032102 acute exacerbations of chronic obstructive pulmonary disease

The Ne w E n g l a nd Jo u r n a l o f Me d i c i ne This Journal feature begins with a case vignette highlighting median rates of 2.4 and 3 episodes per year in two a common clinical problem. Evidence supporting various recent series10,11). Furthermore, active smokers have strategies is then presented, followed by a review of formal more frequent exacerbations than nonsmokers; stop- guidelines, when they exist. The article ends with the author’s ping smoking can reduce the frequency by approxi- mately one third.12 Data reported in 1996 on 1016 pa-tients who were hospitalized for acute exacerbations,13 half of whom required intensive care, demonstrated an CUTE EXACERBATIONS OF CHRONIC
in-hospital mortality rate of 11 percent, and six-month OBSTRUCTIVE PULMONARY DISEASE
and one-year mortality rates of 33 percent and 43 per-cent, respectively. Those who survived the first hos- pitalization had a 50 percent rate of rehospitalizationwithin six months after discharge.
A 68-year-old former heavy smoker with a his- STRATEGIES AND EVIDENCE
tory of chronic obstructive pulmonary disease(COPD) presents to the emergency room with a Overview
two-day history of worsened dyspnea and in- The optimal treatment of an outpatient with an creased purulence and volume of phlegm. Chest acute exacerbation of COPD involves diagnostic as- radiography shows hyperinflation and no acute sessment and use of bronchodilators, systemic corti- infiltrates. Measurement of arterial blood gases costeroids, and antibiotics; for patients who are sick while the patient is breathing room air shows enough to be hospitalized, oxygen and mechanical acute respiratory acidosis. How should this pa- ventilation may also be used. The types and dosages of some commonly used medications for an acute ex-acerbation of COPD are presented in Table 1.
Diagnostic Assessment
COPD, which is characterized by a fixed obstruc- tion of the airway caused by emphysema, chronic For patients assessed in the emergency department bronchitis, or both, is a common and growing clinical or hospital, chest radiography is recommended be- problem that is responsible for a substantial worldwide cause it reveals abnormalities that prompt a change in short-term treatment in 16 percent to 21 percent in the United States and at least 52 million worldwide, of cases. Spirometry is infrequently performed in hos- and it accounted for 2.74 million deaths in 2000.
pitalized patients with acute exacerbations of COPD, In the United States, COPD is now the fourth lead- although observational studies of patients in the emer- ing cause of death2-4 and is the only leading cause of gency department suggest that a forced expiratory vol- death for which the mortality rate is currently increas- ume in one second (FEV ) that is less than 40 percent ing. COPD has been estimated to account for more of the predicted value has a sensitivity of 96 percent than 16 million office visits and 500,000 hospitaliza- for predicting relapse or the need for hospitalization17; tions annually in the United States. Costs attributable hypercapnia is unlikely when the FEV exceeds 35 per- to this condition totaled $30.4 billion in 1995, with $14.7 billion spent directly on health care.2,3,7 Acute exacerbations of COPD are variously defined Although it has been relatively unstudied (perhaps but are characterized by worsened dyspnea and in- because of its evident benefit), supplemental oxygen creased volume of phlegm, purulence of phlegm, or should be included in the initial therapy for a flare of both. They are often accompanied by hypoxemia and COPD associated with hypoxemia; oxygen is usually worsened hypercapnia.8-10 Available series data suggest administered by nasal cannula or through a face mask that patients have such exacerbations regularly (e.g., equipped to control the inspired oxygen fraction. Tar-get oxygen saturation values are 90 to 92 percent, with From the Division of Medicine and the Section of Respiratory Therapy, corresponding target values for partial pressure of ar- Department of Pulmonary and Critical Care Medicine, Cleveland Clinic terial oxygen (PaO ) of 60 to 65 mm Hg. These tar- Foundation, Cleveland. Address reprint requests to Dr. Stoller at the De- gets ensure near-maximal hemoglobin saturation while partment of Pulmonary and Critical Care Medicine, A90, Cleveland ClinicFoundation, 9500 Euclid Ave., Cleveland, OH 44195, or at [email protected].
lessening the likelihood of the hypercapnia that can 988 · N Engl J Med, Vol. 346, No. 13 · March 28, 2002 · www.nejm.org
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2 tablets first day, then1 tablet/day for 5 to 10 days *Quaternary ammonium anticholinergic agents (e.g., ipratropium, glycopyrrolate) are preferred to tertiary ammonium compounds (e.g., atropine) because they have fewer side effects.
