Acute COPD Exacerbation

Acute exacerbation of
chronic obstructive
pulmonary disease
The right clinical information, right where it's needed
Last updated: Apr 12, 2018

Table of Contents
Summary 3
Basics 4
Definition 4
Epidemiology 4
Aetiology 4
Pathophysiology 5
Classification 6
Prevention 7
Primary prevention 7
Secondary prevention 9
Diagnosis 10
Case history 10
Step-by-step diagnostic approach 10
Risk factors 11
History & examination factors 13
Diagnostic tests 15
Differential diagnosis 17
Diagnostic criteria 22
Treatment 23
Step-by-step treatment approach 23
Treatment details overview 26
Treatment options 27
Follow up 37
Recommendations 37
Complications 37
Prognosis 38
Guidelines 39
Diagnostic guidelines 39
Treatment guidelines 39
References 42
Disclaimer 64
Summary
◊ Typically presents with an increased level of dyspnoea, worsening of chronic cough, and/or an
increase in the volume and/or purulence of the sputum produced.
◊ May represent the first presentation of COPD, usually associated with a history of tobacco exposure.
◊ Treatment includes bronchodilators, systemic corticosteroids, and antibiotics.
◊ Antibiotics may be reserved for exacerbations thought to be due to bacteria. An acute change in the
volume and colour of sputum produced is suggestive of a bacterial trigger.
◊ Treatment may be complicated by the development of hyperglycaemia (associated with the use of
corticosteroids) and/or diarrhoea, including Clostridium difficile -associated diarrhoea (associated
with the use of antibiotics).
Acute exacerbation of chronic obstructive pulmonary
disease Basics
Definition
Chronic obstructive pulmonary disease (COPD) is "a common, preventable and treatable disease that is
characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar
BASICS
abnormalities usually caused by significant exposure to noxious particles or gases."[1]
An exacerbation of COPD may be defined as "an acute worsening of respiratory symptoms that results in
additional therapy."[1]
Epidemiology
COPD is the fourth leading cause of death worldwide, and the third leading cause of death in the United
States.[1] [3] The death rate due to COPD increased over 100% between 1970 and 2002.[4] No other major
cause of death in the US has increased at this rate. Globally, COPD has been shown to be responsible for
3.8% of deaths in high-income countries and 4.9% of deaths in low-income countries.[5]
There is significant variability in the prevalence of COPD between countries. [6] [7] [8] This may be due
to differing rates of exposure to tobacco smoke and indoor and occupational pollutants.[5] In the UK, the
prevalence of COPD diagnosed by physicians between 1990 and 1997 was 2% in men and 1% in women.[9]
In the past, men have experienced higher rates of disease due to COPD. This difference has been thought to
be due primarily to greater exposure to tobacco smoke and occupational pollutants. Surveys have shown that
the prevalence of COPD appears to be becoming more equally distributed between men and women.[7] [10]
COPD contributes a significant burden of healthcare costs.[6] Exacerbations are responsible for much of the
morbidity and mortality experienced by people with COPD, and the median number per year ranges between
1 and 3.[11] [12] It has been clearly shown that patients with more severe manifestations of COPD have
greater rates of mortality over time.[6] However, estimates of mortality may be underestimated, as deaths in
this population are often attributed to other aetiologies such as other respiratory disorders, lung cancer, and
cardiovascular disease.[6]
Acute exacerbations of COPD are commonly triggered by bacterial or viral pathogens, pollutants, or
changes in temperature and humidity, and present with an acute-onset, sustained worsening of the patient's
respiratory symptoms, lung function, functional status, and quality of life.[11] [13] [14] [15] [16] [17] [18]
Exacerbation rates and all-cause mortality tend to be higher during winter months.[19] Acute exacerbations
of COPD, particularly those that are moderate to severe, have significant public health impact, with increased
healthcare utilisation and healthcare costs and increased mortality.[20] [21] [22] [23] [24] Early deaths among
patients hospitalised with severe COPD exacerbation are often caused by concurrent problems such as
pulmonary embolus, pneumonia, or CHF. [25] Patients may also be at risk of myocardial infarction and stroke
in the post-exacerbation period.[26]
Aetiology
The most common cause of COPD in the developed world is exposure to tobacco smoke. Data have
shown that, over time, 50% of chronic smokers develop COPD.[6] [27] The development of COPD is a
complex process that is not completely understood. Inflammation, oxidant-antioxidant imbalance, protease-
antiprotease imbalance, and several additional processes including recurrent infection, immunosenescence,
autoimmunity, altered tissue healing, and other mechanisms are all implicated in the pathogenesis of COPD.
