Management of Acute Exacerbations of COPD
Management of Acute Exacerbations of COPD
Author: Vincenza Snow, MD, Senior Medical Associate, Scientific Policy, American College of Physicians—American Society of Internal Medicine, Philadelphia, Pa.
Editor’s Note—In the past 3 years, several important new guidelines on the management of chronic obstructive pulmonary disease (COPD) have appeared in the literature. The Veterans Health Administration/Department of Defense (VHA/DOD) published updated comprehensive guidelines on the management of COPD in 1999.1 In 2001, the World Health Organization/National Heart Lung and Blood Institute (WHO/NHLBI) issued comprehensive guidelines for the management of COPD, also known as the GOLD guidelines.2 Additionally in 2001, the American College of Physicians-American Society of Internal Medicine and the American College of Chest Physicians (ACP-ASIM/ACCP) issued guidelines specifically addressing the management of acute exacerbations of COPD.3,4
COPD affects 16 million adults, accounting annually for 110,000 deaths, more than 16 million office visits, 500,000 hospitalizations, and $18 billion in direct health care costs.4 COPD is the fourth leading cause of death in the United States, and it is estimated that it will be the third leading cause of death worldwide by 2020.5 COPD is a progressive disease and is associated with an abnormal inflammatory response of the lungs. It is characterized by chronic airflow obstruction that is not fully reversible and episodic increases in dyspnea, cough, and sputum production that are commonly called "exacerbations."
General practice for the treatment of acute exacerbations of COPD is the "shot-gun" approach. In other words, on admission usually 2 nebulized bronchodilators are started simultaneously, high-dose IV steroid therapy is instituted, antibiotics are prescribed, low-flow oxygen is administered, and a variety of other elements such as methylxanthines, mucolytics, and chest physical therapy, are added depending on local and individual practice variations. Diagnostic testing tends to include an admission chest x-ray, pre- and postnebulizer treatment peak flows, intermittent pulse oximetry, sputum examination, and occasionally spirometric assessments and arterial blood gases. On discharge, patients receive a "slow" or "fast" steroid taper sometimes lasting more than a month, and complete their antibiotic treatment. It is not unusual for patients to be given an extra refill on their antibiotic for use with the next exacerbation. Many of these practices were supported by previous consensus guidelines from the American Thoracic Society and the European Respiratory Society.6,7 However, more evidence has become available since its publication in 1995, and medical groups are moving away from consensus-based guidelines to evidence-based guidelines. The VHA/DOD, ACP-ASIM/ACCP, and GOLD guidelines are examples of such evidence-based efforts.
Introduction/Epidemiology
COPD is characterized by chronic airflow obstruction that is not fully reversible, and episodic increases in dyspnea, cough, and sputum production that are commonly called "exacerbations." COPD is a progressive disease and is associated with an abnormal inflammatory response of the lungs.1 The prevalence and mortality from COPD is increasing in most populations8 and it is estimated that by 2020 COPD will become the third leading cause of death all over the world.6 Known and suspected risk factors for lung function decline and COPD include smoking, occupational exposures, air pollution, airway hyper-responsiveness, and certain genetic variations.
Definition of Acute Exacerbation of COPD
There is no widely accepted definition of acute exacerbation of COPD, but most published definitions encompass some combination of 3 clinical findings: worsening dyspnea, increase in sputum volume, and increase in sputum purulence. A list of additional symptoms and signs generally accepted as indications of an acute exacerbation are listed in Table 1.
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| Table 1. Symptoms and Signs of Acute Exacerbation of COPD | |
| • | Increased dyspnea |
| • | Increased sputum production |
| • | Increased cough |
| • | Change in sputum color or character |
| • | Development of or increase in wheezing |
| • | Tachycardia (20% above baseline) |
| • | Increased respiratory rate (20% above baseline) |
| • | Accessory muscle use |
| • | Peripheral edema |
| • | Loss of alertness |
| • | Fever |
| • | Worsening of ABG or pulse oximetry |
| • | Chest tightness |
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Unlike stable COPD, there is no standardized system for grading the severity of COPD exacerbations. A severity scale for acute exacerbation of COPD developed by Anthonisen and colleagues9 is the scale used in the ACP-ASIM/ACCP guideline. It is based on 3 cardinal symptoms of increased dyspnea, increased sputum production, and increase in sputum purulence, as well as other signs and symptoms. If all 3 are present, it is called a severe exacerbation. If only 2 are present, it is a moderate exacerbation. If only 1 is present plus any of the following: an upper respiratory tract infection in the last 5 days, fever without other apparent cause, increased wheezing, increased cough, or a 20% increase in heart rate or respiratory rate over baseline, then it is a mild exacerbation. Thus, acute exacerbation is mainly a clinical diagnosis.
