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Management of exacerbations of chronic obstructive pulmonary disease

Author
James K Stoller, MD, MS

Section Editor
Deputy Editor
Peter J Barnes, DM, DSc, FRCP, FRS Helen Hollingsworth, MD

Contributor disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2016. | This topic last updated: Mar 17, 2016.
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 event characterized by a worsening of the patient's
respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication" [1]. This
generally includes an acute change 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
The management of patients with exacerbations of COPD is discussed in detail here. A table to assist with emergency
management of severe acute exacerbations of COPD is provided (table 1). The diagnosis and treatment of infection in
exacerbations and the management of stable COPD are discussed separately. (See "Management of infection in
exacerbations of chronic obstructive pulmonary disease" and "Management of stable chronic obstructive pulmonary
disease".)
RISK FACTORS FOR COPD EXACERBATION According to observational studies, the risk of developing an
exacerbation of chronic obstructive pulmonary disease (COPD) correlates with advanced age, productive cough,
duration of COPD, history of 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) [2-5]. In general, worsening airflow limitation (lower forced expiratory volume in one second
[FEV1]) is associated with an increasing risk of COPD exacerbation, although airflow limitation alone does not provide a
good assessment of exacerbation risk [1].
Other potential contributors to an increased risk of exacerbations include the following:
Severity of COPD and history of prior exacerbations In the prospective Evaluation of COPD Longitudinally to
Identify Predictive Surrogate Endpoints (ECLIPSE) study, 2138 patients with moderate to severe COPD (GOLD
stages 2, 3, or 4 (table 2)) were followed for three years [6]. The single best predictor of exacerbations was a
history of prior exacerbations, regardless of COPD severity.
The GOLD guidelines suggest using a combination of an individual's FEV1, history of exacerbations, history of
hospitalization for exacerbation, and symptoms to assess the exacerbation risk [1]. The number of exacerbations
in the previous 12 months is stratified: a history of zero or one exacerbation suggests a low future risk of
exacerbations, while two or more suggest a high future risk [1]. The severity of lung function impairment is stratified
based on the postbronchodilator FEV1, using the GOLD classification of airflow limitation (table 2). These
components are combined as follows:
Low risk: Typically GOLD 1 or 2 (mild to moderate airflow limitation) and/or 0 to 1 exacerbation per year, no
hospitalization due to an exacerbation
High risk: Typically GOLD 3 or 4 (severe or very severe airflow limitation) and/or 2 exacerbations per year or

1 hospitalization due to an exacerbation

The full COPD staging system used in the GOLD guidelines incorporates information about the severity of
symptoms (based on instruments such as the COPD Assessment Test [CAT] and the modified Medical Research
Council Dyspnea Scale), the degree of airflow limitation (based on the FEV1), and the frequency of prior COPD
exacerbations and is discussed separately [1]. (See "Chronic obstructive pulmonary disease: Definition, clinical
manifestations, diagnosis, and staging", section on 'Staging'.)
Gastroesophageal reflux disease Gastroesophageal reflux disease (GERD) may be an additional risk factor for
COPD exacerbations [7,8]. In the ECLIPSE study noted above, the occurrence of two or more exacerbations in a
year was associated with a history of GERD or heartburn [6]. A similar observation was made in a case-control
study that assessed the presence of GERD symptoms and frequency of COPD exacerbations in 80 patients with
COPD. The presence of GERD symptoms was associated with an increased risk of COPD exacerbations (RR
6.55, 95% CI 1.86-23.11) [7]. Additional studies are needed to determine whether GERD contributes to the
development of COPD exacerbations.
Pulmonary hypertension Secondary pulmonary hypertension may be an additional risk factor for COPD
exacerbations. In a follow-up to the ECLIPSE study, chest computed tomography scans were used to compute the
ratio of the diameter of the pulmonary artery to the diameter of the aorta (PA:A ratio) [9]. In the study, a PA:A ratio
greater than 1 was an independent risk factor for a future severe exacerbation (OR 3.44, 95% CI 2.78-4.25).
Notably, a PA:A ratio >1 suggests the presence of pulmonary hypertension, although it does not clarify the cause of
pulmonary hypertension (eg, hypoxemia due to COPD or other lung disease, left heart failure, sleep apnea). The
clinical usefulness of this observation in terms of treatment decisions is unclear.
TRIGGERS Respiratory infections are estimated to trigger approximately 70 percent of chronic obstructive pulmonary
disease (COPD) exacerbations (table 3). Viral and bacterial infections cause most exacerbations, whereas atypical
bacteria are a relatively uncommon cause [10,11]. The remaining 30 percent are due to environmental pollution,
pulmonary embolism, or have an unknown etiology [1,12-14]. (See "Management of infection in 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 [1,15]. The relationship between COPD exacerbation and
pulmonary embolism was illustrated by a meta-analysis of five observational studies [16]. 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.
CLINICAL MANIFESTATIONS The clinical manifestations of exacerbations of chronic obstructive pulmonary disease
(COPD) range from a mild increase in dyspnea or productive cough to respiratory failure due to acute respiratory
acidosis or hypoxemia.
Medical history By definition, patients present with the acute onset or worsening of respiratory symptoms, such as
dyspnea, cough, and/or sputum production, over several hours to days. These symptoms should be characterized
further in terms of the following features:
Time course of the symptoms
Comparison to baseline level of symptoms
Severity of respiratory compromise (eg, dyspnea at rest, dyspnea climbing stairs)
Delineation of sputum characteristics (eg, amount, purulence, blood)
Associated features that would suggest an alternate diagnosis or comorbidity include:
Constitutional symptoms (eg, fever, chills, night sweats)

