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McCrory DC, Brown C, Gray RN, et al. Management of Acute Exacerbations of Chronic Obstructive Pulmonary Disease. Rockville (MD): Agency for Healthcare Research and Quality (US); 2001 Mar. (Evidence Reports/Technology Assessments, No. 19.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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Management of Acute Exacerbations of Chronic Obstructive Pulmonary Disease.

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Clinical Assessment

The diagnosis of acute exacerbation of COPD is generally made on clinical grounds; laboratory data such as ABGs and leukocyte counts are of little value. Although CXR is not used to diagnose acute exacerbation of COPD, it may be useful to identify the precipitating cause or coexisting problem leading to exacerbation of symptoms. Three studies of CXR findings in patients presenting with acute exacerbation of COPD found that historical data and clinical signs and symptoms associated with two major causes of exacerbation of COPD (CHF and pneumonia) are significant but inexact predictors of abnormalities on CXR, pulmonary edema, and infiltrate, respectively. The studies found a relatively high rate of abnormalities when compared with previous series of patients with asthma. The high rate of abnormalities in patients with acute exacerbation of COPD and the poor performance of predictors of abnormal CXR in this population suggest that, at least for patients treated in EDs or in hospitals, CXR adds important diagnostic information.

The prevalence of clinically unsuspected DVT in patients who were hospitalized for acute exacerbation of COPD was relatively high in some studies, and similar to that observed in patients who were hospitalized for other illnesses (Coon, 1977). However, few data are available to quantify the risk for PE in patients with acute exacerbation of COPD with or without known DVT.

In patients presenting with acute exacerbation, FEV1 is correlated with PaCO2 and pH, but it is not well correlated with PaO2. Physician estimates of FEV1 in patients with acute exacerbation are inaccurate. PEFR is not sufficiently well correlated to substitute for FEV1; however, many patients in respiratory distress are unable to perform full spirometry to obtain FEV1. The use of single or serial measurements with hand-held peak flow meters has not been studied in patients with acute exacerbation of COPD.

In patients on theophylline, clinical data on theophylline use (history of dosage, timing of last dose, past drug levels) and other data (history of cigarette use, body weight) are not accurate predictors of drug level during acute exacerbation of COPD.


Studies of patients presenting with acute exacerbation of COPD show that although some factors are associated with worsening clinical condition, clinical outcomes cannot be accurately predicted. The best predictors were cumulative measures gathered during monitoring of the clinical condition over time, for example, during ED or hospital treatment. Most studies describing prognosis fell naturally into two groups, those describing patients treated as outpatients and those describing patients admitted to a hospital or an ICU.

Outpatient Studies

Risk of relapse in patients presenting with acute exacerbation of COPD and selected for outpatient treatment was between 11 and 17 percent at 48 hours and between 23 and 32 percent at 2 weeks. In all patients presenting to the ED, hospitalization at index visit varied from 24.2 to 71 percent. Mean age, spirometric values, and other descriptive data were reasonably similar in studies, suggesting similar populations. Data from the previous history of individual patients were consistently identified as having value for predicting relapse, (e.g., previous visit within 7 days, number of exacerbations in the past year, and relapsing on previous visits). Also predictive in several studies was baseline pulmonary function, as measured by FEV1 or FVC. Data describing acute respiratory physiology such as FEV1 during exacerbation or ABGs also predicted hospitalization or relapse. Data describing treatments used in the ED and clinical response in the ED also were generally predictive of hospital admission or later relapse. However, despite demonstrating statistically significant associations with outcome, prediction rules were either not sufficiently accurate to be clinically useful or performed poorly on attempts at validation.

Inpatient Studies

Studies describing prognosis in patients hospitalized for acute exacerbation focused on predicting mortality, the need for MV, and LOS; however, there were few data on LOS.

Risk of Mortality

Mortality rates in patients hospitalized for acute exacerbation and cared for in either general or ICU beds varied, ranging from 4 percent to 26 percent; study populations were not described well enough to explain this difference in overall mortality rates. However, there is some agreement between studies about the prognostic factors that explain variation in mortality rate in patients. While potential predictors varied in studies (and the definitions and thresholds used for similar data vary), several trends could be observed. First, measures of acute physiology were well correlated with mortality (e.g., ABGs and APACHE scores). Second, comorbid illness and other baseline preexacerbation health status measures (e.g., BMI and functional status) were associated with mortality. Few of these studies had specific data on baseline pulmonary function. Third, cumulative or longitudinal data on the clinical course also were important in describing mortality.

