Management of COPD Exacerbations

ANN E. EVENSEN

ANN E. EVENSEN, MD

This is a corrected version of the article that appeared in print.

Am Fam Physician. 2010;81(5):607-613

Patient information: See related handout on COPD exacerbations, written by the author of this article.

Author disclosure: Nothing to disclose.

Exacerbations of chronic obstructive pulmonary disease contribute to the high mortality rate associated with the disease. Randomized controlled trials have demonstrated the effectiveness of multiple interventions. The first step in outpatient management should be to increase the dosage of inhaled short-acting bronchodilators. Combining ipratropium and albuterol is beneficial in relieving dyspnea. Oral corticosteroids are likely beneficial, especially for patients with purulent sputum. The use of antibiotics reduces the risk of treatment failure and mortality in moderately or severely ill patients. Physicians should consider antibiotics for patients with purulent sputum and for patients who have inadequate symptom relief with bronchodilators and corticosteroids. The choice of antibiotic should be guided by local resistance patterns and the patient's recent history of antibiotic use. Hospitalized patients with exacerbations should receive regular doses of short-acting bronchodilators, continuous supplemental oxygen, antibiotics, and systemic corticosteroids. Noninvasive positive pressure ventilation or invasive mechanical ventilation is indicated in patients with worsening acidosis or hypoxemia.

In patients with known chronic obstructive pulmonary disease (COPD), exacerbations occur an average of 1.3 times per year.¹ Exacerbations range in severity from transient declines in functional status to fatal events. In the United States, exacerbations have contributed to a 102 percent increase in COPD-related mortality from 1970 to 2002 (21.4 to 43.3 deaths per 100,000 persons).² Effective management of a COPD exacerbation combines relieving acute symptoms and lowering the risk of subsequent exacerbations.

Clinical recommendation	Evidence rating	References	Comments
Noninvasive positive pressure ventilation improves respiratory acidosis and decreases respiratory rate, breathlessness, need for intubation, mortality, and length of hospital stay.	A	⁶, ⁹, ¹⁵, ¹⁸	—
Inhaled bronchodilators (beta agonists, with or without anticholinergics) relieve dyspnea and improve exercise tolerance in patients with COPD.	A	⁶, ⁹	—
Short courses of systemic corticosteroids in patients with COPD increase the time to subsequent exacerbation, decrease the rate of treatment failure, shorten hospital stays, and improve FEV₁ and hypoxemia.	A	¹, ⁶, ⁷, ⁹, ^17–20	—
Low-dosage corticosteroid regimens are not inferior to high-dosage regimens in decreasing the risk of treatment failure in patients with COPD.	B	¹⁷, ¹⁹	—
Oral prednisolone is equivalent to intravenous prednisolone in decreasing the risk of treatment failure in patients with COPD.	B	²²	Because they are bioavailable, inexpensive, and convenient, oral corticosteroids are recommended in patients who can safely swallow and absorb them.
Antibiotics should be used in patients with moderate or severe COPD exacerbations, especially if there is increased sputum purulence or the need for hospitalization.	B	⁶, ⁹, ¹⁸, ²⁴	—
The choice of antibiotic in patients with COPD should be guided by symptoms (e.g., presence of purulent sputum), recent antibiotic use, and local microbial resistance patterns.	C	¹⁸, ²³, ²⁵	There is limited evidence that broad-spectrum antibiotics are more effective than narrow-spectrum antibiotics.
Smoking cessation reduces mortality and future exacerbations in patients with COPD.	A	⁶, ⁷, ³⁰	—
Long-term oxygen therapy decreases the risk of hospitalization and shortens hospital stays in severely ill patients with COPD.	B	⁷, ³²	—

