### Evidence Report/Technology Assessment: Number 19

# Management of Acute Exacerbations of Chronic Obstructive Pulmonary Disease

## Summary

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Under its Evidence-based Practice Program, the Agency for Healthcare Research and Quality(AHRQ) is developing scientific information for other agencies and organizations on which to baseclinical guidelines, performance measures, and other quality improvement tools. Contractorinstitutions review all relevant scientific literature on assigned clinical care topics and produceevidence reports and technology assessments, conduct research on methodologies and theeffectiveness of their implementation, and participate in technical assistance activities. 

Overview / Reporting the Evidence / Methodology / Findings / Future Research / Availability of Full Report

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## Overview

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States. Affecting 16 million people, it accounts for 13,760,000 office visits and 297,000 hospitalizations annually (at a cost of $18 billion).

The natural history of moderate to severe COPD is punctuated by acute exacerbations in which worsening symptoms of dyspnea and an increase in the amount or purulence of sputum may be accompanied by chest discomfort, fever, and other constitutional symptoms. The frequency of exacerbations varies widely from patient to patient, but is generally related to the severity and duration of the underlying COPD. Patients with a history of frequent exacerbations tend to continue to have a high frequency of exacerbations.

Acute exacerbations of COPD are associated with increased short-term mortality compared with stable COPD. Comorbid conditions, particularly heart diseases, are common among patients with COPD and contribute substantially to the mortality associated with acute exacerbations. Patients who survive exacerbations of COPD often experience important decrements in functional status and quality of life.

The objectives of this report are to assess the evidence currently available on the diagnosis, prognosis, and management of acute exacerbation of COPD, and on the use of noninvasive positive pressure ventilation (NPPV) in patients with acute respiratory failure secondary to acute exacerbation of COPD. 

The report deals with acute exacerbation only and excludes from consideration such conditions as:

- Stable COPD. 
-  Asthma. 
- Cystic fibrosis. 
-  Bronchiectasis.

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## Reporting the Evidence

The key questions addressed in the report are:

-  Clinical assessment.  How well does clinical assessment (including history; physical examination; and laboratory, radiographic, and other tests) discriminate between those with acute exacerbation of COPD vs. other causes of worsening respiratory status? How well does clinical assessment predict health outcomes or level-of-care needs (intensive care unit or hospital admission, return visit to the emergency room, need for ventilatory support) for patients presenting for treatment of acute exacerbation of COPD?
-  Treatment.  How effective are the medical modalities used to treat acute exacerbation of COPD (antibiotics, bronchodilators, corticosteroids, and mucous-clearing strategies) in alleviating symptoms, resolving the cause of the exacerbation, preventing hospital admission, and decreasing length of stay?
- NPPV.  Does the use of NPPV in patients with respiratory failure secondary to an acute exacerbation of COPD prevent intubation and/or improve other outcomes, including mortality, morbidity, length of hospital stay, and cost(s) of care?

The interventions considered were:

- Diagnostic or prognostic tests (including clinical history and physical examination).
-  Antibiotics.
-  Bronchodilating drugs.
-  Corticosteroids.
-  Mucous-clearing strategies (including mucolytic drugs and physical treatments).
-  NPPV.

The patient population of interest was adults with COPD (based on clinical diagnosis, spirometry, or known or suspected history) who were experiencing an acute exacerbation of respiratory symptoms. Qualifying symptoms included:

- Increased dyspnea.
-  Increased quantity of sputum.
-  Increased purulence of sputum.
-  Acute respiratory failure. 

For evaluation of assessment strategies, we considered even those cohorts or series that did not exclude other diseases (e.g., congestive heart failure [CHF], pulmonary embolus, or pneumothorax). For trials of NPPV, the population of interest was adults with acute exacerbations of COPD and respiratory failure.

The outcomes of interest were:

-  Ventilatory function.
-  Symptoms related to ventilatory function.
-  General functional or health status.
-  Mortality.
-  Health services utilization. 

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## Methodology

Databases searched included MEDLINE (from 1966 to June 1999), EMBASE (from 1974 to February 1999), and the Cochrane Controlled Trials Register (1998, Issue 4). The search strategies used included index terms and text words for chronic obstructive pulmonary disease and acute exacerbation, and specific terms relating to the interventions and methodology.

For evidence on the efficacy of therapeutic interventions, we considered only randomized and other prospective controlled trials. Data on adverse effects were obtained from these trials and from additional cohort studies and case series. For questions concerning diagnosis and prognosis, we considered retrospective and prospective cohort studies and case series. Systematic reviews were also included when the studies reviewed were of the types just described.