 Chest pain, chest pressure, or peripheral edema

Risk factors for thromboembolic disease or coronary disease
Upper respiratory symptoms that might suggest a viral respiratory infection
The past history of exacerbations should be ascertained: number of prior exacerbations, courses of systemic
glucocorticoids, and exacerbations requiring hospitalization or ventilatory support.
Physical examination Physical findings associated with an exacerbation of COPD often include wheezing and
tachypnea and may include features of respiratory compromise such as difficulty speaking due to respiratory effort, use
of accessory respiratory muscles, and paradoxical chest wall/abdominal movements (asynchrony between chest and
abdominal motion with respiration). If present, decreased mental status could reflect hypercapnia or hypoxemia and
asterixis could indicate increased hypercapnia.
Attention should also be paid to physical findings that might suggest a comorbidity or alternate diagnosis, such as fever,
hypotension, bibasilar fine crackles and peripheral edema.
EVALUATION AND DIAGNOSIS The goals of the initial evaluation of a patient with a suspected exacerbation of
COPD are to confirm the diagnosis, identify the cause (when possible), assess the severity, and determine whether
comorbidities are contributing.
Initial evaluation The choice of specific tests is guided by the severity of the exacerbation and the particular
associated clinical findings. (See 'Clinical manifestations' above.)
For patients with a mild exacerbation (absence of resting dyspnea or respiratory distress, preserved ability to perform
activities of daily living), who do not require emergency department treatment, the evaluation may be limited to clinical
assessment and possibly pulse oxygen saturation.
For patients who require emergency department care, the evaluation should generally include the following (table 1):
Assessment of pulse oxygen saturation
A chest radiograph to exclude pneumonia, pneumothorax, pulmonary edema, pleural effusion
Laboratory studies (eg, complete blood count and differential, serum electrolytes and glucose)
Arterial blood gas analysis, if acute or acute-on-chronic respiratory acidosis is suspected or if ventilatory support is
anticipated. Concern about acute-on-chronic hypercapnia might be prompted by a history of prior elevation in
arterial tension of carbon dioxide (PaCO2), an elevated serum bicarbonate (perhaps reflecting compensation for
chronic hypercapnia), or the presence of severe airflow obstruction (eg, GOLD III or IV (table 2)).
Additional tests are obtained depending on the clinical evaluation of the patient. Often an electrocardiogram and cardiac
troponins are obtained to evaluate tachycardia or potential myocardial ischemia. Studies such as a plasma brain
natriuretic peptide (BNP) to assess for heart failure and a D-dimer to assess for thromboembolic disease are obtained,
as indicated by features such as crackles on chest auscultation, peripheral edema, suggestive chest radiographic
findings (vascular congestion, pleural effusion), or risk factors for thromboembolism. (See "Troponins as biomarkers of
cardiac injury" and "Natriuretic peptide measurement in heart failure" and "Clinical presentation, evaluation, and
diagnosis of the adult with suspected acute pulmonary embolism".)
Sputum Gram stain and culture are often not useful for identifying bacterial infection in patients with COPD
exacerbations and are not obtained for most exacerbations of COPD. Sputum culture may be helpful in patients who are
strongly suspected of having a bacterial infection but fail to respond to initial antibiotic therapy. (See "Management of
infection in exacerbations of chronic obstructive pulmonary disease", section on 'Sputum Gram stain and culture'.)
While not necessary in most patients, evaluation for possible respiratory virus infection, including influenza, may be
useful in selected patients, such as those who are hospitalized and those with a clinical presentation suggestive of
influenza (eg, acute onset of fever, myalgias, coryza during an influenza outbreak). Rapid antigen and
immunofluorescence testing are useful screening tests for influenza infection, but have limited sensitivity; polymerase
chain reaction (PCR)-based testing is more sensitive and specific. In addition, PCR diagnostic panels have been