While tobacco smoking is a well-recognised cause of COPD, the risk for developing COPD may also depend
4 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 12, 2018.
BMJ Best Practice topics are regularly updated and the most recent version
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subject to our disclaimer. © BMJ Publishing Group Ltd 2019. All rights reserved.
disease Basics
on gender, genetic and socioeconomic factors, as well as exposures to dusts, chemicals, or pollutants, and
early childhood severe respiratory infection. Acute exacerbations of COPD occur intermittently throughout
the course of the disease over the patient’s lifetime. Exacerbations vary in severity and are thought to be
triggered primarily by infections (both viral and bacterial) and airborne pollutants.[28] In approximately
BASICS
one third of COPD exacerbations, no clear cause can be identified. A careful search for other causes of
respiratory decompensation (e.g., congestive heart failure or pulmonary embolus) should be considered in
such cases.[5] [6]
During an episode, decreases in the FEV1, forced vital capacity (FVC), and peak expiratory flow (PEF) may
be identified and are due at least in part to airway inflammation.[11] [28] [29] However, exacerbations are
diagnosed by the identification of typical signs and symptoms rather than by spirometry.[30]
Bacterial pathogens are thought to be responsible for triggering 50% to 70% of exacerbations. The most
common bacterial pathogens include Haemophilus influenzae , Streptococcus pneumoniae , and Moraxella
those of the
ear infection
catarrhalis .[28] [31] Atypical bacterial pathogens such as Mycoplasma and Chlamydia pneumoniae are
also thought to trigger exacerbations, as are respiratory viruses such as rhinovirus, influenza, respiratory
syncytial virus, parainfluenza virus, and human metapneumovirus.[32] [33] [34] [35] The severity of baseline
lung function impairment influences the profile of pathogens most likely to be present.[31]
Exacerbations may also be due to environmental pollutants such as smoke particulate matter, sulphur
dioxide, nitrogen dioxide, and ozone.[36] [37]
Pathophysiology
Smoking, or other significant exposure to smoke, is noted in most people with COPD. Components of smoke
lead to impaired integrity of the tight junctions between lung epithelial cells,[38] stimulate inflammation, and
have been shown to decrease respiratory tract mucociliary clearance, increasing the likelihood of microbial
pathogens penetrating the normally sterile lower respiratory tract.[39] [40] [41] The presence of microbial
flora leads to antigen presentation and stimulation of the innate and then the adaptive immune response.[42]
Over time, chronic irritation by smoke and the inflammatory response leads to emphysema, hypertrophy
of airway mucous glands, small airway fibrosis, and a decrease in the elastic recoil of the lung.[43] The
decrease in elastic recoil (due to emphysema) and/or obstruction of the small airways due to inflammation,
oedema, and hypersecretion of mucus leads to decreased FEV1 and FEV1/FVC.[44] Hyperinflation that
results from airflow limitation is a main cause of dyspnoea.[45] Unlike asthma, airflow limitation in COPD is
not fully reversible with medical therapy.[46] Furthermore, while the pathogenesis of both asthma and COPD
is rooted in inflammation, the specific inflammatory process differs between these disorders.[12] However, a
substantial number of patients with COPD do have a component of airflow obstruction that is reversible with
bronchodilator therapy.[47] Indeed, inhaled bronchodilators (beta-2-agonists and anticholinergics) are one of
the primary forms of therapy for all patients with COPD, because, in addition to bronchodilation, they have
also been shown to decrease dynamic hyperinflation.[48] [49]
Acute exacerbations of COPD may be defined as an acute worsening of respiratory symptoms (e.g.,
dyspnoea, cough, sputum production) that results in additional therapy.[1] This worsening appears to
result from increases in airway inflammatory cells and proteins that are triggered by an infection, airborne
pollutants, and/or other factors.[29] [50] [51] [52] The acute on chronic inflammatory response and/or
concurrent bronchoconstriction leads to worsening in expiratory airflow limitation.[14] Worsening of expiratory
airflow limitation leads to increased resistive work of breathing, increased ventilation/perfusion mismatch,
and gas exchange disturbances. It also results in increased hyperinflation, which then further worsens lung
This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 12, 2018.
5
disease Basics
mechanics and can lead to impaired function and fatigue of the respiratory muscles.[14] Due to the difficulty
in obtaining specimens from people with exacerbations of COPD, further complicated by heterogeneous
triggers, knowledge of the inflammatory response during an episode is incomplete.