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## Findings

### Clinical Assessment

The principal findings concerning the clinical assessment of patients with acute exacerbation of COPD were as follows:

- 	Patients presenting with acute exacerbation of COPD have a relatively high rate of abnormalities (such as infiltrates or pulmonary edema) on chest roentgenography (CXR), particularly when compared to previous series of patients with asthma, where relatively low rates of abnormalities have been found.
- 	Historical data and clinical signs and symptoms associated with two common comorbid conditions that often complicate the assessment of acute exacerbation of COPD—CHF and pneumonia—are significant but inexact predictors of two specific abnormalities on CXR, namely pulmonary edema and infiltrate, respectively.
- 	The prevalence of clinically unsuspected deep venous thrombosis (DVT) among patients hospitalized for acute exacerbation of COPD is high in some studies; however, few data are available to help quantify the risk for pulmonary embolus among patients with acute exacerbation of COPD with or without known DVT.
- 	Among patients presenting with acute exacerbation of COPD, forced expiratory volume in 1 second (FEV 1 ) during exacerbation is not well correlated with PaO 2  (partial pressure of oxygen) without supplemental oxygen, but is correlated with PaCO 2  (partial pressure of carbon dioxide) and pH.
- 	Physician estimates of FEV 1  during acute exacerbation of COPD are generally inaccurate. Peak expiratory flow rate (PEFR) is not sufficiently well correlated with FEV 1  to substitute for it.
- 	Among patients on theophylline, neither clinical data on theophylline use (history of dosage, timing of last dose, past drug levels) nor other data (history of cigarette use, body weight) are accurate predictors of drug level during acute exacerbation of COPD. 

### Prognosis

Major findings related to prognosis were:

- 	While several factors are associated with worsening clinical condition in patients with acute exacerbation of COPD, no predictive model accurately predicts clinical outcomes, so ongoing clinical monitoring is needed for many patients. 
- 	Among patients presenting with acute exacerbation of COPD and selected for outpatient treatment, cumulative relapse rates were between 11 percent and 17 percent at 48 hours and between 23 percent and 32 percent at 2 weeks. Hospitalization at index visit ranged from 24.2 percent to 71 percent among patients presenting to the emergency department (ED).
- 	Data from the previous history of individual patients—e.g., previous visit within 7 days, number of exacerbations in the past year, and relapsing on previous visits—were consistently identified as predictive of relapse. Also found to be predictive in several studies was baseline pulmonary function, as measured by FEV 1  or FVC (forced vital capacity). Data describing acute respiratory physiology, such as FEV 1  during exacerbation or arterial blood gases, predicted hospitalization or relapse. Data describing treatments used in the ED and clinical response were generally also predictive of hospitalization or later relapse.
- 	Among patients hospitalized for acute exacerbation of COPD and cared for in either ward beds or intensive care units, short-term or hospital mortality ranged from 4 percent to 26 percent. Study populations were not described well enough to explain these differences in overall mortality rates.
- 	The following were all associated with mortality due to acute exacerbation of COPD:     - Acute physiology (as measured by arterial blood gases, FEV 1  during exacerbation, and scores from the Acute Physiology and Chronic Health Evaluation).
  - 	Comorbid illness and other baseline, pre-exacerbation health status measures (such as body mass index and functional status).
  - 	Cumulative or longitudinal data on the clinical course (e.g., baseline spirometry, number and frequency of previous acute exacerbations, and previous response to treatment of acute exacerbation of COPD).
- 	Acute respiratory physiology, as measured by blood gases, was predictive of the need for mechanical ventilation, as were baseline measures such as nutritional status.

### Antibiotics

The antibiotic drugs studied were tetracycline, doxycycline, chloramphenicol, penicillin plus streptomycin, ampicillin, amoxicillin, and cotrimoxazole. The major findings related to these drugs were:

- 	Placebo-controlled randomized trials of antibiotic treatment of acute exacerbations of COPD show overall evidence of improvement in pulmonary function.
- 	The included trials suggest that patients with more evidence of bacterial infection (sputum purulence) and more severe illness (worse PEFR) benefit more from antibiotics; however, this has not been conclusively demonstrated. 

### Bronchodilators

The bronchodilators studied were:

-  The anticholinergics ipratropium bromide and glycopyrrolate.
- 	 The beta2-agonists albuterol (salbutamol).
- 	 Fenoterol.
- 	 Metaproterenol.
- 	 Salmeterol.
- 	 Terbutaline.
- 	The methylxanthines aminophylline and doxofylline. 

The major findings related to this class of drugs were:

- 	Inhaled ipratropium and beta2-agonists were shown in comparative trials to have similar effects. However, neither class has demonstrated conclusive evidence of benefit in placebo or other no-treatment control trials. Most trials were too small to demonstrate a minimally clinically important benefit. 
- 	Ipratropium is generally associated with fewer adverse effects than are the beta2-agonists, but it needs to be used cautiously in patients with pre-existing urinary retention problems. Beta2-agonists can cause cardiac arrhythmias in those predisposed to the condition. The arrhythmias are usually not life threatening.
- 	Bronchodilator therapy delivered by nebulizers and metered-dose inhalers (MDIs) show equivalent bronchodilation among patients with stable COPD. However, among patients with acute exacerbation of COPD, who may be unable to hold their breath, nebulizers may be necessary.
- 	Glycopyrrolate may have a synergistic effect in bronchodilation when given with a beta2-agonist.
- 	Parenteral aminophylline did not improve FEV 1 , hospitalization rates, or relapse in three placebo-controlled trials. Parenteral doxofylline did show a significant improvement in FEV 1  in a placebo-controlled trial. Moreover, methylxanthines have numerous, sometimes life-threatening, adverse effects and drug interactions.