†Aminophylline is sometimes administered after a loading dose; the dose should be determined on the basis of serum ‡The dose varies among and within patients.
§Recommendations are according to Saint et al.14 ¶According to Anthonisen et al.,8 all should be 10-day courses.
accompany the use of supplemental oxygen.19 Al- of COPD. Specifically, the administration of a bron- though the cause of such hypercapnia can be multi- chodilator can increase the FEV and the forced vital factorial, increased inhomogeneity of ventilation and capacity (FVC) by 15 to 29 percent over a period of perfusion accompanied by increased dead-space ven- 60 to 120 minutes.20-23 Beta-adrenergic agonists have tilation appears to be more important than decreased not been shown to be superior to anticholinergic alveolar ventilation caused by the suppression of the agents.7,20-23 Factors such as the time to peak effect (which is slightly more rapid with beta-adrenergic ago-nists) and the frequency of adverse effects (which are Bronchodilators
generally fewer and milder with ipratropium bromide) Substantial evidence shows that both inhaled beta- may influence the choice of agent for a given patient.
adrenergic agonists (for example, albuterol, fenoterol, Data from randomized clinical trials have not shown metaproterenol, and terbutaline) and anticholinergic a benefit of the combined use of beta-adrenergic ago- agents (including ipratropium bromide and glycopyr- nists and anticholinergic agents over therapy with ei- rolate) can improve airflow during acute exacerbations ther class alone. A recent meta-analysis22 supports a N Engl J Med, Vol. 346, No. 13 · March 28, 2002 · www.nejm.org · 989
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The Ne w E n g l a nd Jo u r n a l o f Me d i c i ne strategy of initial use of an inhaled anticholinergic not been useful,8 and sputum culture has generally agent, with subsequent addition of a beta-adrenergic been reserved for patients with no response to initial agonist only if it is needed despite the use of maximal empirical therapy directed at the common causal doses of the anticholinergic medication. However, this pathogens (e.g., Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae). Without de- The benefits of using a methylxanthine drug such finitive data regarding the optimal duration of therapy, as aminophylline as an additional bronchodilator re- most clinicians prescribe courses of 5 to 10 days.
main unclear. In three randomized, controlled tri-als,7,20,24-26 the addition of intravenous aminophylline Corticosteroids
did not result in improvements on tests of pulmonary Several randomized, placebo-controlled trials7,19 function, produce apparent clinical benefit, or reduce have demonstrated that systemic corticosteroids accel- the likelihood of a return to the emergency depart- erate improvement in airflow, gas exchange, and symp- ment during the succeeding week. Furthermore, ami- toms and reduce the rate of treatment failure. In the nophylline was associated with an increased rate of largest of these trials,29 271 hospitalized veterans were adverse effects, especially nausea and vomiting.25 How- randomly assigned to receive a 3-day course of intra- ever, in one study, patients treated with aminophyl- venous methylprednisolone (125 mg every six hours) line in the emergency department had a hospitaliza- or placebo, and the recipients of corticosteroids were tion rate that was 70 percent lower than that in a further assigned to have the dose of oral prednisone tapered over the course of either 15 days or 8 weeks.
