A. Acute Exacerbation of COPD - Acute exacerbation is defined as a recent deterioration of the patient's clinical and functional state that is due to worsening of their COPD. Typical symptoms and signs of COPD exacerbation are given below (adapted from the European Respiratory Society Consensus Statement, Siafakas 1995).

• Worsening dyspnea, sometimes at rest
• Increased cough
• Increased sputum production, often with change in character from mucoid to purulent
• Development or increase in wheezing
• Loss of energy
• Fever
• Increased respiratory rate
• Tachycardia
• Increased cyanosis
• Use of accessory muscles
• Peripheral edema
• Loss of alertness
• Worsening airflow obstruction by FEV₁ or peak expiratory flow rate
• Worsening of arterial blood gases or pulse oximetry O₂ saturation.

Parameters that suggest a serious COPD exacerbation

The decision whether to manage the patient initially at home or refer for acute evaluation depends, not only on the severity of the exacerbation, but also on many factors, including the severity of the underlying COPD, comordibities, the medical sophistication, judgment and reliability of the patient and caregivers, and distance from the medical center or clinic.

Loss of alertness or a combination of two or the other parameters suggests a severe exacerbation and a need for referral to the emergency department (ED). These parameters are not designed to replace a provider's judgment for need for referral. Some of these criteria, such as dyspnea at rest or loss of alertness, may be noted while attempting to evaluate the severity of the exacerbation on a telephone call.

C. Is There Evidence of Respiratory Infection?

These include increased cough, increase in the volume and change in the color of sputum, and fever. This often is due to viral illness but may be due to bacterial infection.

In cases of bacterial infection, S. pneumoniae, H. influenzae and M. catarrhalis are frequent pathogens.

In patients with evidence of respiratory infection as indicated in Annotation C, a white cell count and chest X-ray may be considered. If an infiltrate is present on the chest X-ray, suggesting pneumonia, the patient usually should be considered for admission, depending on the severity of the underlying COPD. Some patients with a small infiltrate and a mild-to-moderate exacerbation of COPD can be managed with antibiotic therapy as outpatients.

Evidence of respiratory infection with a clear chest X-ray suggests that the exacerbation of COPD is due to purulent bronchitis. Antibiotic therapy should be considered.

A recent meta-analysis of nine randomized, placebo-controlled studies suggested a small benefit from antibiotic treatment. Antibiotic therapy may be of greater importance in preventing deterioration rather than expediting improvement in outpatients with COPD exacerbation. Mild COPD exacerbations may not benefit from antibiotics.

Older patients, those with a more severe COPD and exacerbations featured by increased purulent sputum production are more likely to benefit.

A conventional antibiotic usually is sufficient, such as sulfamethoxazole-trimethroprim (SMZ-TMP) or doxycycline. The choice may be influenced by local community antibiotic resistance patterns. Broader spectrum antibiotics may be required if the patient had a recent hospitalization or course(s) of antibiotics, or if the patient does not respond to conventional antibiotics.

 
1. These factors require treatment in their own right and some (e.g., pulmonary embolism) may require admission to hospital. A high degree of suspicion is required to detect some relatively common disorders in the presence of COPD such as heart failure, pulmonary embolism and pneumothorax. 
   
   
2. It is relatively unlikely, however, that a mild to moderate exacerbation of COPD, manageable on an outpatient basis, is due to a serious cause such as pulmonary embolism.
 

Disorders that Can Mimic or Cause a COPD Exacerbation



• Air pollutants
• Viral infection
• Bacterial infection
• Pneumonia
• Congestive heart failure
• Cardiac arrhythmia
• Pulmonary embolism
• Spontaneous pneumothorax
• Inappropriate oxygen therapy
• Drugs (hypnotics, tranquilizers, etc.)
• Metabolic diseases (diabetes mellitus, electrolyte disorders such as hypophosphatemia, hypokalemia)
• Other diseases (undernutrition, GI hemorrhage, stroke, thoracic vertebral collapse)
• Myopathy (e.g., steroid myopathy)
• End-stage respiratory disease.

