch Intern Med1997;157,1736-1744. [CrossRef] [PubMed]
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