Managing COPD, part 2: Acute exacerbations

Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and costs, but it can be successfully managed. In the July 2005 issue of The Journal of Respiratory Diseases, I reviewed the importance of risk reduction and the available treatment options for patients with stable disease.

In this article, I will discuss the management of acute exacerbations of COPD. Topics covered include the use of bronchodilators and oxygen therapy.

OVERVIEW

COPD is significantly complicated by recurrent acute exacerbations, which caused nearly 120,000 deaths and more than 725,000 hospitalizations in the United States in 2000, with a total cost of over $30 billion annually.¹ Acute exacerbations negatively affect patients' quality of life for up to 7 months after the acute event.²

In the United States, patients with frequent acute exacerbations of COPD, particularly those requiring hospitalization, account for most of the COPD-relatedhealth care costs.³In one group of patients with acute exacerbations and hypercapnia, the mortality rates were 33% at 6 months and 49% at 2 years.²Mortality rates are even higher for patients older than 65 years. In one study, the mortality rate reached 59% at 1 year after an acute exacerbation that required ICU treatment.⁴

The classic definition of an acute exacerbation of COPD is based on a landmark trial by Anthonisen and associates⁵ and includes the presence of at least one of the following respiratory symptoms: increased shortness of breath, increased sputum production, and sputum purulence. Guidelines published by the European Respiratory Society (ERS) and the American Thoracic Society (ATS) state that an acute exacerbation is an event in the natural course of COPD that is characterized by a change in the patient's baseline dyspnea, cough, or sputum--beyond the day-to-day variability--that is sufficient to warrant a change in management.⁶

TREATMENT

There are many approaches to managing acute exacerbations, but these recommendations are largely based on expert opinion and have not been prospectively evaluated in clinical trials.^6-9 An important first step is the identification of patients who should be hospitalized. The ATS/ERS guidelines recommend that patients who meet the following criteria should be hospitalized:

• ;The presence of high-risk comorbid conditions, including pneumonia, cardiac arrhythmia, congestive heart failure (CHF), diabetes mellitus, and renal or liver failure.

• ;Inadequate response of symptoms to outpatient management.

• ;Marked increase in dyspnea.

• ;Inability to eat or sleep because of symptoms.

• ;Worsening hypoxemia.

• ;Worsening hypercapnia.

• ;Changes in mental status.

• ;Inability of the patient to care for himself or herself; inadequate home care.

•;Uncertain diagnosis.⁶

What to do: Interventions that are helpful

• ;Chest radiography is useful for patients with acute exacerbations of COPD who present to the emergency department or the hospi- tal.^10,11 A chest radiograph may be helpful in an outpatient clinic setting if the patient appears ill, has crackles on lung examination (suggesting possible pneumonia), or has fever or pleuritic chest pain.

• ;Short-acting bronchodilators are useful for acute exacerbations and should be administered for acute symptoms.Regimens include albuterol, 4 to 8 puffs by metered-dose inhaler (MDI); ipratropium, 4 to 8 puffs by MDI; albuterol-ipratropium, 4 to 8 puffs by MDI; and albuterol-ipratropium via nebulizer.Puffs of the MDI should be taken 1 minute apart.The short-acting bronchodilators should be given initially every 2 to 4 hours, but then less frequently (as quickly as possible) so that tachyphylaxis does not develop.

• ;If the patient is hypoxemic, oxygen should be administered. For most patients, an oxygen saturation goal of 90% or greater is appropriate. However, if the patient has known ischemic heart disease or active chest pain, the oxygen saturation goal should be higher than 95%. In contrast, if the patient has a histo- ry of hypercapnia or an elevated serum bicarbonate level, oxygen should be administered to raise the oxygen saturation to no higher than 88% to 92%. Administering high levels of oxygen--levels that raise the oxygen saturation to higher than 95%--to patients with hypercapnia may cause or worsen respiratory acidosis (resulting in a reduced pH and markedly increased PaCO₂).