Definition and Classification

Criteria for the diagnosis of COPD have been established.³ However, there is no validated diagnostic test or biomarker of COPD exacerbations.⁴ The American Thoracic Society (ATS) and European Respiratory Society (ERS) define an exacerbation as an acute change in a patient's baseline dyspnea, cough, or sputum that is beyond normal variability, and that is sufficient to warrant a change in therapy.⁵ The ATS and ERS classify COPD exacerbations as mild, moderate, or severe, based on the intensity of the medical intervention required to control the patient's symptoms (Table 1).^4,5 In addition to the hallmark symptoms of a COPD exacerbation (cough, dyspnea, and increased sputum), systemic inflammation also causes extrapulmonary symptoms (Table 2).^6–8 Factors that increase the risk of a severe exacerbation are listed in Table 3.^5–7,9–11

Severity of exacerbation	Description
Mild	Can be controlled with an increase in dosage of regular medications
Moderate	Requires treatment with systemic corticosteroids or antibiotics
Severe	Requires hospitalization or evaluation in the emergency department

Body system	Symptoms
Cardiac	Chest tightness
Cardiac	Tachycardia
Musculoskeletal	Decreased exercise tolerance
Psychiatric	Confusion
	Depression
	Insomnia
	Sleepiness
Pulmonary	Change in volume, color, or tenacity of sputum
	Cough
	Dyspnea
	Tachypnea
	Wheezing
Systemic	Fatigue
	Fever
	Malaise

Altered mental status

At least three exacerbations in the previous 12 months

Body mass index of 20 kg per m² or less

Marked increase in symptoms or change in vital signs

Medical comorbidities (especially cardiac ischemia, congestive heart failure, pneumonia, diabetes mellitus, or renal or hepatic failure)

Poor physical activity levels

Poor social support

Severe baseline COPD (FEV₁/FVC ratio less than 0.70 and FEV₁ less than 50 percent of predicted)

Underutilization of home oxygen therapy

Etiology

Infection of the tracheobronchial tree and air pollution (e.g., tobacco smoke, occupational exposures, ozone) are the most common identifiable causes of COPD exacerbations. One third of exacerbations have no identifiable cause.⁶ Other medical problems, such as congestive heart failure, nonpulmonary infections, pulmonary embolism, and pneumothorax, can also prompt a COPD exacerbation.⁹

Initial Evaluation

The initial evaluation of patients with a suspected COPD exacerbation should include a history of baseline and current symptoms, such as limitations in activities of daily living. If available, previous chest radiographs, arterial blood gas measurements, and spirometry results can help establish the baseline lung function and illustrate a typical exacerbation. Because increasing confusion is a hallmark of respiratory compromise, the physical examination should include a mental status evaluation, as well as heart and lung examinations.

Recommended diagnostic evaluation of an exacerbation depends on its severity (Table 4).^5,8,9,12,13 Pulse oximetry should be performed in all patients. Chest radiography is appropriate in hospitalized patients and can guide treatment by revealing comorbid conditions such as congestive heart failure, pneumonia, and pleural effusion. A room air arterial blood gas (ABG) measurement should be obtained at the time of hospital admission to quantify hypercarbia and hypoxemia. Measurement of brain natriuretic peptide and serial cardiac enzyme levels should be considered in hospitalized patients, because cardiac ischemia and congestive heart failure are common comorbidities in patients with COPD.^5,12,13

Test	Potential diagnosis
Perform routinely
Pulse oximetry	Hypoxemia
Perform if hospitalized
Arterial blood gas measurement	Hypercarbia
	Hypoxemia
	Respiratory acidosis
Chest radiography	Alternate sources of dyspnea
Complete blood count	Anemia
	Leukocytosis
	Polycythemia
Electrocardiography	Cardiac arrhythmias
	Cardiac ischemia
Metabolic panel	Electrolyte disturbances
	Hypo- or hyperglycemia
	Metabolic acid-base changes
Consider performing, especially if patient is not responding to conventional exacerbation treatment
Brain natriuretic peptide measurement	CHF (one third of dyspnea in chronic lung disease may be attributable to CHF)
Cardiac enzyme measurement	Cardiac ischemia (myocardial infarction is underdiagnosed in patients with COPD)