developed that can detect multiple respiratory viruses (eg, influenza, adenovirus, parainfluenza virus, respiratory
syncytial virus, human metapneumovirus, coronavirus, and rhinovirus) simultaneously, although the exact indications for
their use in COPD exacerbations are not clear. (See "Management of infection in exacerbations of chronic obstructive
pulmonary disease".)
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, pneumonia, and
pneumothorax [1,17,18]. The importance of considering these alternate diagnoses was illustrated in an autopsy study of
43 patients with COPD who died within 24 hours of admission for a COPD exacerbation [17]. The primary causes of
death were heart failure, pneumonia, pulmonary thromboembolism, and COPD in 37, 28, 21, and 14 percent,
respectively. A chest radiograph will differentiate among several of these possibilities (eg, heart failure, pneumonia,
pneumothorax); a clear chest radiograph may be a clue to pulmonary embolism, especially when dyspnea and
hypoxemia are more prominent than cough or sputum production.
TRIAGE TO HOME OR HOSPITAL An important step in the initial evaluation is to determine whether the patient
needs hospitalization or can be safely managed at home. If the exacerbation appears life-threatening, the patient should
be admitted to the intensive care unit as quickly as possible. On the other hand, more than 80 percent of exacerbations
of chronic obstructive pulmonary disease (COPD) can be managed on an outpatient basis, sometimes after initial
treatment in the office or emergency department.
Criteria that might lead to a decision to hospitalize the patient have been proposed in the GOLD guidelines and include
[1]:
Inadequate response to outpatient or emergency department management
Marked increase in intensity of symptoms over baseline (eg, new onset resting dyspnea)
Severe underlying COPD (eg, forced expiratory volume in one second [FEV1] 50 percent of predicted)
Onset of new signs (eg, cyanosis or peripheral edema)
Acute or acute-on-chronic respiratory acidosis
Older age
Insufficient home support
History of frequent exacerbations
Serious comorbidities including pneumonia, cardiac arrhythmia, heart failure, diabetes mellitus, renal failure, or
liver failure
Intensive home care, which generally includes nurse visits, home oxygen, and physical therapy, may be an alternative in
certain locations for selected patients with an exacerbation of COPD [19-23]. A meta-analysis of seven trials noted that
intensive home care resulted in equivalent clinical outcomes and substantial cost savings compared to hospitalization
[24]. 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. In general, home management of the patient who
satisfies criteria for hospitalization should be considered infrequently and only when optimal home care is available.
HOME MANAGEMENT OF COPD EXACERBATIONS Home management of chronic obstructive pulmonary disease
(COPD) exacerbations generally includes intensification of bronchodilator therapy and initiation of a course of oral
glucocorticoids; oral antibiotics are added based on individual characteristics.
Beta adrenergic agonists Inhaled short-acting beta adrenergic agonists (eg, albuterol, levalbuterol) are the mainstay
of therapy for an acute exacerbation of COPD because of their rapid onset of action and efficacy in producing
bronchodilation [25,26]. For patients being managed at home, these medications are usually administered by a metered
dose inhaler (MDI) with a spacer device and may be combined with a short acting anticholinergic agent (eg, ipratropium)
[1,27]. (See "Delivery of inhaled medication in adults" and "The use of inhaler devices in adults" and 'Anticholinergic
agents' below.)

Patients who already have a nebulizer at home frequently find that administration of beta adrenergic agonists via
nebulizer is helpful during COPD exacerbations. However, most studies have not supported a greater effect from
nebulizer treatments over properly administered metered dose inhaler medication. (See 'Beta adrenergic agonists' below
and "Delivery of inhaled medication in adults", section on 'Home use'.)
Anticholinergic agents Ipratropium bromide, an inhaled short-acting anticholinergic agent (also known as a shortacting muscarinic agent) is an effective bronchodilator for exacerbations of COPD and is often used in combination with
inhaled short-acting beta adrenergic agonists [1].
The usual dose of ipratropium for an acute exacerbation of COPD is two inhalations by metered dose inhaler (MDI)
every four to six hours. The usual doses of combined albuterol and ipratropium are two inhalations by MDI every four to
six hours OR one inhalation by soft mist inhaler (SMI, Respimat) every six hours.
The evidence for using the combination of a short-acting beta agonist with a short acting anticholinergic agent comes
from 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 [27-29]. However, this
finding has not been universal, and other studies not found an additive effect in COPD exacerbations [30].
For patients who have a history of benign prostatic hypertrophy or prior urinary retention, the addition of ipratropium to a
long-acting anticholinergic agent (eg, tiotropium) may increase the risk of acute urinary retention, although data are
conflicting. (See "Role of anticholinergic therapy in COPD", section on 'Acute urinary retention'.)
Oral glucocorticoid therapy Systemic glucocorticoid therapy appears to have a small but beneficial effect in
outpatients with exacerbations of COPD. Our practice reflects current guidelines, which suggest using a dose that is the
equivalent of prednisone 40 mg per day for five days [1]. Occasional patients may benefit from a higher dose or a longer
course depending on the severity of the exacerbation and response to prior courses of glucocorticoids. The role of oral
glucocorticoid therapy in the outpatient management of COPD exacerbations is discussed separately. (See "Role of
systemic glucocorticoid therapy in COPD", section on 'Outpatient exacerbations'.)
Even short courses of systemic glucocorticoids can have adverse effects, such as hyperglycemia, upper gastrointestinal
bleeding, and psychiatric disorders. (See "Role of systemic glucocorticoid therapy in COPD", section on 'Short-term
therapy and complications'.)
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 in COPD exacerbations.
Antibiotics The efficacy of antibiotics for COPD exacerbations is less well-established for outpatients than for
inpatients. To try to maximize the benefit of antibiotic therapy, many clinical practice guidelines recommend antibiotic
therapy only for those patients who are most likely to have bacterial infection or are most ill.
The GOLD guidelines recommend antibiotics for moderately or severely ill patients with COPD exacerbations who have
increased cough and sputum purulence [1]. We vary slightly from the GOLD guidelines in our clinical practices:
We recommend antibiotics in outpatients with a moderate or severe exacerbation of COPD, which is defined as
having at least two of these three symptoms increased dyspnea, increased sputum volume, or increased sputum
purulence.
We do not initiate antibiotic therapy in patients whose exacerbation is mild, which we define as having only one of
these three symptoms and not requiring hospitalization.
The initial antibiotic regimen should target likely bacterial pathogens (Haemophilus influenzae, Moraxella catarrhalis, and
Streptococcus pneumoniae in most patients) and take into account local patterns of antibiotic resistance (algorithm 1).
The role of antibiotics in exacerbations of COPD, including antibiotic selection, is discussed separately. (See
"Management of infection in exacerbations of chronic obstructive pulmonary disease", section on 'Summary and
recommendations'.)