1. There is not a good relationship between spirometry and blood gases in COPD exacerbation, at least in ED patients; a PaO₂ less than 60 mmHg may be found in patients with a FEV₁ up to 54 percent of normal. For that reason, O₂ saturation at least should be obtained in patients with mild-to-moderate COPD exacerbations.
   
   
2. If ambulatory facilities are available, oxygen should be given by nasal prongs at a flow rate to keep O₂ saturation > 90 percent while the patient receives more aggressive bronchodilator therapy. In some centers this may require ED management. Blood gases should be obtained to guide oxygen therapy in known CO₂ retainers or if the status of CO₂ retention is unknown.
   
   
3. Patients who are stabilized after aggressive drug therapy but continue to have hypoxemia may require home oxygen therapy at least on a temporary basis. Blood gases should be checked in 1 month when the patient is stable to determine the need for continued long-term home oxygen therapy.

 
1. Short-acting, inhaled beta2-agonists (SAIBA), such as albuterol, metaproterenol, and terbutaline are the bronchodilators of choice in COPD exacerbations. They incur less risk of causing tachycardia, cardiac arrhythmias and tremor than nonselective bronchodilators. These agents are comparable in efficacy, duration of effect, and adverse effects when given as aerosols. A small number of studies suggest that SAIBA, as a class, are of benefit in exacerbations of COPD, showing improvements in FEV₁ and in dyspnea scores.
   
   
2. The maximal effective dose of SAIBA in COPD exacerbation is not known. However, limited data from studies of COPD exacerbations indicate that 3 to 4 puffs of beta2-agonists produce significant (18 to 22 percent) levels of bronchodilation. The functional duration of effect of SAIBA is decreased in COPD exacerbations. Thus, if 3 to 4 puffs every 4 hours have not been effective, SAIBA should be administered 3 to 4 puffs every 1 to 2 hours, if tolerated, until clinical improvement occurs. The ATS recommendation for severe COPD exacerbation is 6 to 8 puffs every to 2 hours (ATS Consensus Statement, 1995).
   
   
3. The frequency and dose of administration then can be reduced as the progress of improvement of the exacerbation allows.
   
   
4. It should be noted that spacers were used in most studies of MDI beta2-agonists in COPD exacerbations. Use of spacers in COPD exacerbation is strongly encouraged.
   
   
5. The risk of adverse reactions, such as tremor and cardiac arrhythmias, also is increased with use of maximal doses of these agents. Caution should be used in patients with known coronary artery disease, left ventricular dysfunction, or history of arrhythmia if using maximal doses (3 to 4 puffs every 1 to 2 hours) of inhaled beta2-agonists. In this group, a wise alternative is to employ additional inhaled ipratropium at higher doses in association with moderate doses of beta2-agonists.

1. Ipratropium bromide is the only antimuscarinic (anticholinergic) agent available at present. It is also appears of benefit in COPD exacerbations; doses of 54 to 72 g (3 to 4 puffs) produce increases of 25 percent in FEV₁, comparable with the effect of short-acting inhaled beta2-agonists.
   
   
2. Ipratropium is less well documented than SAIBA in COPD exacerbations, and as yet should be used as monotherapy only in cases with a history of poor response to SAIBA or for those who cannot tolerate higher doses of SAIBA.
   
   
3. The onset of bronchodilation is slower with ipratropium than short-acting beta2-agonists, but the duration of action is longer.
   
   
4. A reasonable maximum dose is 3 to 4 puffs every 3 to 4 hours. Since systemic toxicity is low (Gross 1988), higher doses may be given, although the dose-response relationship of ipratropium in COPD exacerbation at higher doses has not been established. The ATS recommendation for severe exacerbation is 6 to 8 puffs every 3 to 4 hours.
   