Equivalent bronchodilation appears to be achieved Patients who received corticosteroids had an FEV that with the use of metered-dose inhalers or nebulizers.27 was slightly but significantly higher (by 0.1 liter) than Because metered-dose inhalers cost less than nebuliz- that in the placebo group on day 1. Other benefits ers, but are frequently ineffective during respiratory associated with corticosteroid use were a lower rate distress, it is reasonable to initiate therapy with nebu- of treatment failure at 30 and 90 days and a shorter lizers and then switch to metered-dose inhalers when hospital stay. The difference in FEV between the cor- ticosteroid group and the placebo group was no long-er significant at 2 weeks, and outcomes were no better Antibiotics
with an 8-week course of corticosteroids than with Bacterial infection may contribute to acute exac- erbations of COPD. Two recent meta-analyses of 11 The optimal duration of corticosteroid therapy for randomized, placebo-controlled trials of antibiotics an acute exacerbation of COPD remains uncertain, but for acute exacerbations of COPD support their use recent data support a course of 5 to 10 days.30-32 Spe- when there is purulent sputum.14,20 Pooled data from cifically, in a randomized trial comparing oral prednis- six trials that evaluated peak expiratory flow rates olone (a two-week regimen of 30 mg per day) with showed a mean increase in the peak expiratory flow placebo, the FEV improved through day 5 more in rate of 10.75 liters per minute, in contrast to the de- the corticosteroid group than in the placebo group.30 crease in peak expiratory flow rate that has been ob- In a more recent study comparing a 3-day regimen served during an acute flare.11 In the largest trial from with a 10-day regimen of intravenous methylprednis- which the results are available, symptoms resolved olone in hospitalized patients,31 improvements in FEV1 within 21 days in 68 percent of the patients who re- and PaO were evident after 3 days of therapy, but the ceived antibiotics, as compared with 55 percent of 10-day course was associated with greater improve- ment in FEV , FVC, and PaO , as well as with more Antibiotics appear to be most useful in patients with rapid resolution of symptoms. No difference was ob- severe exacerbations. For example, in a randomized served in the rate of recurrence at six months.
trial involving 173 patients who were assigned to a10-day course of doxycycline, trimethoprim–sulfa- Noninvasive Positive-Pressure Ventilation
methoxazole, or amoxicillin,8 patients with more se- Enhancing ventilation by unloading fatigued ven- vere exacerbations (as assessed in terms of worsened tilatory muscles is an important treatment goal in the dyspnea and the purulence and volume of phlegm) re- case of an acute exacerbation of COPD that is compli- ceived greater benefit from treatment than those with cated by respiratory failure. In six of seven randomized, controlled trials of positive-pressure ventilation with- Although concern about resistant flora has prompt- out intubation, patients who received this type of ther- ed some to advocate the initial use of broader-spec- apy had better outcomes than those who did not.33-35 trum antibiotics, there have been no definitive studies Benefits included lower rates of intubation, lower in- supporting the first-line use of newer, more expensive hospital mortality rates, accelerated symptomatic and antibiotics. Gram’s staining of sputum has generally physiological improvement, and shorter hospital stays.
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Noninvasive positive-pressure ventilation33,36-38 SUMMARY AND RECOMMENDATIONS
should be considered when there is a need for ventila- My approach to treating the patient with an acute tory assistance, as indicated by such symptoms as wor- exacerbation of COPD is as follows. For patients sened dyspnea, acute respiratory acidosis, and wor- who present to the emergency department or who sened oxygenation (e.g., a ratio of PaO to the fraction are deemed sick enough to be hospitalized, diagnostic of inspired oxygen of less than 200). Patients unlikely assessment includes chest radiography and, if the pa- to benefit from noninvasive positive-pressure ventila- tient’s distress or somnolence prompts concern about tion include those with respiratory arrest, medical in- acute respiratory acidemia, measurement of arterial stability (e.g., hypotensive shock or uncontrolled car- blood gases. Initial therapy includes supplemental oxy- diac ischemia), an inability to protect the airway, gen, usually through a face mask to ensure an oxyhe- excessive secretions, agitation or uncooperativeness, moglobin saturation, measured by pulse oximetry, of or conditions that preclude the placement of a mask 90 to 92 percent. For both inpatients and outpatients, or the achievement of a proper fit. Although there has combined bronchodilator therapy should be used, been some concern to the contrary, management of with ipratropium bromide and albuterol administered noninvasive positive-pressure ventilation does not re- every four to six hours initially; nebulizers are recom- quire more of health care providers’ time and does not mended whenever the patient’s distress level raises cost more than the treatment of intubated patients.36-40 doubt about the effective use of a metered-dose in-haler. As the condition improves and the distress level AREAS OF UNCERTAINTY