Adjunctive care For patients being managed at home, supportive care may include efforts at cigarette smoking
cessation, nutritional support, and continuation of ongoing supplemental oxygen therapy. Patients who have a new
requirement for supplemental oxygen are usually managed in the hospital, at least initially. (See 'Triage to home or
hospital' above and "Overview of smoking cessation management in adults" and "Nutritional support in advanced lung
disease" and "Pulmonary rehabilitation in COPD".)
HOSPITAL MANAGEMENT OF COPD EXACERBATIONS Similar to at-home management, the major components
of in-hospital management of exacerbations of chronic obstructive pulmonary disease (COPD) include reversing airflow
limitation with inhaled short-acting bronchodilators and systemic glucocorticoids, treating infection, ensuring adequate
oxygenation, and averting intubation and mechanical ventilation [1,31]. An approach to emergency management of
severe exacerbations of COPD is summarized in the table (table 1).
Other goals of care are to prevent complications of immobility, such as thromboemboli and deconditioning, improve
nutritional status, and aid patients who smoke with smoking cessation.
In-hospital monitoring typically includes frequent assessment of respiratory status (eg, respiratory rate and effort,
wheezing, pulse oxygen saturation), heart rate and rhythm, and also fluid status. Arterial blood gas measurement is
performed to look for respiratory acidosis (eg, if the patient's respiratory status is deteriorating), confirm the accuracy of
pulse oxygen saturation, and to monitor known hypercapnia. (See "Simple and mixed acid-base disorders", section on
'Respiratory acid-base disorders'.)
Oxygen therapy Supplemental oxygen is a critical component of acute therapy. Because of the risk of prompting
worsened hypercapnia with excess supplemental oxygen, administration of supplemental oxygen should target a pulse
oxygen saturation (SpO2) of 88 to 92 percent or an arterial oxygen tension (PaO2) of approximately 60 to 70 mmHg
[1,31,32]. In two small randomized trials, titrating supplemental oxygen to SpO2 88 to 92 percent resulted in a lower
mortality compared with high flow (nontitrated) oxygen [32]. (See "The evaluation, diagnosis, and treatment of the adult
patient with acute hypercapnic respiratory failure".)
There are numerous devices available to deliver supplemental oxygen during an 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 cannula 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 a higher FiO2 is needed, simple facemasks can provide an FiO2 up to 55 percent using flow rates of 6 to 10
L per minute. However, variations in minute ventilation and inconsistent entrainment of room air affect the FiO2
when simple facemasks (or nasal cannula) 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, but are generally not needed in this setting.
A high FiO2 is not required to correct the hypoxemia associated with most exacerbations of COPD. Inability to correct
hypoxemia with a relatively low FiO2 (eg, 4 L/min by nasal cannula or 35 percent by mask) 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 (ie, to achieve an oxygen saturation of 88 to 92 percent) 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 "Oxygen toxicity", section on 'Accentuation of
hypercapnia' and 'Mechanical ventilation' below and "The evaluation, diagnosis, and treatment of the adult patient with
acute hypercapnic respiratory failure".)
Beta adrenergic agonists As noted above, inhaled short-acting beta adrenergic agonists (eg, albuterol, levalbuterol)