Generally, patients with COPD whose FEV1 is less than 50% of predicted are at greater risk for suffering acute exacerbations, and those patients whose FEV1 is less than 30% of predicted value may have life-threatening exacerbations.2 Exacerbations requiring hospitalization are associated with an inpatient mortality rate of 3-4%.10 Among patients admitted to the ICU, mortality rates are substantially higher—at 11-24% during the hospitalization and 43-46% within a year.11-14 After an acute exacerbation, most patients experience a decrease in quality of life, transitory or permanent, and nearly half of patients discharged are readmitted more than once in the following 6 months.11,15
Acute exacerbations can be triggered by tracheobronchial infections; however, controversy surrounds the nature of the infectious agents in acute exacerbations of COPD, as well as their exact role. Sputum cultures taken during acute exacerbations of COPD frequently grow a variety of bacteria such as Haemophilus influenza, Streptococcus pneumoniae, Moraxella catarrhalis, and Pseudomonas aeruginosa. But these bacteria are also known colonizers of the respiratory tracts of COPD patients and are just as easily cultured from sputum during stable disease.16,17 As a result, their causal relationship in the pathogenesis of acute exacerbations of COPD is unclear, and their presence makes the interpretation of any sputum culture difficult. In all likelihood, most acute exacerbations are predominantly viral infections, just as most upper respiratory infections in the non-COPD population, particularly acute bronchitis, are viral rather than bacterial.8,9 Acute exacerbations are also associated with environmental exposures, and patients often have associated clinical conditions such as heart failure, extra-pulmonary infections, or pulmonary embolism. Table 2 lists some conditions that can contribute to an acute exacerbation or be part of the differential diagnosis for an acute exacerbation.
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| Table 2. Differential Diagnosis of Acute Exacerbation of COPD | |
| • | Congestive heart failure |
| • | Pulmonary embolus |
| • | Cardiac ischemia |
| • | Arrhythmias |
| • | Pneumothorax |
| • | Pneumonia |
| • | Respiratory depression secondary to drugs (hypnotics, CNS depressants) |
| • | Extra-pulmonary infection |
| • | Natural deterioration of disease |
| • | Respiratory compensation for metabolic diseases, electrolyte disturbances |
| • | Myopathy |
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Diagnostic Testing
Once an acute exacerbation is diagnosed based on the clinical manifestations described above, additional testing can be used. Chest radiography is useful since it has been shown to change management in up to 21% of exacerbations, mostly due to new infiltrates.3,20 It also serves to bring to light other possible triggers of exacerbation such as pulmonary edema, pneumothorax, and pulmonary embolism. An electrocardiogram is also a good tool to evaluate for the presence of ischemia, arrhythmias, or pulmonary embolus. Although it is commonly recommended, the use of peak expiratory flow rate (PEFR) as an assessment tool is not well supported by the evidence. This measurement is effort-dependent, and it has not been shown to correlate well with FEV1 in patients with COPD.3 Additionally, acute changes in clinical status are not well correlated with changes in spirometric measures.4 Thus, PEFR is not recommended in the ACP-ASIM/ACCP guidelines, although the VHA and GOLD continue to recommend its use. Similarly, acute spirometry, while recommended by some, is also not useful in diagnosing or assessing the severity of acute exacerbation of COPD. When measured at the time of an exacerbation, FEV1 showed no significant correlation with PO2 and only a weak correlation with PCO2.21 There is no direct clinical evidence regarding the usefulness of obtaining arterial blood gases, white blood cell counts, or other biochemical parameters. However, indirect evidence suggests that arterial blood gases are helpful for determining the present need for oxygen therapy and the potential need for mechanical ventilatory support. Additionally, depending on the patients’ comorbidities and medications, it is reasonable to obtain other biochemical parameters, such as glucose levels or theophylline levels for example. Sputum smear and culture have not been shown to be useful and are not recommended by the ACP-ASIM/ACCP, VHA, or the GOLD.
Management
Bronchodilators. Increased broncho-constriction during acute exacerbations of COPD is best treated with inhaled bronchodilating agents. There is abundant evidence that shows that inhaled short-acting ß2-agonists (such as albuterol) and inhaled anticholinergic bronchodilators (such as ipratropium) are equally efficacious in patients with acute exacerbations of COPD.1,3,22 These medications are also superior to all parenterally administered bronchodilators, including methylxanthines and sympathomimetic agents. Although it is common practice to initiate therapy with the 2 classes of inhaled bronchodilators, the evidence shows that there is no benefit to adding a second bronchodilating agent until the first agent is at maximum doses.1,3 Since the inhaled anticholinergic bronchodilators have fewer and more benign side effects, the ACP-ASIM/ACCP recommend considering these agents first, and then adding the short-acting ß-agonists once maximum doses of the anticholinergic agent are achieved. The GOLD and VHA guidelines recommend the ß2-agonists as the first-line agents, and then add anticholinergics.