Other physical examination maneuvers, laboratory tests, and assessments of cardiac function have not been proven beneficial in the treatment of COPD exacerbations.⁹

Indications for Hospitalization

About 50 percent of COPD exacerbations are not reported to physicians, suggesting that many exacerbations are mild.¹⁴ The risk of death from an exacerbation increases with the development of respiratory acidosis, the presence of significant comorbidities, and the need for ventilatory support.⁵ Patients with symptoms of respiratory distress and those at risk of distress should be admitted to the hospital to provide access to critical care personnel and mechanical ventilation. Inpatient mortality for COPD exacerbations is 3 to 4 percent.⁹ Patients admitted to the intensive care unit have a 43 to 46 percent risk of death within one year after hospitalization.⁹

Nonambulatory patients should receive routine pro-phylaxis for deep venous thrombosis. Because COPD is a progressive and often fatal illness, physicians should consider discussing and documenting the patient's wishes concerning end-of-life care.

Oxygenation and Ventilation

Oxygen supplementation should be titrated to an oxygen saturation level of at least 90 percent. High-flow oxygen devices deliver oxygen more reliably than nasal prongs, but nasal prongs may be better tolerated. Noninvasive positive pressure ventilation (NIPPV) is indicated if adequate oxygenation or ventilation cannot be achieved using a high-flow mask.¹⁵ Patients requiring NIPPV should be monitored continuously for decompensation.

If the patient cannot be adequately oxygenated, complications, such as pulmonary embolism or edema, should be considered.⁶ Carbon dioxide retention is possible in moderately and severely ill patients; therefore, ABG should be measured 30 to 60 minutes after initiating oxygen supplementation.

Invasive mechanical ventilation is needed if the patient cannot tolerate NIPPV; has worsening hypoxemia, acidosis, confusion, or hypercapnia despite NIPPV; or has severe comorbid conditions, such as myocardial infarction or sepsis.⁶ Worsening hypercarbia and acidosis herald respiratory failure. A pH of less than 7.36 and an arterial partial pressure of carbon dioxide of more than 45 mm Hg indicate the need for mechanical ventilation.

Therapeutic Options

SHORT-ACTING BRONCHODILATORS

Inhaled short-acting bronchodilators include beta agonists (e.g., albuterol, levalbuterol [Xopenex]) and anti-cholinergics (e.g., ipratropium [Atrovent]). These agents improve dyspnea and exercise tolerance.^6,9 The first step in treating a COPD exacerbation is increasing the dosage of albuterol delivered via metered dose inhaler or nebulizer.⁹ Levalbuterol is more expensive than albuterol but has similar benefits and adverse effects.¹⁶ If the patient is not already taking ipratropium, it can be added to the treatment regimen.⁵ Fixed-dose albuterol/ipratropium (Combivent) is available.

CORTICOSTEROIDS

Short courses of systemic corticosteroids increase the time to subsequent exacerbation, decrease the rate of treatment failure, shorten hospital stays, and improve hypoxemia and forced expiratory volume in one second (FEV₁).^{1,6,7,9,17–20} Administration of oral corticosteroids early in an exacerbation decreases the need for hospitalization.²¹ A randomized controlled trial (RCT) of patients with COPD compared eight weeks of corticosteroids, two weeks of corticosteroids, and placebo; participants in the treatment groups had fewer treatment failures than those in the control group.¹⁷ Treatment failure rates were the same for long and short courses of corticosteroids.

