INTRODUCTION — The Global Initiative for Chronic Obstructive Lung Disease (GOLD) - a report produced by the National Heart, Lung, and Blood Institute (NHLBI) and the World Health Organization (WHO) - defines an exacerbation of chronic obstructive pulmonary disease (COPD) as an acute increase in symptoms beyond normal day-to-day variation [1]. This generally includes an acute increase in one or more of the following cardinal symptoms:
- Cough increases in frequency and severity
- Sputum production increases in volume and/or changes character
- Dyspnea increases
Constitutional symptoms, an unchanged chest radiograph, a variable decrease in pulmonary function, and tachypnea are typical in acute exacerbations [1,2]. However, severe cases can lead to respiratory failure and death.
The management of patients with acute exacerbations of COPD is discussed in detail here. The diagnosis and treatment of infection in acute exacerbations, and the management of stable COPD are discussed separately. (See "Diagnosis and treatment of infection in acute exacerbations of chronic obstructive pulmonary disease" and "Management of stable chronic obstructive pulmonary disease".)
PRECIPITANTS — It is estimated that 50 to 60 percent of exacerbations are due to respiratory infections (mostly bacterial and viral), 10 percent are due to environmental pollution, and 30 percent are of unknown etiology [3,4]. (See "Diagnosis and treatment of infection in acute exacerbations of chronic obstructive pulmonary disease".)
Some COPD exacerbations of unknown etiology may be related to other medical conditions, such as myocardial ischemia, heart failure, aspiration, or pulmonary embolism [1,5]. The relationship between COPD exacerbation and pulmonary embolism was illustrated by a meta-analysis of five observational studies [6]. Among the 550 patients having a COPD exacerbation, the prevalence of pulmonary embolism was 20 percent. The prevalence was even higher (25 percent) among those hospitalized. An important limitation of the meta-analysis was its inability to determine whether the pulmonary embolism was the cause of the COPD exacerbation, a result of the COPD exacerbation, or a mere bystander.
RISK FACTORS — According to observational studies, the risk of developing an exacerbation of COPD correlates with advanced age, productive cough, duration of COPD, antibiotic therapy, COPD-related hospitalization within the previous year, chronic mucous hypersecretion, theophylline therapy, and having one or more comorbidities (eg, ischemic heart disease, chronic heart failure, or diabetes mellitus) [7-10]. In contrast, a high forced expiratory volume in one second (FEV1) is associated with a lower risk of COPD exacerbation.
Gastroesophageal reflux disease (GERD) may be an additional risk factor for COPD exacerbations. In a prospective study, the presence of GERD symptoms and frequency of COPD exacerbations were assessed in 80 patients with COPD. The presence of GERD symptoms was associated with an increased occurrence of COPD exacerbations (RR 6.55, 95% CI 1.86 to 23.11) [11]. Additional studies are needed to confirm this observation.
INITIAL EVALUATION — Initial evaluation of a patient with a suspected exacerbation of COPD includes a medical history, physical examination, chest radiograph, and routine laboratory studies. Arterial blood gas analysis should be performed in most patients to assess the severity of the exacerbation and to establish a baseline from which improvement or deterioration can be measured. Sputum examination, which is also part of the evaluation, is discussed separately. (See "Diagnosis and treatment of infection in acute exacerbations of chronic obstructive pulmonary disease".)
The patient must be triaged to inpatient or outpatient management following initial evaluation. Several criteria for hospitalization were proposed in a 2004 position paper from the American Thoracic Society/European Respiratory Society (ATS/ERS) [2]:
- Inadequate response of symptoms to outpatient management
- Marked increase in dyspnea
- Inability to eat or sleep due to symptoms
- Worsening hypoxemia
- Worsening hypercapnia
- Changes in mental status
- Inability to care for oneself (ie, lack of home support)
- Uncertain diagnosis
- High risk comorbidities including pneumonia, cardiac arrhythmia, congestive heart failure, diabetes mellitus, renal failure, or liver failure
In addition, there is general consensus that acute respiratory acidosis justifies hospitalization.
Many triage decisions are made by the emergency department. One study identified the following as risk factors for relapse after discharge from the emergency department: a greater number of doses of nebulized bronchodilator required in the emergency department, use of theophylline in the emergency department, use of supplemental oxygen at home, an emergency department visit within the past week, prior relapse after an emergency department visit, and prescription of glucocorticoids, antibiotics, or both at the time of emergency department discharge [12].