Need for Mechanical Ventilation

Individual factors have been shown to be associated with the need for MV resulting from ARF in acute exacerbation. Acute respiratory physiology, as measure by blood gases, was associated with MV. As blood gases are amont several criteria used clinically to decide when MV is necessary, these findings are self-evident. In one study, worsening acidosis after initiation of supplemental oxygetn therapy added additional prognostic value to the blood gas values alone. Other baseline measures such as nutritional status also were found to be predictive. One study (Bone, Pierce, and Johnson, 1978) reported a multivariable model that discriminated between patients needing MV and those not needing it; although this model was validated, it was not sufficitenly accurate for clinical decisionmaking.


Placebo-controlled randomized trials of antibiotic treatment of acute exacerbation of COPD showed evidence of a small improvement in pulmonary function. These trials suggest that patients with more evidence of bacterial infection (sputum purulence) and more severe illness (worse PEFR) benefit more from antibiotics; hosever, this has not been conclusively demonstrated. Likewise, a hypothesized interaction between corticosteroids and antibiotic use cannot be addressed by existing trial data.

Bronchodilating Drugs

Inhaled ipratropium and beta2-agonists were shown in comparative trials to have similar effects in acute exacerbation of COPD; however, neither class has demonstrated conclusive evidence of benefit compared with placebo or no treatment. Most trials were too small to demonstrate a minimum clinically important benefit. Ipratropium, because of less systemic absorption, has fewer adverse effects, but is should be used in caution in patients with preexisting urinary retention problems. Beta2-agonists can cause cardiac arrhythmias in those predisposed to the condition. Bronchodilator therapy that is delivered by nebulizers and MDIs showed equivalent bronchodilation in patients with stable COPD; however, in patients with acute exacerbation of COPD, who may be unable to hold their breath, nebulizers may be necessary. Parenteral aminophylline did not improve FEV1, hospitalization rates, or relapse in three placebo-controlled trials. Parenteral doxofylline did show a significant improvement in FEV1 in a placebo-controlled trial. Moreover, methylxanthines have numerous, sometimes life-threatening, adverse effects and drug interactions. Glycopyrrolate may have a synergistic effect in bronchodilation when given with a beta2-agonist.


Several placebo-controlled randomized trials provided strong evidence for benefit from a course of systemic corticosteroids in patients with acute exacerbation of COPD who reauired hospitalization. The risk of treatment failure was reduced by approximately 10 percent, and FEV1 showed an immediate improvement averaging about 0.1 L in the first hours to days of treatment. Although the improvement was relatively small, it was large enough to exceed day-to-day measurement variability (American Thoracic Society, 1991) and is generally considered to be clinically important. The SCCOPE trial showed that a 2- and 8-week course of systemic corticosteroids were not importantly different in clinical outcome, and investigators thus concluded that the shorter course, which should reduce adverse effects, is preferred. The minimal dose and duration of treatement remain uncertain, as some studies suggest that doses of prednisone as low as 30 mg daily and courses as short as 3 days are effective. Inhaled corticosteroids have not been tested in acute exacerbation. Adverse effects associated with systemic corticosteroids that are used in acute exacerbation are frequent, with the most frequent adverse effect being hyperglycemia.

Mucous Clearance Strategies-Drugs and Physiotherapy

Available studies showed no benefit from any mucolytic drugs studied (ambroxol, bromhexine, domiodol, potassium iodide, and S-carboxymethyl cysteine) in improving ventilatory function in acute exacerbation; however, some studies reported subjective improvement in symptoms associated with decreasing sputum viscosity. Studies of chest percussion likewise failed to show any benefit in improving short-term ventilatory function for patients with acute exacerbation.

Noninvasive Positive Pressure Ventilation

NPPV is an effective alternative to MV by endotracheal intubation for acute exacerbation in patients with ARF. The studies showed that it was able to correct hypercarbia and the resulting acidosis. When supplemental oxygen is used, it is able to correct hypoxia. Communication, administration of cointerventions, and nutrition can continue in the normal fashion, and the morbidity and mortality associated with invasive ventilation are avoided. However, to optimize its effectiveness, some criteria must be met. Throughout all the studies, investigators emphasized that patient cooperation and tolerance of the apparatus are essential to its effectiveness. Several methods were used to assist in this effort. In some cases, mild sedation was utilized, requiring close monitoring. In other studies, a respiratory therapist or other trained health care worker “coached” the patient at the onset of NPPV treatment. The selection of mask interface and/or ventilator mode can be important to patient cooperation and tolerance, and thus to the efficacy of the intervention. Each type of mask and ventilation mode is associated with its own set of morbidities. The PSV and continuous or bilevel positive airway pressure modes of ventilation appear to be best tolerated and most effective for correcting hypercarbia. The ACV mode was not well received by patients in any of the studies.