are the mainstay of therapy for an exacerbation of COPD because of their rapid onset of action and efficacy in producing
bronchodilation [25,26]. These medications may be administered via a nebulizer or a metered dose inhaler (MDI) with a
spacer device and may be combined with a short acting muscarinic agent (eg, ipratropium) [1,27]. (See "Delivery of
inhaled medication in adults" and "The use of inhaler devices in adults" and 'Anticholinergic agents' below.)
Despite evidence that MDI devices may have equal efficacy during 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 many patients with COPD have difficulty using proper MDI technique in the setting of an exacerbation.
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 four to eight 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 [33]. Similarly,
continuously nebulized beta agonists have not been shown to confer an advantage in COPD.
Patients with severe COPD are at risk for hypercapnia with administration of supplemental oxygen, so concern has been
raised about the risk of hypercapnia during bronchodilator treatments that are administered using oxygen-driven
nebulizers [34]. We concur with the British Thoracic Society guidelines that suggest using air, rather than oxygen-driven
bronchodilator nebulization, or limiting oxygen-driven treatments to six minutes [35].
Subcutaneous injection of short-acting beta adrenergic agonists (eg, terbutaline, epinephrine) carries a high risk for
inotropic and chronotropic adverse effects, such as arrhythmias or myocardial ischemia, and is almost never used for
COPD exacerbations.
Anticholinergic agents As noted above, the evidence is conflicting regarding the use of inhaled short-acting
anticholinergic agents (eg, ipratropium bromide) in combination with inhaled short-acting beta adrenergic agonists to
treat exacerbations of COPD [1]. Nonetheless these agents are typically used together for patients who require hospitalbased treatment of a COPD exacerbation. (See 'Anticholinergic agents' above.)
Typical doses of ipratropium in this situation are 500 mcg by nebulizer every four hours as needed. Alternatively, two to
four puffs (18 mcg per puff) can be administered by MDI with a spacer every four hours as needed. (See "Role of
anticholinergic therapy in COPD".)
Systemic glucocorticoids
Efficacy Systemic glucocorticoids, when added to the bronchodilator therapies described above, improve
symptoms and lung function, and decrease the length of hospital stay [1,36-38]. This was illustrated by a trial that
randomly assigned 271 patients with a COPD exacerbation to receive either systemic glucocorticoids or placebo
for up to two weeks [37]. 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 (8 versus 10 days),
while improving lung function. (See "Role of systemic glucocorticoid therapy in COPD".)
Route Oral glucocorticoids are rapidly absorbed (peak serum levels achieved at one hour after ingestion) with
virtually complete bioavailability and appear equally efficacious to intravenous glucocorticoids for treating most
exacerbations of COPD. For example, a randomized trial assigned 210 patients hospitalized with a COPD
exacerbation to receive oral or intravenous prednisolone (60 mg daily) for five days and found no difference
between the two groups in the rate of treatment failure, length of hospital stay, improvement in spirometry, or
improvement in quality of life [39].
However, intravenous glucocorticoids are typically administered to patients who present with a severe
exacerbation, who respond poorly to oral glucocorticoids, who are unable to take oral medication, or who may
have impaired absorption due to decreased splanchnic perfusion (eg, patients in shock).
Dose The optimal dose of systemic glucocorticoids for treating a COPD exacerbation is unknown [1]. The Global
Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines advise using the equivalent of prednisone 40
mg once daily for the majority of COPD exacerbations (table 4) [1]. Frequently used regimens range from

prednisone 30 to 60 mg, once daily, to methylprednisolone 60 to 125 mg, two to four times daily, depending on the
severity of the exacerbation [39-41]. A growing body of evidence favors using a moderate, rather than high dose of
glucocorticoids, for most patients with an exacerbation of COPD. As an example, a comparative analysis of
glucocorticoid dosing examined outcomes of 79,985 patients admitted to the hospital with an exacerbation of
COPD, excluding those requiring intensive care [40]. The median glucocorticoid dose administered in the first two
days was 60 mg for those on oral therapy and 556 mg for intravenous therapy. The risk of treatment failure was no
greater with the lower dose. As this was an observational study and did not include objective measures of airflow
limitation, it is possible that less ill patients were more likely to receive oral treatment.
On the other hand, for patients with impending or actual acute respiratory failure due to a COPD exacerbation,
many clinicians use an intravenous formulation at a higher dose, such as the equivalent of methylprednisolone 60
mg intravenously, one to four times daily, although outcomes data to guide this practice are limited. In an
observational cohort study, among 17,239 patients admitted to an intensive care unit (ICU) with an exacerbation of
COPD, a dose of methylprednisolone of 240 mg/day or less, compared with a higher dose (methylprednisolone
>240 mg/day), was not associated with a mortality benefit, but was associated with slightly shorter hospital (-0.44
days, 95% CI -0.67 to -0.21) and ICU (-0.31 days; 95% CI -0.46 to -0.16) lengths of stay [42]. Length of
mechanical ventilation and need for insulin therapy were also lower in the lower dose group. As this was an
observational study, further research is needed to determine the optimal glucocorticoid dose in this setting.
Duration The optimal duration of systemic glucocorticoid therapy is not clearly established and often depends on
the severity of the exacerbation and the observed response to therapy [1,43]. As a rough guide, full dose therapy
(eg, prednisone 40 mg daily) is given for 5 to 14 days. (See "Role of systemic glucocorticoid therapy in COPD",
section on 'Hospitalized patients' and "Role of systemic glucocorticoid therapy in COPD", section on 'Short-term
therapy and complications'.)
Data in support of a 14-day course, rather than a longer duration, comes from the Systemic Corticosteroids in
COPD Exacerbations (SCCOPE) trial, which compared two and eight week regimens and did not find any
additional benefit to the longer course [37]. Patients in the eight week group experienced more
glucocorticoid-related side effects.
Other studies have examined whether courses shorter than 14 days are also effective for COPD
exacerbations. As an example, the Reduction in the Use of Corticosteroids in Exacerbated COPD (REDUCE)
trial randomly assigned 314 patients with exacerbations of COPD, of whom 289 required hospitalization, to
prednisone 40 mg daily for 5 or 14 days [41]. No difference was noted in the time to the next exacerbation,
the likelihood of an exacerbation in the subsequent 180 days, or the recovery of lung function. The mean
cumulative prednisone dose was significantly higher in the 14-day group, but treatment-related adverse
effects, such as hyperglycemia and hypertension, were not different between the groups. While this study
suggests that a five-day course may be comparable to 14 days for many patients, further study is needed to
determine whether some patients might do better with the longer course.
A systematic review compared different durations of systemic glucocorticoid therapy and found no difference
in the risk of treatment failure with courses of three to seven days compared with longer courses [43].
Including the data from the REDUCE trial above, the systematic review concluded that a five-day course of
oral glucocorticoids is probably comparable to a 14-day or longer course, but that further research is needed
to conclude equivalence.
At the end of the treatment course, glucocorticoid therapy may be discontinued rather than tapered, if the patient
has substantially recovered. Alternatively, the dose is tapered over another seven days, as a trial to determine
whether a longer course of glucocorticoid therapy is required. However, long-term systemic glucocorticoids should
rarely be used for stable COPD if therapy is otherwise optimized. 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 "Management of stable chronic obstructive pulmonary disease", section on 'Systemic
glucocorticoids' and "Glucocorticoid withdrawal", section on 'Recommended tapering regimen'.)