   
5. Ipratropium also can be given by nebulizer, 0.5 mg every 2 to 8 hours to patients who cannot use an MDI properly.
   
   
6. Use of a spacer with MDI delivery of ipratropium is recommended.

 
1. While the effect of ipratropium or a beta2-agonist are comparable in COPD exacerbation, the evidence that addition of ipratropium to a beta2-agonist regimen improves outcomes in moderate COPD exacerbation is not proven.
   
   
2. However, since some patients may benefit from the combination, and the toxicity of ipratropium is low, it is reasonable to add ipratropium to a beta2-agonist regimen. This is especially the case in unmonitored patients in whom there may be concern about toxicity from high-dose SAIBA.

 
1. A limited number of studies indicate that administration of inhaled beta2-agonists by MDI offers as much benefit as by nebulizer. Metaproterenol (3 puffs) or albuterol (4 puffs) MDI were deemed equivalent in effect to nebulized delivery of metaproterenol (15 mg) or albuterol (2.5 mg). Patients were either in ED or hospitalized settings. It is likely, but not certain, that results can be extrapolated to outpatients. MDIs were delivered by spacer technique.
   
   
2. If a patient can inhale effectively using a spacer then MDI delivery is reasonable. Otherwise nebulizers should be used.

1. Patients already on higher doses or oral corticosteroids in the range used for treatment of COPD exacerbation (typically 40 to 60 mg daily), and who have not responded to the more intensive bronchodilator therapy as outlined above, are unlikely to benefit from further outpatient management.
   
   
2. They should be referred on an emergent basis for specialist consultation or for admission to the hospital.

• Patients on oral steroids or on inhaled steroids
• Patients who recently stopped oral steroids
• Patients who previously have had a response to oral steroids
• Patients with low O₂ saturation (< 90 percent)
• PEF < 100 L/min
• Patients not responding to initial bronchodilator therapy

 
1. Although corticosteroids are widely used in patients with COPD exacerbations, this practice is based on a small number of studies. These studies do not uniformly support the use of corticosteroids.
   
   
2. A typical oral dose is 0.6 to 0.8 mg/kg prednisone per day. Once the patient is stabilized, the dose should be tapered carefully, monitoring for relapse of the exacerbation. The goal should be to wean the patient off steroids. This may not be possible in some patients who should then be treated with the smallest effective dose. (See Chronic COPD Pharmacotherapy Module A4).
   
   

1. Theophylline used chronically may benefit COPD patients by means of bronchodilation and other effects including improvement of respiratory muscle strength.

2. Limited evaluation of COPD exacerbation has not demonstrated a definitive role for introduction of theophylline in acute COPD exacerbations. Theophylline is unlikely to be indicated in moderate COPD exacerbation.

3. If the patient is already taking theophylline, it would be prudent to measure a plasma theophylline concentration and if low (< 5 g/ml) additional dosing can be given to achieve therapeutic levels (5 to 12 g/ml). Assuming 100 percent bioavailability, the oral loading dose (mg) of short-acting theophylline required to reach a concentration of 10 g/ml equals (10 - plasma concentration in g/ml) x 0.5 body weight in kg (volume of distribution is 0.5 L/kg).

1. Evidence of improvement of COPD exacerbation includes:
 
1. Decrease in cough, sputum production or dyspnea
2. Decrease in respiratory rate
3. Decrease in heart rate
4. Increase in function and endurance
 

 
1. Once the patient is stabilized, with improvement in the level of function, he or she can begin to reduce the intensity of the bronchodilator regimen down to the usual level of treatment over the course of a few days.
   
   
2. Tapering of corticosteroids depends on the prior history of use and tapering, but often is done over one to two weeks. This can be done in consultation with the primary care provider.
   
   
3. The provider should see the patient soon to ensure that the course of action is appropriate and for consideration of any further therapy such as smoking cessation, or changes in pharmacotherapy in view of the recent exacerbation.