is reduced, metered-dose inhalers can be used in place Better methods are needed to encourage smoking of nebulizers. Since many patients do not use their cessation, since smoking is a key causative factor in inhalers appropriately, spacer devices should be pre- COPD. More attention to detecting and treating scribed and appropriate techniques should be re- alpha -antitrypsin deficiency is also needed.41 In ad- dition, standards are needed for the definition of an On the basis of data from a randomized trial,8 a 10- acute exacerbation of COPD and for the stratification day course of a narrow-spectrum antibiotic (e.g., tri- of risk. The optimal bronchodilator regimen and route methoprim–sulfamethoxazole, doxycycline, or amox- of delivery remain uncertain, especially with the advent icillin) should be prescribed when there is increased of new drugs (e.g., tiotropium). The role of broader- dyspnea and increased purulence and volume of spectrum antibiotics and guidelines for their use, and phlegm. Sputum staining and cultures are reserved for the indications for noninvasive positive-pressure ven- cases that are refractory to antibiotic therapy. Oral sys- tilation, especially outside the intensive care unit, re- temic corticosteroids are prescribed both for outpa- tients (tapering over the course of eight days, begin-ning with 40 mg per day and decreasing the dose by GUIDELINES
10 mg every other day) and for inpatients (Table 1).29 Five sets of guidelines for managing acute exacerba- Given the lack of evidence to support the usefulness tions of COPD have been issued by five widely recog- of chest physiotherapy or mucokinetic drugs, neither nized professional societies and health organizations of these should be routinely prescribed.
since 1994: the European Respiratory Society,5 the For eligible patients with acute respiratory acidemia, British Thoracic Society,6 the American Thoracic So- bilevel noninvasive positive-pressure ventilation should ciety,1 a joint panel of the American College of Chest be implemented for multiple-hour stretches, with oc- Physicians and the American College of Physicians– casional interruption, during the first several days of American Society of Internal Medicine,20-22 and a joint hospitalization. Such ventilation is initially adminis- panel of the National Heart, Lung, and Blood Insti- tered in the intensive care unit to ensure close mon- tute and the World Health Organization (known as itoring and ready access to intubation and mechanical the Global Initiative for Chronic Obstructive Lung ventilation, should the trial of noninvasive positive- Disease, or GOLD).2 These guidelines, summarized in Table 2, are similar in many respects; most (includ- For patients who present for the first time with an ing those proposed by GOLD) endorse a short course exacerbation of underlying COPD, recovery from of systemic corticosteroids and antibiotics for severe the acute episode provides an opportunity to discuss exacerbations and the use of noninvasive ventilation for smoking cessation, to explore the possibility of alpha - exacerbations complicated by acute ventilatory failure.
antitrypsin deficiency, to vaccinate the patient against Unlike some of the guidelines, those from GOLD fa- pneumococcus and influenza, and to consider referral vor beta-adrenergic agonists as first-line bronchodilator to a pulmonary rehabilitation program. For patients therapy, recommend adding an anticholinergic agent who require hospitalization, an outpatient follow-up if there is no response to the beta-adrenergic agonist, visit should be scheduled for four to eight weeks after and endorse consideration of a methylxanthine drug.
hospital discharge. Spirometry should be performed N Engl J Med, Vol. 346, No. 13 · March 28, 2002 · www.nejm.org · 991
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after the administration of a bronchodilator, and the patient’s need for supplemental oxygen both while at rest and during activity should be reassessed. Bron- chodilator therapy should be continued over the long term, with the addition of an inhaled corticosteroid reserved for patients in whom the obstruction of air- flow has been demonstrated to be reversible (e.g., those who have an increase of at least 12 percent and 200 ml in the FEV after the use of a bronchodilator) and patients who have frequent exacerbations.