With regard to delivery systems for inhaled bronchodilators, evidence shows that the efficacy of wet nebulization and dry aerosol delivery (metered-dose inhaler plus spacer) are clinically equivalent.23 The VHA recommends using nebulizer when the patient is severely dyspneic and cannot effectively breathe or coordinate for effective MDI use.
The methylxanthine bronchodilators, such as theophylline, have not been found to be beneficial in acute exacerbations of COPD, and, due to their narrow therapeutic window and potentially serious side effects, can be harmful.1,3,24 The VHA warns, "clinicians who choose to use this agent must be thoroughly familiar with its metabolism, drug interactions, and toxicity."1 Tables 3 and 4 list the common formulations of short-acting ß2-agonists and anticholinergic bronchodilators.
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| Table 3. Commonly Used Medications in Acute Exacerbations of COPD: Short-Acting Beta 2-agonists | ||||
| Medication | Formulation | Dose | ||
| Short-acting Beta 2 agonists | MDI* | 3-4 puffs q 30 min to 2 h | ||
| Nebulization | 2.5 mg q 30 min to 2 h | |||
| Bitolterol | MDI | 3 puffs q 6 h or 2 puffs q 4 h | ||
| Nebulization | ||||
| Isoproterenol | MDI | 1-2 puffs q 3-4 h | ||
| Nebulization | 0.5 mL 1:2000 solution in 2.5 mL q 6 h | |||
| Metaproterenol | MDI | 3-4 puffs q 30 min to 2 h | ||
| Nebulization | 10-15 mg q 30 min to 2 h | |||
| Pirbuterol | MDI | 2 puffs q 4-6 h, max 12 puffs in 24 h | ||
| Terbutaline | MDI | 3-4 puffs q 30 min to 2 h | ||
| * MDI: metered dose inhaler with space | ||||
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| Table 4. Commonly Used Medications in Acute Exacerbations of COPD: Anticholinergics | ||||
| Anticholinergics | Formulation | Dose | ||
| Ipratropium | MDI | 3-6 puffs q 2-4 h | ||
| bromide | Nebulization | 500 mg q 204 | ||
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Corticosteroids. There is good evidence that the use of systemic corticosteroids is beneficial in the management of acute exacerbations of COPD. It is not uncommon for clinicians to speak of "slow" and "quick" tapers of oral corticosteroid treatment in acute exacerbation of COPD, with some tapers lasting up to a month, depending on the severity of the exacerbation. The evidence has shown (the SCCOPE trial in particular25) that treatment with systemic corticosteroids beyond 2 weeks duration is not beneficial, regardless of the exacerbation severity. In the SCCOPE trial, patients received 3 days of intravenous methylprednisolone 125 mg every 6 hours for the first 3 days. This was followed by oral prednisone for a total of 2 weeks of therapy (60 mg/d on days 4-7, 40 mg/d on days 8-11, and 20 mg/d on days 12-15). A statistically significant difference in FEV1 was seen between the glucocorticoid group and the placebo group for the first 3 days of treatment; however, the difference was no longer significant after 2 weeks. This has prompted some evidence reviews to state that the evidence does not support using systemic steroids past 72 hours.26 Despite this, the ACP-ASIM/ACCP and the VHS both recommend systemic steroids for no more than 2 weeks. Moreover, the use of inhaled steroids in the treatment of acute exacerbations of COPD is inappropriate.
Antibiotics. The evidence shows that antibiotic treatment is beneficial only in selected patients with acute exacerbation of COPD. In particular, the ACP-ASIM/ACCP states that patients with more severe exacerbations are more likely to experience benefit, albeit small, than those whose exacerbations are less severe. The VHA guidelines also underscore that most patients with acute exacerbations of COPD do well without antibiotic therapy. These conclusions are supported by a recent meta-analysis27 and 2 studies that stratified patients by exacerbation severity.9,28 The trial by Anthonisen et al9 found that patients with more severe exacerbations experienced benefit from antibiotic treatment, 63% of antibiotic-treated patients vs. 43% of patients receiving placebo. This was not seen in the moderate or mild exacerbation groups (70% vs 60% for the moderate exacerbations and 74% vs 70% for the mild exacerbations). In the second study, physician-assigned severity correlated well with likelihood of benefit from antibiotics.28 There were no significant differences between antibiotics and placebo in the mild exacerbation group. In the moderate-to-severe groups, patients who received antibiotics had significantly less severe symptoms on days 2 and 7 of treatment. Typical administration periods in the trials ranged from 3 to 14 days, and the favored antibiotics are amoxicillin, trimethoprim-sulfamethoxazole, and tetracycline. Although most of these trials took place before the emergence of multidrug-resistant organisms, particularly Streptococcus pneumoniae, to date, no randomized, placebo-controlled trials have proven the superiority of newer broad-spectrum antibiotics in acute exacerbation of COPD. What’s more, in the pursuit of a small benefit, there is the risk to the patient of adverse events, allergic reactions, drug-drug interactions, and increased costs to the patient and health system.