Nonetheless, oxygen must be administered to patients who are hypoxemic (oxygen saturation of less than 88% to 90%), even if respiratory acidosis occurs. Supplemental oxygen must not be withdrawn if respiratory acidosis develops, but other interventions, such as noninvasive ventilation (bilevel positive airway pressure [BiPAP]) or mechanical ventilation, must be added to reverse the respiratory acidosis.

• ;Patients with progressive respiratory acidosis, impending respiratory failure, or markedly increased work of breathing resulting from an acute exacerbation usually benefit from BiPAP. At least 6 randomized controlled trials and multiple uncontrolled trials have demonstrated success rates of 80% to 85% with BiPAP in reducing intubation rates, nosocomial infections, and mortality in patients with acute exacerbations of COPD.^10-12

BiPAP should not be used in patients with respiratory failure associated with severe pneumonia, acute respiratory distress syndrome, or sepsis, because it has been associated with increased mortality in these patients. However, BiPAP is a very good option for respiratory failure associated with an acute exacerbation.¹²

• ;Systemic corticosteroids (prednisone) should be used for moderate to severe acute exacerbations.^10,11 The optimal dosage and duration of therapy have not been clearly defined because most of the trials have been performed in inpatients. One randomized controlled trial demonstrated improved outcomes in outpatients with acute exacerbations who were treated with 40 mg of prednisone for 10 days.¹³

A prolonged course (8 weeks) is as effective as a 2-week course, but the longer course is associated with many more adverse effects.¹⁴ Therefore, many experts recommend prescribing relatively low doses of prednisone (30 to 40 mg) for 7 to 14 days.¹⁵

What not to do: Interventions that are not helpful

• ;Measurement of peak expiratory flow rates or spirometry in patients with acute exacerbations is not indicated and is not helpful in assessing the severity of exacerbations or the response to therapy.^10,11 In contrast, these measurements are very important in patients with acute exacerbations of asthma.

• ;Mucolytics, such as acetylcysteine, are not beneficial in patients with acute exacerbations of COPD and may be associated with significant bronchospasm.^10,11

• ;Chest physiotherapy (percussion and postural drainage) has no role in patients with acute exacerbations of COPD.^10,11

Areas that remain controversial

In the management of acute exacerbations of COPD, 2 topics remain particularly controversial:

• ;Risk factors for treatment failure and/or relapse (defined as treatment failure requiring a return visit within 14 days of the index visit) and how to use risk factors to direct therapy.

• ;Antibiotic choices, which include when to prescribe an antibiotic and which specific agent to use.

Predicting treatment failure or relapse: Relapses or treatment failures occur in 15% to 25% of patients and are associated with high morbidity, such as significantly worse quality of life, need for hospitalization, need for intubation, and a prolonged clinical course.^16-19 Developing a scheme to accurate- ly stratify patients according to their risk of relapse is important, but unfortunately, the proposed schemes published thus far are not sensitive or specific for predicting which patients will experience treatment failure or relapse.^10,11

Some of the risk factors that have been associated with relapse include age over 65 years; 4 or more previous acute exacerbations within the past year; cardiovascular comorbidities, particularly CHF or ischemic heart disease; and low (less than 50% of predicted) forced expiratory volume in 1 second (FEV₁).^7,8 Other risk factors that have been suggested by some investigators include previous relapse, need for long-term supplemental oxygen, diagnosed COPD of more than 10 years' duration, severe hypoxemia and hypercapnia, and requirement of multiple doses of bronchodilators at the time of diagnosis.^10,11

Antibiotic therapy: The most controversial aspect of treating patients with acute exacerbations is the optimal use and choice of antibiotics. Bacterial infections can be identified in approximately 50% of these patients.²⁰ Factors such as pollutants, viruses, allergens, atypical infections, and other noxious stimuli also contribute to acute exacerbations. Some episodes resolve spontaneously and do not require treatment with antibiotics.²⁰ However, in general, there are no reliable criteria to distinguish definitively between episodes that are caused by bacterial infection and those that are not.