Given this approach, the short-term treatment of the patient described in the vignette should include admission to the hospital because of acute respiratory acidemia, and the administration of a combination of bronchodilators, a limited-spectrum antibiotic, and in- travenous corticosteroids. Unless there is rapid rever- sal of acidemia, bilevel noninvasive positive-pressure REFERENCES
1. American Thoracic Society. Standards for the diagnosis and care of pa-
tients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995;152:Suppl:S77-S121. (Also available at http://www.thoracic.org.) 2. Pauwels RA, Buist AS, Calverley PMA, Jenkins CR , Hurd SS. Global
strategy for the diagnosis, management, and prevention of chronic obstruc- tive pulmonary disease: NHLBI/WHO Global Initiative for Chronic Ob- structive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001;163:1256-76. (Also available at http://www.goldcopd.com.) 3. Fact sheet: chronic obstructive pulmonary disease (COPD). New York:
American Lung Association, January 2001. (Accesssed January 28, 2002, at http://www.lungusa.org/pub/minority/copd-00.html.) 4. Statistical abstract of the United States, 2000. Washington, D.C.:
5. Siafakas NM, Vermeire P, Pride NB, et al. Optimal assessment and man-
agement of chronic obstructive pulmonary disease (COPD). Eur Respir J 6. The COPD Guidelines Group of the Standards of Care Committee of
the BTS. BTS guidelines for the management of chronic obstructive pul- monary disease. Thorax 1997;52:Suppl 5:S1-S28.
7. Sherk PA, Grossman RF. The chronic obstructive pulmonary disease ex-
acerbation. Clin Chest Med 2000;21:705-21.
8. Anthonisen NR , Manfreda J, Warren CPW, Hershfield ES, Harding
GK, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 1987;106:196-204.
9. Rodriguez-Roisin R. Toward a consensus definition for COPD exacer-
bations. Chest 2000;117:Suppl 2:398S-401S.
10. Seemungal TAR , Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha
JA. Time course and recovery of exacerbations in patients with chronic ob- structive pulmonary disease. Am J Respir Crit Care Med 2000;161:1608- 11. Seemungal TAR , Donaldson GC, Paul EA, Bestall JC, Jeffries DJ,
Wedzicha JA. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 12. Kanner RE, Anthonisen NR , Connett JE. Lower respiratory illnesses
promote FEV1 decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease: results from the Lung Health Study. Am J Respir Crit Care Med 2001;164:358-64.
13. Connors AF Jr, Dawson NV, Thomas C, et al. Outcomes following
acute exacerbation of severe chronic obstructive lung disease. Am J Respir Crit Care Med 1996;154:959-67. [Erratum, Am J Respir Crit Care Med 14. Saint S, Bent S, Vittinghoff E, Grady D. Antibiotics in chronic ob-
structive pulmonary disease exacerbations: a meta-analysis. JAMA 1995; 15. Emerman CL, Cydulka RK. Evaluation of high-yield criteria for chest
radiography in acute exacerbation of chronic obstructive pulmonary dis- 16. Tsai TW, Gallagher EJ, Lombardi G, Gennis P, Carter W. Guidelines
N Engl J Med, Vol. 346, No. 13 · March 28, 2002 · www.nejm.org · 993
Downloaded from www.nejm.org at SOROKA MEDICAL CENTER on September 19, 2003.
Copyright 2002 Massachusetts Medical Society. All rights reserved.
The Ne w E n g l a nd Jo u r n a l o f Me d i c i ne for the selective ordering of admission chest radiography in adult obstruc- 30. Davies L, Angus RM, Calverley PM. Oral corticosteroids in patients
tive airway disease. Ann Emerg Med 1993;22:1854-8.
admitted to hospital with exacerbation of chronic obstructive pulmonary 17. Emerman CL, Effron D, Lukens TW. Spirometric criteria for hospital
disease: a prospective randomised controlled trial. Lancet 1999;354:456- admission of patients with acute exacerbation of COPD. Chest 1991;99: 31. Sayiner A, Aytemur ZA, Cirit M, Unsal I. Systemic glucocorticoids in
18. Emerman CL, Connors AF, Lukens TW, Effron D, May ME. Rela-
severe exacerbations of COPD. Chest 2001;119:726-30.
tionship between arterial blood gases and spirometry in acute exacerba- 32. Stanbrook MB, Goldstein RS. Steroids for acute exacerbations of
tions of chronic obstructive pulmonary disease. Ann Emerg Med 1989;18: COPD: how long is enough? Chest 2001;119:675-6.