A number of controlled trials have compared hospitalization with intensive home care, which generally includes nurse visits, home oxygen, and physical therapy [13-17]. A meta-analysis of seven of these trials noted that home care resulted in equivalent clinical outcomes and substantial cost savings compared to hospitalization [18]. However, these trials excluded sicker patients with an impaired level of consciousness, respiratory acidosis (arterial pH <7.35), acute electrocardiographic or chest radiographic changes, or coexisting medical morbidities. Although care at home is feasible in highly selected patients without these characteristics, implementation requires a dedicated support team to conduct ongoing clinical assessments and provide home care.
DIFFERENTIAL DIAGNOSIS — Patients with COPD who present to the hospital with acute worsening of dyspnea should be evaluated for potential alternative diagnoses, such as heart failure, pulmonary thromboembolism, and pneumonia. This was illustrated in an autopsy study of 43 patients with COPD who died within 24 hours of admission for a COPD exacerbation [19]. The primary causes of death were heart failure, pneumonia, pulmonary thromboembolism, and COPD in 37, 28, 21, and 14 percent, respectively.
TREATMENT GOALS — Successful management of acute exacerbations of COPD in either the inpatient or outpatient setting requires attention to a number of key issues [20,21]:
- Identifying and ameliorating the cause of the acute exacerbation, if possible
- Optimizing lung function by administering bronchodilators and other pharmacologic agents
- Assuring adequate oxygenation and secretion clearance
- Averting the need for intubation, if possible
- Preventing complications of immobility, such as thromboemboli and deconditioning
- Addressing nutritional needs
OXYGEN THERAPY — Supplemental oxygen is a critical component of acute therapy. It should target an arterial oxygen tension (PaO2) of 60 to 70 mmHg, with an oxyhemoglobin saturation of 90 to 94 percent [1,22,23].
There are numerous devices available to deliver supplemental oxygen during an acute exacerbation of COPD:
- Venturi masks are the preferred means of oxygen delivery because they permit a precise delivered fraction of inspired oxygen (FiO2). Venturi masks can deliver an FiO2 of 24, 28, 31, 35, 40, or 60 percent.
- Nasal cannulae can provide flow rates up to 6 L per minute with an associated FiO2 of approximately 40 percent (calculator 1). They are more comfortable and convenient for the patient, especially during oral feedings.
- When higher inspired concentrations of oxygen are needed, simple facemasks can provide an FiO2 up to 55 percent using flow rates of 6 to 10 L per minute.
Variations in minute ventilation and inconsistent entrainment of room air affect the FiO2 when nasal cannulae or simple facemasks are used.
- Non-rebreathing masks with a reservoir, one-way valves, and a tight face seal can deliver an inspired oxygen concentration up to 90 percent.
A high FiO2 is not required to correct the hypoxemia associated with most acute exacerbations of COPD. Inability to correct hypoxemia with a relatively low FiO2 should prompt consideration of pulmonary emboli, acute respiratory distress syndrome, pulmonary edema, or severe pneumonia as the cause of respiratory failure. (See "Oxygenation and mechanisms of hypoxemia".)
Adequate oxygenation must be assured, even if it leads to acute hypercapnia. Hypercapnia is generally well tolerated in patients whose arterial carbon dioxide tension (PaCO2) is chronically elevated. However, mechanical ventilation may be required if hypercapnia is associated with depressed mental status, profound acidemia, or cardiac dysrhythmias. (See "Use of oxygen in patients with hypercapnia", section on 'Hypercapnia in COPD' and "Oxygen toxicity", section on 'Accentuation of hypercapnia'.)
PHARMACOLOGIC TREATMENT — The major components of managing an acute exacerbation of COPD include inhaled short-acting bronchodilators (beta adrenergic agonists and anticholinergic agents), glucocorticoids, and antibiotics [22].
Beta adrenergic agonists — Inhaled short-acting beta adrenergic agonists (eg, albuterol) are the mainstay of therapy for an acute exacerbation of COPD because of their rapid onset of action and efficacy in producing bronchodilation [24,25]. These medications may be administered via a nebulizer or a metered dose inhaler (MDI) with a spacer device [26]. (See "Delivery of inhaled medication in adults" and "Metered dose inhaler techniques in adults".)
Despite evidence that the MDI may have equal efficacy during acute exacerbations of COPD, many clinicians prefer nebulized therapy on the presumption of more reliable delivery of drug to the airway [1]. We favor nebulized therapy because we find that many patients have difficulty using proper MDI technique in this setting.