Oxygen Therapy. There is ample evidence that oxygen therapy provides important benefits to patients with acute exacerbation of COPD and hypoxemia. The major concern with the administration of oxygen in patients with obstructive disease is the risk of resultant hypercarbia and subsequent respiratory failure. Several observational studies have shown that most patients with acute exacerbations of COPD do develop hypercarbia after administration of oxygen at FiO2s from 24% to 28%.29-32 But, not all these patients develop respiratory failure; rather, only those with significant hypoxemia, rather than significant hypercarbia, required mechanical ventilation. These studies emphasized the fact that patients who present with significantly altered gas exchange are at greatest risk for respiratory failure.
Noninvasive Positive Pressure Ventilation (NPPV). NPPV is frequently used in the inpatient management of patients with acute exacerbations of COPD. It not only improves ventilation and decreases CO2 levels, but in many instances is also a means of avoiding intubation. Several studies have shown NPPV to be a beneficial support strategy, and some data suggest that NPPV may improve survival of patients with acute exacerbations of COPD.33-36 Further research needs to be done in order to identify the patients who might benefit most from this technology. Tables 5, 6, and 7 list recommended indications for mechanical ventilation, intubation, and admission to the intensive care unit.
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| Table 5. Indications for Mechanical Ventilation (invasive or noninvasive) in Acute Exacerbations of COPD | |
| • | Severe respiratory or combined respiratory and metabolic acidosis |
| • | Sustained respiratory rate = 40 per minute |
| • | Abnormal breathing pattern suggestive of increased respiratory workload and/or respiratory muscle fatigue |
| • | Depressed mental status |
| • | Severe hypoxemia |
| Adapted from VHA/ATS | |
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| Table 6. Indications for Intubation in Acute Exacerbations of COPD | |
| • | Depressed mental status |
| • | Suspected airway obstruction |
| • | High risk of aspiration |
| • | Difficulty managing secretions |
| Adapted from VHA | |
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| Table 7. Criteria for Admission to ICU | |
| • | Severe dyspnea that responds inadequately to initial emergency room therapy |
| • | Confusion, lethargy, or respiratory muscle fatigue |
| • | Persistent or worsening hypoxemia despite supplemental oxygen therapy or severe worsening of respiratory acidosis (PO2 < 50 mm Hg and PCO2 > 70 mm Hg) |
| • | Patient intubated or requiring noninvasive ventilation |
| Adapted from VHA/ATS/GOLD | |
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Mucolytic Agents and Mucous Clearance Strategies. While it was previously thought that mucolytic agents and mucous clearance strategies would help patients with acute exacerbations of COPD manage their secretions more effectively and help clear infections more rapidly, the evidence has not supported this view. Several randomized trials failed to show that mucolytic agents shorten the disease course or improve patient outcomes.37,38 Other trials showed that mechanical percussion of the chest as applied by a physical or respiratory therapist is ineffective in that it does not increase FEV1 in patients with acute exacerbations of COPD.39-41 In fact, two of those studies showed a decrease in FEV1 after chest physical therapy.40,41 For these reasons, the ACP-ASIM/ACCP, VHA, and GOLD do not recommend these strategies in acute exacerbations of COPD.
An Unanswered Question
The diagnosis and management of acute exacerbations of COPD is a prevalent problem in primary care. One of the most important questions clinicians ask themselves when faced with a patient suffering from an acute exacerbation of COPD is "Do I hospitalize or try treating as an outpatient?" This is a difficult question and there is not an evidence-based answer. The VHA and the GOLD have recommended indications for hospital admission, which are summarized in Table 8.
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| Table 8. Indications for Hospitalization for Acute Exacerbation of COPD | |
| • | Inadequate response of symptoms to outpatient management |
| • | Marked increase in intensity of symptoms such as dyspnea at rest |
| • | New or worsening hypoxemia or hypercarbia |
| • | Significant comorbidities |
| • | Severe background COPD |
| • | Older age |
| • | Insufficient home support |
| Adapted from GOLD and VHA | |
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References
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