Limitations of the Current Literature

Perhaps the major limitation of the literature is that studies in COPD are performed more often on patients in a period of stable symptoms rather than on those experiencing acute exacerbations. We examined literature specifically describing patients presenting with acute exacerbation of COPD and we attempted to characterize the study populations according to severity. However, it was difficult to assess the comparability of patients between studies. First, there is little consistency in the definition of acute exacerbation. We based our working definition on the Winnipeg criteria, which are widely cited in current literature (Anthonisen, Manfreda, Warren, et al., 1987); however, many of the studies we reviewed were conducted before these criteria were proposed. This definition was developed for a study of the efficacy of antibiotics, and it may function to identify a subset of patients who are more likely to have an infectious etiology and who may benefit more from antibiotic treatment. However, because of the lack of uniformity in the studies, we embraced diverse definitions of acute exacerbation in our inclusion criteria. Second, important prognostic factors often were not included in the description of the study populations; in particular, data on spirometry at baseline or during exacerbation often were missing. Third, studies differed regarding the extent to which comorbid illness or identifiable causes for exacerbation were included in study populations. Patients with acute exacerbation are generally elderly and have significant comorbidities; in particular, CHF is common in patients with acute exacerbation. These comorbidities are not directly caused by acute exacerbation, and the treatment for acute exacerbation is not consistent in its effect on the comorbidity; this form of heterogeneity makes interpretation difficult. Finally, the comparability of studies is limited by the substantial variations in time and geographical location across studies—variations that stem from inconsistency in diagnosis or management.

Another important limitation of the literature is that distinguishing between patients with asthma and COPD based on study reports is often difficult. Many studies used a test of reversibility of airway obstruction with bronchodilators—commonly using a threshold of 15 percent improvement after bronchodilator—to describe someone as having an asthmatic component. This population was inconsistently represented in the studies in this report. In particular, patients meeting this criterion were overrepresented in trials of bronchodilating drugs (where this was often an inclusion criterion), but they were underrepresented in many prognostic studies (where this was often an exclusion criterion).

In addition to difficulties with evaluating studies relating to a heterogeneous population, there were problems with the outcome measures reported. While objective measures such as FEV1 were the most common type of outcome, these measures are not as relevant to patients as are symptoms, relapse, or health status measures.

Investigators of prognostic studies used various approaches to select factors as possible predictors. One paper considered only data that were available by clinical history and could be applied to telephone care (Murata, Gorby, Kapsner, et al., 1992b). However, most studies used clinical measurements that were taken at the time of presentation, including ABGs, measures of ventilatory function, and other clinical data. Studies also included information about the early clinical course in making predictions (e.g., response to bronchodilators and the need for MV on day 1). When such prospective data from clinical monitoring in the ED or hospital were examined as predictors, these were informative of subsequent events.

We did not attempt to perform a meta-analysis of the data on strength of predictors for several reasons. First, while nearly all studies identified factors with a statistically significant association to clinical outcomes, many studies did not present sufficient data to estimate the strength of association (e.g., OR or relative risk). These factors include blood gas values (PaO2, PaCO2, pH) and change in pH after initial oxygen therapy. Second, even when quantitative data were available, profound methodological difficulties with combining data about predictors make an analysis problematic. Univariable associations are subject to wide variability because they do not account for important confounding variables. Estimates from multivariable models that control for known confounding variables are more stable and accurate; however, estimates from different models may control for different confounding variables. Finally, definitions, measurement issues, and artifacts of variable selection may lead to unpredictable conclusions when one attempts to compare results from different studies. We do not believe a quantitative synthesis is possible with these data.

An additional limitation is the current standard of care that was developed before the more modern use of randomized trials. Therefore, evidence from RCTs tends to be more available for newer treatments such as NPPV.


Patients with acute exacerbation of COPD present with a range of symptoms and severity of illness. Worsening degrees of airway obstruction are associated with a higher likelihood that outpatient management will fail and, as demonstrated in other critical illnesses, the presence of comorbid diseases and worse acute physiological derangements are associated with higher mortality. Blood gas parameters (pH, PaO2, and PaCO2) are closely aligned with decisions to intubate and mechanically ventilate. Ongoing clinical monitoring is necessary for many patients because none of these prognostic factors provides particularly accurate, clinically useful predictions. Regarding treatment, several conservative therapies that were utilized for the management of acute exacerbation show benefit (antibiotics, corticosteroids, and bronchodilators); however some lack evidence of efficacy (mucolytics and physical therapy). The more aggressive strategy of NPPV may obviate the need for invasive ventilation for some patients with severe exacerbation, but it is poorly tolerated by many patients.

Table 12 summarizes our findings regarding the effectiveness of treatments described in this report.

Table 12. Summary of effectiveness of treatments.


Table 12. Summary of effectiveness of treatments.

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