Typical doses of albuterol for this indication are 2.5 mg (diluted to a total of 3 mL) by nebulizer every one to four hours as needed, or 4 to 8 puffs (90 mcg per puff) by MDI with a spacer every one to four hours as needed. Increasing the dose of nebulized albuterol to 5 mg does not have a significant impact on spirometry or clinical outcomes [27]. Similarly, continuously nebulized beta agonists have not been shown to confer an advantage.
Subcutaneous injection of short-acting beta adrenergic agonists is reserved for situations in which inhaled administration is not possible. Parenteral use of these agents results in greater inotropic and chronotropic effects, which may cause arrhythmias or myocardial ischemia in susceptible individuals.
Anticholinergic agents — Inhaled short-acting anticholinergic agents (eg, ipratropium bromide) are used with inhaled short-acting beta adrenergic agonists to treat exacerbations of COPD [1]. This is based on several studies that found that combination therapy produces bronchodilation in excess of that achieved by either agent alone in patients with a COPD exacerbation, an asthma exacerbation, or stable COPD [26,28,29]. However, this finding has not been universal in patients having an exacerbation of COPD [28,30].
Typical doses of ipratropium for this indication are 500 mcg by nebulizer every four hours as needed. Alternatively, 2 puffs (18 mcg per puff) by MDI with a spacer every four hours as needed. (See "Role of anticholinergic therapy in COPD".)
Glucocorticoids — Systemic glucocorticoid therapy improves lung function and treatment success, while reducing the length of hospital stay [31-33]. This was illustrated by a trial that randomly assigned 271 patients having a COPD exacerbation to receive either systemic glucocorticoids or placebo for up to two weeks [32]. Systemic glucocorticoid therapy significantly reduced the 30 day treatment failure rate (23 versus 33 percent), the 90 day treatment failure rate (37 versus 48 percent), and hospital stay (eight versus ten days), while improving lung function. (See "Role of systemic glucocorticoid therapy in COPD".)
Intravenous glucocorticoids should be given to patients who present with a severe exacerbation, who respond poorly to oral glucocorticoids, who are vomiting, or who may have impaired absorption due to decreased splanchnic perfusion (eg, patients in shock). Oral administration is used in most other patients.
Oral glucocorticoids are rapidly absorbed (peak serum levels achieved at one hour after ingestion) with virtually complete bioavailability and their efficacy is comparable to that with intravenous therapy. This was demonstrated in a double-blind trial in which 210 patients having a COPD exacerbation were randomly assigned to receive either oral or intravenous prednisolone (60 mg daily) for five days [34]. There were no differences between the two groups in treatment failure, length of hospital stay, improvement in spirometry, or improvement in quality of life.
The optimal dose of systemic glucocorticoids for treating a COPD exacerbation is unknown [1]. Frequently used regimens include:
High doses of systemic glucocorticoids increase the risk of side effects. Lower doses (eg, equivalent of 30 to 40 mg of prednisone) may be equally effective and safe [1]. (See "Major side effects of systemic glucocorticoids".)
The duration of systemic glucocorticoid therapy varies from patient to patient and exacerbation to exacerbation. As a rough guide, most exacerbations should be treated with full dose therapy for 7 to 10 days [1]. After this time, many pulmonologists taper over about seven days as a trial to see if continued glucocorticoid therapy is required. Tapering solely because of concerns about adrenal suppression is not necessary if the duration of therapy is less than three weeks (a duration too brief to cause adrenal atrophy). (See "Glucocorticoid withdrawal", section on 'Recommended tapering regimen'.)
The efficacy of inhaled glucocorticoids on the course of a COPD exacerbation has not been studied in randomized trials. Thus, they should not be used as a substitute for systemic glucocorticoid therapy.
Antibiotics — Antibiotics are indicated for many patients having a COPD exacerbation. The importance, diagnosis, and treatment of infection in exacerbations of COPD is discussed separately. (See "Diagnosis and treatment of infection in acute exacerbations of chronic obstructive pulmonary disease", Summary and Recommendations section).
Mucoactive agents — There is little evidence supporting the use of mucoactive agents (eg, N-acetylcysteine) in acute exacerbations of COPD [24,25,35]. Some mucoactive agents may worsen bronchospasm. (See "Role of mucoactive agents in the treatment of COPD".)
The lack of efficacy of mucoactive agents in the treatment of COPD exacerbations was best demonstrated by a double-blind trial that randomly assigned 50 patients with a COPD exacerbation to receive N-acetylcysteine (600 mg, twice daily) or placebo for seven days [35]. There was no difference in the rate of change of FEV1, vital capacity, oxygen saturation, breathlessness, or length of stay between the two groups.