Antibiotics and antiviral agents Antibiotics are indicated for patients having a moderate to severe COPD
exacerbation that requires hospitalization [1]. The optimal antibiotic regimen for the treatment of exacerbations of COPD
has not been determined. We use a "risk stratification" approach when selecting initial antibiotic therapy, providing a
broader antibiotic regimen for patients at risk for resistant organisms (algorithm 2). The rationale, diagnosis, and
treatment of infection in exacerbations of COPD, including antibiotic selection, are discussed separately. (See
"Management of infection in exacerbations of chronic obstructive pulmonary disease", section on 'Summary and
recommendations'.)
Antiviral therapy is recommended for patients with clinical and laboratory evidence of influenza infection who require
hospitalization for an exacerbation of COPD. Because of the risk of acute bronchoconstriction with inhalation of
zanamivir, oseltamivir is preferred unless local resistance patterns suggest a likelihood of oseltamivir-resistant influenza.
Antiviral treatment of influenza is discussed in greater detail separately. (See "Treatment of seasonal influenza in adults",
section on 'Antiviral therapy'.)
Information regarding antiviral resistance that emerges during the influenza season is available through the United
States Centers for Disease Control and Prevention. Clinicians should review antiviral resistance patterns and the CDC's
web site for updated antiviral recommendations should increased resistance emerge.
Supportive care Supportive care for patients hospitalized with an exacerbation of COPD may include one or more of
the following therapies:
Cigarette smoking cessation Hospitalization may provide an opportunity for patients who continue to smoke to
move towards cigarette smoking cessation. (See "Overview of smoking cessation management in adults", section
on 'Hospitalized smokers'.)
Thromboprophylaxis Hospitalization for exacerbations of COPD increases the risk for deep venous thrombosis
and pulmonary embolism [1]. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized
medical adults".)
Nutritional support Oral nutritional supplementation may have some benefit in the rate of improvement in
pulmonary function during COPD exacerbations [44]. (See "Nutritional support in advanced lung disease", section
on 'Frequency of malnutrition'.)
Palliative care Given the high one-year mortality rate after hospitalization for a COPD exacerbation, it may be
appropriate to consider a palliative care referral during or shortly after a hospitalization for COPD. Palliative care
assessment can help explore the patient's understanding of their illness and prognosis, assess and manage
symptoms, discuss the patient's goals of care and advance care planning, and help plan end-of-life care. (See
"Palliative care for adults with nonmalignant chronic lung disease".)
Treatments without documented benefit Mucoactive agents, methylxanthines, and mechanical techniques to
augment sputum clearance have not been shown to confer benefit for patients with a COPD exacerbation.
Mucoactive agents There is little evidence supporting the use of mucoactive agents (eg, N-acetylcysteine) in
exacerbations of COPD [25,26,45]. Some mucoactive agents may worsen bronchospasm. (See "Role of
mucoactive agents and secretion clearance techniques in 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 [45]. 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 The methylxanthines, aminophylline and theophylline, are considered second-line therapy for
exacerbations of COPD [1]. 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'.)
Nebulized magnesium While intravenous magnesium has a bronchodilator effect in acute severe exacerbations
of asthma, nebulized isotonic magnesium (151 mg per dose) had no effect on FEV1 when added to nebulized
salbutamol (albuterol) in patients with exacerbations of COPD [46].
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 exacerbations of
COPD (in the absence of bronchiectasis) is not supported by clinical trials [1,25,26].
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 exacerbation of COPD. Suggested
indications for NPPV in this setting include severe dyspnea with clinical signs of respiratory muscle fatigue, increased
work of breathing, or both, and also respiratory acidosis (arterial pH 7.35 and arterial tension of carbon dioxide [PaCO2]
45 mmHg [6 kPa]) [1].
Optimal initial settings for NPPV have not been established. A reasonable approach is to initiate NPPV in a
spontaneously triggered mode with a backup respiratory rate, an inspiratory pressure of 8 to 12 cm H2O, and an
expiratory pressure of 3 to 5 cm H2O. The inspiratory pressure is gradually increased as needed to achieve alleviation of
dyspnea and good patient-ventilator synchrony. 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 "Invasive mechanical ventilation in acute respiratory failure complicating
chronic obstructive pulmonary disease".)
PROGNOSIS Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with increased
mortality [1]. In-hospital mortality ranges from three to nine percent [47-49]. Mortality following hospital discharge after
an exacerbation of COPD is influenced by a number of factors, including older age, the severity of the underlying COPD,
requirement for long-term oxygen at discharge, presence of comorbidities (eg, cardiovascular disease or lung cancer),
and the presence of Pseudomonas aeruginosa in the patient's sputum as described in the following studies [50-55]:
It is estimated that 14 percent of patients admitted for an exacerbation of COPD will die within three months of
admission [50,51].
Among 1016 patients with an exacerbation of COPD and a PaCO2 of 50 mmHg or more, the 6 and 12 month
mortality rates were 33 and 43 percent, respectively [52].
In a study of 260 patients admitted with a COPD exacerbation, the one year mortality was 28 percent [53].
Independent risk factors for mortality were age, male gender, prior hospitalization for COPD, PaCO2 45 mmHg (6
kPa), and urea >8 mmol/L.
Patients hospitalized for a COPD exacerbation who have Pseudomonas aeruginosa in their sputum have a higher
risk of mortality at three years than those without (59 versus 35 percent, HR 2.33, 95% CI 1.29-3.86), independent
of age, comorbidity, or COPD severity [54].
Even if the COPD exacerbation resolves, many patients never return to their baseline level of health [56].
PREVENTION
General measures Several measures have been shown to reduce chronic obstructive pulmonary disease (COPD)