The available evidence supports the use of antibiotics in patients with 2 or 3 of the symptoms of an exacerbation: increased shortness of breath, increased sputum production, and sputum purulence.^5,10,11 One major problem with the evidence is that most of the trials of antibiotics versus placebo were performed before 1990, before the development of significant antimicrobial resistance. Therefore, most of the recommendations regarding the use of antibiotics are based on expert opinion.^6-8

The most common bacteria associated with acute exacerbations of COPD are Streptococcus pneumoniae,Haemophilus influenzae, and Moraxella catarrhalis. However, some data suggest that patients with severe or very severe COPD are at greater risk for infections caused by Gram-negative organisms, such as Klebsiella pneumoniae, Pseudomonas aeruginosa, and Stenotrophomonas.^21,22

Does it matter which antibiotic is used? One study retrospectively evaluated the differences in outcomes of patients with acute exacerbations who received first-line (amoxicillin, trimethoprim-sulfamethoxazole, erythromycin, or tetracycline) versus third-line (amoxicillin-clavulanate, azithromycin, or ciprofloxacin) antibiotics.²³ Patients who received the third-line antibiotics had significantly better outcomes, including lower failure rates (7% vs 20%), prolonged disease-free interval (34 vs 17 weeks from initial exacerbation to the next exacerbation), and lower overall cost ($542 vs $942) than patients treated with one of the first-line antibiotics.

Another retrospective study demonstrated that overall, patients who received antibiotics had lower relapse rates (19%) than those who did not receive antibiotics (32%).¹⁶ However, patients who received amoxicillin had even higher relapse rates (54%) than those who did not receive any antibiotics (32%).

One of the most reasonable approaches is based on using certain clinical criteria to risk-stratify patients with COPD.^7-9 One such approach stratifies patients into 4 groups as follows:

Group 1 includes previously healthy patients without significant underlying lung disease (near-normal FEV₁) who present with acute respiratory symptoms. These patients most likely have a post-viral tracheobronchitis and usually do not require antibiotics. One study compared azithromycin with vitamin C in such patients and was prematurely stopped by the data safety monitoring committee because the interim analysis did not demonstrate any differences in outcomes such as time to return to normal activities and health-related quality of life.²⁴ Therefore, antibiotics are not indicated in patients stratified to group 1.^7-9

Patients in group 2 account for the majority of patients seen by primary care providers (more than 70% of patients who present with acute exacerbations of COPD) and include those who have had fewer than 4 exacerbations within the previous year, have no significant cardiovascular comorbidities, and have an FEV₁ of greater than 50% of predicted. These patients most likely have a typical bacterial infection and may be treated with one of the newer macrolides (azithromycin, clarithromycin, or dirithromycin), a ketolide (telithromycin), a newer cephalosporin, or doxycycline (Table).^7-9

Groups 3 and 4 include patients (usually fewer than 15% of those with acute exacerbations) who are older than 65 years, have had 4 or more exacerbations within the previous year, have an FEV₁ of less than 50% of predicted, or have significant cardiac comorbidities (CHF or ischemic heart disease). These patients are at higher risk for relapse or for antibiotic resistance and, therefore, treatment with amoxicillin-clavulanate or a fluoroquinolone may be considered.^7-9

References:

REFERENCES

1. Mannino DM, Homa DM, Akinbami LJ, et al. Chronic obstructive pulmonary disease surveillance--United States, 1971-2000.

MMWR.

2002;51(6):1-16.
2. Connors AF Jr, Dawson NV, Thomas C, et al. Outcomes following acute exacerbation of severe chronic obstructive lung disease. The SUPPORT investigators (Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments) [published correction appears in

Am J Respir Crit Care Med.

1997;155:386].

Am J Respir Crit Care Med.

1996;154:959-967.
3. Niederman MS , McCombs JS, Unger AN, et al. Treatment cost of acute exacerbations of chronic bronchitis.

Clin Ther.

1999;21:576-591.
4. Seneff MG, Wagner DP, Wagner RP, et al. Hospital and 1-year survival of patients admitted to intensive care units with acute exacerbation of chronic obstructive pulmonary disease.

JAMA.