### Corticosteroids

Principal findings related to corticosteroid treatment were the following:

- 	Several randomized controlled trials provided strong evidence that a course of systemic corticosteroids provides benefit in patients hospitalized with acute exacerbation of COPD. The risk of treatment failure was reduced by approximately 10 percent, and FEV 1  showed an improvement averaging about 0.1 liters in the first hours to days of treatment.
- 	Doses as low as prednisone 30 mg daily and duration as short as 3 days have been shown to be effective in single trials; however, the optimal dose and duration is not clear from available trials. A single well-designed trial found that there were no significant differences in clinical outcomes between a 2-week course of systemic corticosteroids and an 8-week course.
- 	Inhaled corticosteroids have not been tested adequately in patients with acute exacerbation of COPD.
- 	Adverse effects were common in patients treated for acute exacerbation of COPD with systemic corticosteroids. The most frequently observed adverse effect was hyperglycemia.

### Mucous-Clearing Treatments

Considered under this heading were mucolytic drugs and physical therapy interventions. The principal findings were:

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

### NPPV

Major findings related to NPPV are the following:

- 	NPPV is an effective alternative to mechanical ventilation by endotracheal intubation for some patients with acute respiratory failure secondary to acute exacerbation of COPD.
- 	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 comes with its own set of morbidities. The pressure-support ventilation (PSV) and continuous or bi-level positive airway pressure modes of ventilation appear to be best tolerated and most effective for correcting hypercarbia. Assist control ventilation (ACV) mode with NPPV is generally poorly tolerated unless volume and rate are adjusted to the individual patient.

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## Future Research

Most published studies in acute exacerbation of COPD are conducted among patients who require hospitalization; however, most of the burden of this disease occurs in the outpatient setting. More studies relevant to outpatient management decisions are needed, focusing on patients who present in office-based practices or by telephone.

Patients with acute exacerbation of COPD present at varying degrees of severity of illness, ranging from those who barely meet the Winnipeg criteria to those with impending ventilatory failure. In the published literature, the description of study subjects is rarely sufficient to fully characterize the severity of illness of the study population. Our assessment of the severity of illness of the study populations was also based on the setting in which subjects were recruited (e.g., office-based practice versus intensive care unit), and on the outcomes reported (e.g., proportion of patients requiring intubation and mechanical ventilation). It will be necessary to develop, validate, and use a better system for describing the severity of acute exacerbation of COPD in order to improve the quality and applicability of clinical research on this condition.

An empirical classification of patients has been proposed (which is based primarily on association with microbial pathogens) as a means of guiding antimicrobial treatment. This approach should be validated in a prospective trial to test its effectiveness in clinical practice. Because of the array of different therapies aimed at different physiological derangements in acute exacerbation of COPD, it may be the case that no single severity scale will be sufficient to guide treatment decisions in acute exacerbation of COPD. For example, it may be necessary to have one scale related to likely microbial pathogens to guide antibiotic treatment, another to assess airway reactivity and likely response to different bronchodilator treatments, and yet another to assess ventilatory function and need for ventilatory assistance.

Although current research has adequately demonstrated that NPPV can reduce the need for invasive ventilation, additional research efforts are needed to improve the ease of use for both physician and patient. Experimentation with ventilator modes and newer mask interfaces for administering NPPV are likely directions.

Further study of appropriate selection of patients in whom to try NPPV may help to define how best to incorporate this treatment modality into the care of patients with acute exacerbation of COPD in the ED or outpatient setting, as well as after hospital admission.

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## Availability of Full Report

The full evidence report from which this summary was derived was prepared for the Agency for Healthcare Research and Quality by the Duke University Evidence-based Practice Center under contract  No. 290-97-0014. Printed copies of this report are available free of charge from the AHRQ Publications Clearinghouse by calling 800-358-9295. Requestors should ask for Evidence Report/Technology Assessment  No. 19, *Management of Acute Exacerbations of Chronic Obstructive Pulmonary Disease* (AHRQ Publication  No. 01-E003). 

The Evidence Report can also be downloaded as a zipped file online at: www.ahrq.gov/clinic/evrptfiles.htm#copd.

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*AHRQ Publication Number 00-E020Current as of September 2000*

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**Internet Citation:**

*Management of Acute Exacerbations of ChronicObstructive Pulmonary Disease*. Summary, Evidence Report/Technology Assessment: Number 19. AHRQ Publication  No. 00-E020, September 2000. Agency for Healthcare Researchand Quality, Rockville, MD. http://www.ahrq.gov/clinic/epcsums/copdsum.htm

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