33. Mehta S, Hill NS. Noninvasive ventilation. Am J Respir Crit Care Med
19. Aubier M, Murciano D, Milic-Emili J, et al. Effects of administration
of O on ventilation and blood gases in patients with chronic obstructive 34. Keenan SP, Kernerman PD, Cook DJ, Martin CM, McCormack D,
pulmonary disease during acute respiratory failure. Am Rev Respir Dis Sibbald WJ. Effect of noninvasive positive pressure ventilation on mortality in patients admitted with acute respiratory failure: a meta-analysis. Crit 20. McCrory DC, Brown C, Gelfand SE, Bach PB. Management of exac-
erbations of COPD: a summary and appraisal of the published evidence. 35. Plant PK, Owen JL, Elliott MW. Early use of non-invasive ventilation
for acute exacerbations of chronic obstructive pulmonary disease on gen- 21. Bach PB, Brown C, Gelfand SE, McCrory DC. Management of exac-
eral respiratory wards: a multicentre randomised controlled trial. Lancet erbations of chronic obstructive pulmonary disease: a summary and ap- praisal of published evidence. Ann Intern Med 2001;134:600-20.
36. International consensus conferences in intensive care medicine: nonin-
22. Snow V, Lascher S, Mottur-Pilson C. Evidence base for management
vasive positive pressure ventilation in acute respiratory failure. Am J Respir of acute exacerbations of chronic obstructive pulmonary disease. Ann In- 37. American Association for Respiratory Care. Consensus Conference IV
23. Ferguson GT. Recommendations for the management of COPD.
(noninvasive positive pressure ventilation): preamble and consensus state- 24. Wrenn K, Slovis CM, Murphy F, Greenberg RS. Aminophylline ther-
38. Clinical indications for noninvasive positive pressure ventilation in
apy for acute bronchospastic disease in the emergency room. Ann Intern chronic respiratory failure due to restrictive lung disease, COPD, and noc- turnal hypoventilation — a consensus conference report. Chest 1999;116: 25. Rice KL, Leatherman JW, Duane PG, et al. Aminophylline for acute
exacerbations of chronic obstructive pulmonary disease: a controlled trial. 39. Kramer N, Meyer TJ, Meharg J, Cece RD, Hill NS. Randomized, pro-
spective trial of noninvasive positive pressure ventilation for acute exacer- 26. Seidenfeld JJ, Jones WN, Moss RE, Tremper J. Intravenous amino-
bations of COPD. Am J Respir Crit Care Med 1995;151:1799-806.
phylline in the treatment of acute bronchospastic exacerbations of chronic 40. Nava S, Evangelisti I, Rampulla C, Campagnoni ML, Fracchia C, Ru-
obstructive pulmonary disease. Ann Emerg Med 1984;13:248-52.
bini F. Human and financial costs of noninvasive mechanical ventilation in 27. Turner MO, Patel A, Ginsburg S, FitzGerald JM. Bronchodilator de-
patients affected by COPD and acute respiratory failure. Chest 1997;111: livery in acute airflow obstruction — a meta-analysis. Arch Intern Med 41. Stoller JK. Clinical features and natural history of severe alpha 1-anti-
28. Stoller JK, Lange PA. Inpatient management of chronic obstructive
trypsin deficiency: Roger S. Mitchell Lecture. Chest 1997;111:Suppl:123S- pulmonary disease. Respir Care Clin N Am 1998;4:425-38.
29. Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic
glucocorticoids on exacerbations of chronic obstructive pulmonary disease.
N Engl J Med 1999;340:1941-7.
Copyright 2002 Massachusetts Medical Society.
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