1995;274:1852-1857.
5. Anthonisen NR, Manfreda J, Warren CP, et al. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease.

Ann Intern Med.

1987;106:196-204.
6. Celli BR, MacNee W, ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper

. Eur Respir J.

2004;23:932-946.
7. Balter MS, Hyland RH, Low DE, et al. Recommendations on the management of chronic bronchitis: a practical guide for Canadian physicians [abstract].

Can Med Assoc J. 1994; 151(suppl 10):5-23.
8. Balter MS, La Forge J, Low DE, et al; Chronic Bronchitis Working Group; Canadian Thoracic Society; Canadian Infectious Disease Society. Canadian guidelines for the management of acute exacerbations of chronic bronchitis: executive summary. Can Respir J.2003;10:248-258.
9. Balter MS, La Forge J, Low DE, et al; Canadian Thoracic Society; Canadian Infectious Disease Society. Canadian guidelines for the management of acute exacerbations of chronic bronchitis. Can Respir J.2003;10(suppl B):3B-32B.
10. Bach PB, Brown C, Gelfand SE, McCrory DC; American College of Physicians-American Society of Internal Medicine; American College of Chest Physicians. Management of acute exacerbations of chronic obstructive pulmonary disease: a summary and appraisal of published evidence. Ann Intern Med.2001;134:600-620.
11. Snow V, Lascher S, Mottur-Pilson C; Joint Expert Panel on Chronic Obstructive Pulmonary Disease of the American College of Chest Physicians and the American College of Physicians-American Society of Internal Medicine. Evidence base for management of acute exacerbations of chronic obstructive pulmonary disease. Ann Intern Med.2001;134: 595-599.
12. Girou E, Brun-Buisson C, Taille S, et al. Secular trends in nosocomial infections and mortality associated with noninvasive ventilation in patients with exacerbation of COPD and pulmonary edema. JAMA. 2003;290:2985-2991.
13. Aaron SD, Vandemheen KL, Hebert P, et al. Outpatient oral prednisone after emergency treatment of chronic obstructive pulmonary disease. N Engl J Med. 2003;348: 2618-2625.
14. Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group. N Engl J Med.1999;340:1941-1947.
15. Pauwels RA, Buist AS, Calverley PM, et al; GOLD Scientific Committee. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med.2001;163:1256-1276.
16. Adams SG, Melo J, Luther M, Anzueto A. Antibiotics are associated with lower relapse rates in outpatients with acute exacerbations of COPD. Chest.2000;117:1345-1352.
17. Murata GH, Gorby MS, Chick TW, Halperin AK. Use of emergency medical services by patients with decompensated obstructive lung disease. Ann Emerg Med. 1989;18:501-506.
18. Murata GH, Gorby MS, Kapsner CO, et al. A multivariate model for the prediction of relapse after outpatient treatment of decompensated chronic obstructive pulmonary disease. Arch Intern Med.1992;152:73-77.
19. Ball P, Harris JM, Lowson D, et al. Acute infective exacerbations of chronic bronchitis. QJM. 1995;88:61-68.
20. Murphy TF, Sethi S. Bacterial infection in chronic obstructive pulmonary disease. Am Rev Respir Dis.1992;146:1067-1083.
21. Eller J, Ede A, Schaberg T, et al. Infective exacerbations of chronic bronchitis: relation between bacteriologic etiology and lung function. Chest.1998;113:1542-1548.
22. Miravitlles M, Espinosa C, Fernandez-Laso E, et al. Relationship between bacterial flora in sputum and functional impairment in patients with acute exacerbations of COPD. Study Group of Bacterial Infection in COPD. Chest.1999;116:40-46.
23. Destache CJ, Dewan N, O'Donohue WJ, et al. Clinical and economic considerations in the treatment of acute exacerbations of chronic bronchitis. J Antimicrob Chemother. 1999;43(suppl A):107-113.
24. Evans AT, Husain S, Durairaj L, et al. Azithromycin for acute bronchitis: a randomised, double-blind, controlled trial. Lancet.2002;359:1648-1654.