exacerbations, including smoking cessation, pulmonary rehabilitation, increased physical activity [57], proper use of
medications (including metered dose inhaler technique), and vaccination against seasonal influenza and pneumococcus
[1,58,59]. (See "Pulmonary rehabilitation in COPD" and "The use of inhaler devices in adults" and "Management of
stable chronic obstructive pulmonary disease", section on 'Supplemental therapy' and "Overview of smoking cessation
management in adults" and "Management of infection in exacerbations of chronic obstructive pulmonary disease",
section on 'Vaccination'.)
A number of medications, such as tiotropium, combination inhaled glucocorticoid and long-acting beta agonist (LABA),
roflumilast, and N-acetylcysteine (NAC), can help to reduce the frequency of COPD exacerbations, although the
evidence for roflumilast and NAC is less convincing than for the other two [59]. The effect of long-term therapy with
these agents on exacerbation frequency is discussed separately. (See "Management of stable chronic obstructive
pulmonary disease", section on 'Anticholinergics' and "Management of stable chronic obstructive pulmonary disease",
section on 'Bronchodilators plus inhaled glucocorticoids' and "Management of stable chronic obstructive pulmonary
disease", section on 'PDE-4 inhibitors' and "Management of stable chronic obstructive pulmonary disease", section on
'Mucoactive agents'.)
Pulmonary rehabilitation While pulmonary rehabilitation is associated with a number of benefits in terms of
exercise tolerance and quality of life, the effect on COPD exacerbations and rehospitalization is less clear and may be
dependent on timing relative to hospitalization [59].
In a systematic review, participation in pulmonary rehabilitation immediately after a hospitalization (within four weeks)
reduced rehospitalization (odds ratio 0.24, 95% CI 0.07-0.88), but significant heterogeneity was noted among studies
[59]. Participation in pulmonary rehabilitation more than four weeks after an exacerbation does not appear to reduce
exacerbations, although it has other important benefits.
In a randomized trial, 389 patients hospitalized with an acute exacerbation of COPD were assigned to a six week course
of rehabilitation starting within 48 hours of admission or usual care [60]. Early rehabilitation did not reduce the risk of
subsequent readmission or enhance recovery. Furthermore, the rehabilitation group had a higher one-year mortality
(odds ratio 1.74, 95% CI 1.05-2.88). While the cause of increased mortality was unclear, these data suggest that
pulmonary rehabilitation should not be initiated during an acute illness.
Action plan Some clinicians advocate a COPD exacerbation "action plan" in order to mitigate the severity of
exacerbations, although the data regarding the benefit of action plans are conflicting. Approximately two-thirds of
patients know when an exacerbation of COPD is imminent because symptoms tend to be similar from one exacerbation
to another [61]. 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 [62]. However, there was no significant effect on healthcare utilization, quality of life, lung function,
functional capacity, symptom scores, or mortality. Also, although we continue to manage selected COPD patients with
such action plans, the role of such a comprehensive management program including such action plans has been
questioned since a 2012 randomized trial was terminated early for excess mortality in the "comprehensive management
program" arm [59,63]. Importantly, reasons for the excess mortality in this trial were not clear and further study of the
issue is needed.
Prophylactic antibiotics Prevention of infection, a precipitant of exacerbations of COPD, is discussed separately.
(See "Management of infection in exacerbations of chronic obstructive pulmonary disease", section on 'Prophylactic
antibiotics'.)
Potential benefit of beta-blockers Preliminary observational data suggest that therapy with selective beta-blockers
for comorbid cardiovascular disease is associated with a reduction in COPD exacerbations [64,65]. A meta-analysis of
15 observational studies found that beta-blocker use was associated with a decrease in exacerbations (relative risk 0.63,
95% CI 0.57-0.71) and a decrease in mortality (relative risk 0.72, 95% CI 0.63-0.83) [64]. A subsequent observational
study followed 3464 patients with COPD (severity GOLD class 2 to 4) for a median duration of 2.1 years [65]. Beta-