Methylxanthines — Aminophylline and theophylline are NOT recommended for the treatment of acute exacerbations of COPD [24]. Randomized controlled trials of intravenous aminophylline in this setting have failed to show efficacy beyond that induced by inhaled bronchodilator and glucocorticoid therapy. In addition to lack of efficacy, methylxanthines caused significantly more nausea and vomiting than placebo and trended toward more frequent tremor, palpitations, and arrhythmias. (See "Role of methylxanthines in the treatment of COPD", section on 'Acute exacerbation'.)
CHEST PHYSIOTHERAPY — Mechanical techniques to augment sputum clearance, such as directed coughing, chest physiotherapy with percussion and vibration, intermittent positive pressure breathing, and postural drainage, have not been shown to be beneficial in COPD and may provoke bronchoconstriction. Their use in acute exacerbations of COPD is not supported by clinical trials [1,24,25].
MECHANICAL VENTILATION
Noninvasive ventilation — Noninvasive positive pressure ventilation (NPPV) refers to mechanical ventilation delivered through a noninvasive interface, such as a face mask, nasal mask, or nasal prongs. It improves numerous clinical outcomes and is the preferred method of ventilatory support in many patients with an acute exacerbation of COPD. NPPV is discussed in detail elsewhere. (See "Noninvasive positive pressure ventilation in acute respiratory failure in adults".)
Invasive ventilation — Invasive mechanical ventilation should be administered when patients fail NPPV, do not tolerate NPPV, or have contraindications to NPPV. Invasive mechanical ventilation for acute respiratory failure due to a COPD exacerbation is discussed separately. (See "Mechanical ventilation in acute respiratory failure complicating COPD".)
PROGNOSIS — It is estimated that 14 percent of patients admitted for an exacerbation of COPD will die within three months of admission [36,37]. Even if the acute exacerbation resolves, many patients never return to their baseline level of health [38]. Among patients with an acute exacerbation and a PaCO2 of 50 mmHg or more, the six- and 12-month mortality rates are approximately 33 and 43 percent, respectively [39].
PREVENTION — Once the patient begins to improve, measures should be taken to prevent future exacerbations, including smoking cessation, pulmonary rehabilitation, proper use of medications (including metered dose inhaler technique), and vaccination [40]. (See "Management of smoking cessation" and "Pulmonary rehabilitation in COPD" and "Metered dose inhaler techniques in adults" and "Management of stable chronic obstructive pulmonary disease", section on 'Supplemental therapy'.)
Approximately two-thirds of patients know when an exacerbation of COPD is imminent because symptoms tend to be similar from one exacerbation to another [41]. As a result, some clinicians advocate a COPD exacerbation "action plan." An action plan encourages early intervention by giving patients guidelines on how to recognize an exacerbation, how to change their medication regimen accordingly, and when to contact their healthcare provider. A meta-analysis of three randomized, controlled trials (367 patients) revealed that use of an action plan was associated with earlier recognition of an exacerbation by the patient, earlier initiation of antibiotics, and earlier initiation of glucocorticoids [42]. However, there was no significant effect on healthcare utilization, quality of life, lung function, functional capacity, symptom scores, or mortality.
Prevention of infection, a precipitant of exacerbations of COPD, is discussed separately. (See "Diagnosis and treatment of infection in acute exacerbations of chronic obstructive pulmonary disease", section on 'Prevention'.)
INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Chronic obstructive pulmonary disease (COPD)" and "Patient information: Chronic obstructive pulmonary disease (COPD) treatments".) We encourage you to print or e-mail these topic reviews, or to refer patients to our public web site, www.uptodate.com/patients, which includes these and other topics.
SUMMARY AND RECOMMENDATIONS
- An acute exacerbation of COPD is characterized by an acute increase in symptoms beyond normal day-to-day variation (see 'Introduction' above.
- We recommend that all patients having a COPD exacerbation receive both an inhaled short-acting beta adrenergic agonist and an inhaled short-acting anticholinergic agent, rather than either medication alone (Grade 1B). (See 'Beta adrenergic agonists' above and 'Anticholinergic agents' above.)
- We suggest that all patients who are hypoxemic be given supplemental oxygen targeting a PaO2 of 60 to 70 mmHg, with an oxyhemoglobin saturation of 90 to 94 percent (Grade 2C). (See 'Oxygen therapy' above.)