High-dosage corticosteroid regimens (methylprednisolone [Solu-Medrol], 125 mg intravenously every six hours) and low-dosage regimens (prednisolone, 30 mg orally daily) decrease the length of hospitalization and improve FEV₁ compared with placebo.^17,19 [ corrected] An RCT comparing oral and intravenous prednisolone in equivalent dosages (60 mg daily) showed no difference in lengths of hospitalization and rates of early treatment failure.²²

Because oral corticosteroids are bioavailable, inexpensive, and convenient, parenteral corticosteroids should be reserved for patients with poor intestinal absorption or comorbid conditions that prevent safe oral intake (e.g., decreased mental status, vomiting).^5,6 Inhaled corticosteroids have no role in the management of an acute exacerbation.⁸

ANTIBIOTICS

One half of patients with COPD exacerbations have high concentrations of bacteria in their lower airways.^6,23 Cultures often show multiple infectious agents, including Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, and viruses.^6,23

The use of antibiotics in moderately or severely ill patients with COPD exacerbations reduces the risk of treatment failure and death.²⁴ Antibiotics may also benefit patients with mild exacerbations and purulent sputum.⁵ The optimal choice of antibiotic and length of use are unclear. Increasing microbial resistance has prompted some physicians to treat exacerbations with broad-spectrum agents, such as second- or third-generation cephalosporins, macrolides, or quinolones. One meta-analysis showed a lower risk of treatment failure with broad-spectrum antibiotics compared with narrow-spectrum antibiotics (odds ratio = 0.51; 95% confidence interval, 0.34 to 0.75), but no change in mortality rates.²⁵ Another meta-analysis showed no difference in clinical cure rates when broad-spectrum antibiotics were administered for at least five days versus less than five days.²⁶ There is no comparable study of narrow-spectrum antibiotics. The decision to use antibiotics and the choice of antibiotic should be guided by the patient's symptoms (e.g., presence of purulent sputum), recent antibiotic use, and local microbial resistance patterns.^18,23,25 Prophylactic, continuous use of antibiotics does not improve outcomes in patients with COPD.⁶

OTHER TREATMENT OPTIONS

Parenteral methylxanthines, such as theophylline, are not routinely recommended for the treatment of COPD exacerbations.²⁷ These agents are less effective and have more potentially adverse effects than inhaled bronchodilators.

Several therapies lack adequate evidence for routine use in the treatment of COPD exacerbations, including mucolytics (e.g., acetylcysteine [formerly Mucomyst]), nitric oxide, chest physiotherapy, antitussives, morphine, nedocromil, leukotriene modifiers, phosphodiesterase IV inhibitors (drug class not available in the United States), and immunomodulators (e.g., OM-85 BV, AM3 [neither drug available in the United States]).^6,7 Table 5 summarizes the treatment options for acute COPD exacerbations.^{5,6,8,9,18,25}