blocker use was associated with a significantly lower risk of exacerbations (incidence risk ratio 0.73, 95% CI 0.60-0.90),
but no decrease in mortality.
Further study with a randomized trial is needed to determine whether beta-blockers can improve COPD outcomes in this
setting. (See "Management of the patient with severe COPD and cardiovascular disease".)
Ineffective interventions High dose vitamin D supplementation and statins (hydroxymethylglutaryl [HMG] CoA
reductase inhibitors) were not found to diminish COPD exacerbations, although they may have other health benefits.
(See "Vitamin D and extraskeletal health" and "Vitamin D deficiency in adults: Definition, clinical manifestations, and
treatment" and "Treatment of lipids (including hypercholesterolemia) in secondary prevention" and "Statins: Possible
noncardiovascular benefits".)
The effect of high dose vitamin D supplementation on the incidence of COPD exacerbations was assessed in patients
with moderate or more severe COPD who were randomly assigned to take vitamin D 100,000 IU or placebo orally every
four weeks for a year [66]. The median time to first exacerbation did not differ between the groups, nor did exacerbation
rates, FEV1, hospitalization, quality of life, or death. However, patients with severe vitamin D deficiency (serum 25-[OH]
D levels <10 ng/mL) at baseline experienced a significant reduction in exacerbations. Further research is needed to
determine whether daily dosing of vitamin D supplementation for a longer period would be beneficial and whether this
effect is dependent on the baseline vitamin D level [67].
In observational studies of COPD, statins have been associated with a reduced rate and severity of exacerbations, rate
of hospitalizations, and mortality [68-71]. However, these beneficial effects were not supported in a trial that randomly
assigned 885 participants with COPD, but without other indications or contraindications for statin therapy, to simvastatin
40 mg daily or placebo for up to 36 months [72]. Simvastatin did not reduce the rate of exacerbations or the time to first
exacerbation. (See "Treatment of lipids (including hypercholesterolemia) in secondary prevention" and "Treatment of
lipids (including hypercholesterolemia) in primary prevention".)
INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond
the Basics. The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and
they answer the four or five key questions a patient might have about a given condition. These articles are best for
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education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade
reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to
your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and
the keyword(s) of interest.)
Basics topics (see "Patient information: Chronic bronchitis (The Basics)" and "Patient information: Medicines for
chronic obstructive pulmonary disease (COPD) (The Basics)")
Beyond the Basics topics (see "Patient information: Chronic obstructive pulmonary disease (COPD) treatments
(Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
A table to assist with emergency management of severe exacerbations of COPD is provided (table 1).
An exacerbation of COPD is characterized by an acute increase in symptoms beyond normal day-to-day variation
that leads to a change in medication. (See 'Introduction' above.).
We recommend that all patients having a COPD exacerbation receive inhaled short-acting bronchodilator therapy
(Grade 1B). Short-acting beta-adrenergic agonists (SABA, eg, albuterol, levalbuterol) are the mainstay of therapy;
a short-acting anticholinergic agent (eg, ipratropium) may be used as an alternative, or in combination with the
SABA. For more severe exacerbations, the combination is usually preferred. (See 'Beta adrenergic agonists' above
and 'Anticholinergic agents' above.)

 We recommend that all patients having a COPD exacerbation receive systemic glucocorticoids (Grade 1A). A
reasonable dose for patients not requiring intensive care unit admission is prednisone 40 to 60 mg orally once
daily, or the equivalent, for 5 to 14 days. (See 'Systemic glucocorticoids' above.)
Antibiotics are indicated for many patients having a COPD exacerbation. (See "Management of infection in
exacerbations of chronic obstructive pulmonary disease", section on 'Summary and recommendations'.)
Mucoactive agents, methylxanthines, and mechanical techniques to augment sputum clearance have not been
shown to confer benefit for COPD exacerbations. (See 'Treatments without documented benefit' above.)
Patients with hypoxemia due to an exacerbation of COPD should receive supplemental oxygen. We suggest that
supplemental oxygen be titrated to a target of 88 to 92 percent pulse oxygen saturation, rather than using highflow, untitrated oxygen (Grade 2B). (See 'Oxygen therapy' above.)
Noninvasive positive pressure ventilation (NPPV) improves numerous clinical outcomes and is the preferred
method of ventilatory support in many patients with an acute exacerbation of COPD. Invasive mechanical
ventilation is required in patients with respiratory failure who fail NPPV, do not tolerate NPPV, or who have
contraindications to NPPV. Both NPPV and invasive mechanical ventilation for patients with an exacerbation of
COPD are discussed separately. (See "Noninvasive positive pressure ventilation in acute respiratory failure in
adults" and "Invasive mechanical ventilation in acute respiratory failure complicating chronic obstructive pulmonary
disease".)
Several measures have been shown to reduce COPD exacerbations, including smoking cessation, pulmonary
rehabilitation, proper use of medications (including metered dose inhaler technique), and vaccination against
seasonal influenza and pneumococcus. (See 'Prevention' above.)
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