Therapy	Outpatient management	Inpatient management	Benefits	Disadvantages/common adverse effects	Typical dosage
Antibiotic, broad spectrum (e.g., amoxicillin/clavulanate [Augmentin], macrolides, second- or third-generation cephalosporins, quinolones)	Consider if sputum is purulent or after treatment failure	Use if local microbial patterns show resistance to narrow-spectrum agents	Decreases risk of treatment failure and mortality compared with narrow-spectrum agents	Antibiotic resistance, diarrhea, yeast vaginitis; side effects specific to the antibiotic prescribed	Amoxicillin/clavulanate: 875 mg orally twice daily or 500 mg orally three times daily for 5 days
	Use if local microbial patterns show resistance to narrow-spectrum agents
					Levofloxacin (Levaquin): 500 mg daily for 5 days
Antibiotic, narrow spectrum (e.g., amoxicillin, ampicillin, trimethoprim/sulfamethoxazole [Bactrim, Septra], doxycycline, tetracycline)	Consider if sputum is purulent or after treatment failure	Use if local microbial patterns show minimal resistance to these agents and if patient has not taken antibiotics recently	Believed to decrease mortality risk, but has not been tested in placebo-controlled trials	Antibiotic resistance, diarrhea, yeast vaginitis; side effects specific to the antibiotic prescribed	Amoxicillin: 500 mg orally three times daily for 3 to 14 days Doxycycline: 100 mg orally twice daily for 3 to 14 days
	Use if local microbial patterns show minimal resistance to these agents and if patient has not taken antibiotics recently
Anticholinergic, short acting (e.g., ipratropium [Atrovent])	May add to beta agonist; if patient is already taking an anticholinergic, increase dosage	May add to beta agonist; if patient is already taking an anticholinergic, increase dosage	Improves dyspnea and exercise tolerance	Dry mouth, tremor, urinary retention	Ipratropium: 500 mcg by nebulizer every 4 hours as needed; alternatively, 2 puffs (18 mcg per puff) by MDI every 4 hours as needed*
Beta agonist, short acting (e.g., albuterol, levalbuterol [Xopenex])	Increase dosage	Increase dosage	Improves dyspnea and exercise tolerance	Headache, nausea, palpitations, tremor, vomiting	Albuterol: 2.5 mg by nebulizer every 1 to 4 hours as needed, or 4 to 8 puffs (90 mcg per puff) by MDI every 1 to 4 hours as needed*
Corticosteroid	Consider using oral corticosteroids in moderately ill patients, especially those with purulent sputum	Use oral corticosteroids if patient can tolerate; if not suitable for oral therapy, administer intravenously	Decreases risk of subsequent exacerbation, rate of treatment failures, and length of hospital stay Improves FEV₁ and hypoxemia	Gastrointestinal bleeding, heartburn, hyperglycemia, infection, psychomotor disturbance, steroid myopathy	Oral prednisone: 30 to 60 mg once daily Intravenous methylprednisolone (Solu-Medrol): 60 to 125 mg 2 to 4 times daily
Mechanical ventilation	NA	Use if patient cannot tolerate NIPPV; has worsening hypoxemia, acidosis, confusion, or hypercapnia despite NIPPV; or has comorbid conditions such as myocardial infarction or sepsis	Decreases short-term mortality risk in severely ill patients	Aspiration, cardiovascular complications, need for sedation, pneumonia	Titrate to correct hypercarbia and hypoxemia
NIPPV	NA	Use in patients with worsening respiratory acidosis and hypoxemia when oxygenation via high-flow mask is inadequate	Improves respiratory acidosis and decreases respiratory rate, breathlessness, need for intubation, mortality, and length of hospital stay	Expensive, poorly tolerated by some patients	Titrate to correct hypercarbia and hypoxemia
Oxygen supplementation	NA	Use in patients with hypoxemia (PaO₂ less than 60 mm Hg)	Decreases mortality risk	Hypercarbia	Titrate to PaO₂ > 60 mm Hg or oxygen saturation ≥ 90 percent

Preparation for Hospital Discharge

To qualify for discharge, a patient should have stable clinical symptoms and a stable or improving arterial partial pressure of oxygen of more than 60 mm Hg for at least 12 hours. The patient should not require albuterol more often than every four hours. If the patient is stable and can use a metered dose inhaler, there is no benefit to using nebulized bronchodilators.²⁸ Patient education may improve the response to future exacerbations²⁹; suggested topics include a general overview of COPD, available medical treatments, nutrition, advance directives, and advice about when to seek medical help. In-home support, such as an oxygen concentrator, nebulizer, and home health nurse services, should be arranged before discharge.

Preventing Future Exacerbations

Smoking cessation, immunization against influenza and pneumonia, and pulmonary rehabilitation have been shown to improve function and reduce subsequent COPD exacerbations.^6,7,30 Long-term oxygen therapy decreases the risk of hospitalization and shortens hospital stays in severely ill patients with COPD.^7,31,32 The indications for long-acting inhaled bronchodilators and inhaled corticosteroids to improve symptoms and reduce the risk of exacerbations in patients with stable COPD are reviewed elsewhere.^5,7,33–38

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