BASICS
Acute exacerbations have significant impact on activity level, functional status, and quality of life experienced
by people with COPD.[1] [12] [53] Moreover, recovery from exacerbations may be prolonged, and some
patients never regain their prior level of lung function and/or functional status.[11] There is evidence to
suggest that exacerbations not only tend to be more frequent and more severe as COPD progresses,[54] [55]
but may themselves accelerate the decline in lung function in COPD.[22] Indeed, some patients may also be
at increased risk for COPD exacerbations (i.e., have a phenotype of increased susceptibility) independent
of disease severity.[55] Currently recommended assessment of COPD patients includes determination
of the severity of the airflow obstruction, assessment of symptoms, as well as assessment of the risk of
exacerbations. People with severe or very severe airflow obstruction, those with a history of two or more
exacerbations in the preceding year, or those with history of hospitalisation due to exacerbation in the
previous year are considered at high risk of subsequent exacerbations.[1] Several additional factors are also
associated with exacerbations and/or hospitalisations for COPD.[56] [57] COPD exacerbations, particularly
those requiring hospitalisation, are associated with increased mortality, as well as significant healthcare
costs.[1]
Classification
Global Initiative for Chronic Obstructive Lung Disease (GOLD)
criteria[1]
In pulmonary function testing, a postbronchodilator FEV1/FVC ratio of <0.70 is commonly considered
diagnostic for COPD. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) system categorizes
airflow limitation into stages. In patients with FEV1/FVC <0.70:
• GOLD 1 - mild: FEV1 ≥ 80% predicted

• GOLD 2 - moderate: 50% ≤ FEV1 < 80% predicted
• GOLD 3 - severe: 30% ≤ FEV1 < 50% predicted
• GOLD 4 - very severe: FEV1 <30% predicted.
The GOLD guideline uses a combined COPD assessment approach to group patients according to
symptoms and previous history of exacerbations. Symptoms are assessed using the Modified British Medical
Research Council (mMRC) or COPD assessment test (CAT) scale.
• Group A: low risk (0-1 exacerbation per year, not requiring hospitalisation) and fewer symptoms
(mMRC 0-1 or CAT <10)
• Group B: low risk (0-1 exacerbation per year, not requiring hospitalisation) and more symptoms
(mMRC≥ 2 or CAT≥ 10)
• Group C: high risk (≥2 exacerbations per year, or one or more requiring hospitalisation) and fewer
symptoms (mMRC 0-1 or CAT <10)
• Group D: high risk (≥2 exacerbations per year, or one or more requiring hospitalisation) and more
symptoms (mMRC≥ 2 or CAT≥ 10).
disease Prevention
Primary prevention
Given the detrimental impact of COPD exacerbations on the patient, every effort should be made to
prevent their occurrence. Previous exacerbation history is a key risk factor for future exacerbations.[1] [55]
People with a high burden of symptoms and history of frequent exacerbations (Global Initiative for Chronic
Obstructive Lung Disease [GOLD] group D) are at particular risk of future exacerbations and mortality.[1]
[79] However, multiple factors impact the risk of subsequent exacerbations and relevant factors vary among
individual patients. Following COPD exacerbation, every effort should be made to both identify and intervene
in potentially modifiable factors to reduce risk of subsequent exacerbation events.
Trigger avoidance, smoking cessation, and immunisation
• Avoiding smoke and smoking cessation are the best measures not only to prevent the onset of COPD
but also to prevent progression of the severity of COPD.[80] [81] Smoking cessation can also reduce
risk of exacerbations,[82] and smoking cessation counselling and treatment is recommended for
people with COPD.[83] Patients should also be advised to avoid other potential triggers such as
airborne pollutants. More severe COPD is associated with both more frequent and more severe
exacerbations.[55] [84] There is evidence that influenza vaccination is effective in preventing
complications of COPD,[85] [86] [87] particularly among people with severe airflow obstruction.[88]
PREVENTION
Yearly influenza vaccine is recommended for adults with COPD.[83] The benefits of pneumococcal
vaccination in reducing overall morbidity from COPD (including exacerbations) is less clear,[83]
[89] but the vaccine does reduce the risk of pneumococcal pneumonia.[88] An updated Cochrane
review concluded that pneumococcal vaccination in people with COPD reduced the chance of an
acute exacerbation and provided some protection against community-acquired pneumonia.[90]
Pneumococcal vaccinations, PCV13 (13-valent conjugated pneumococcal vaccine) and PPSV23 (23-
valent pneumococcal polysaccharide vaccine), are recommended for all patients over 65 years of age.
The PPSV23 is also recommended for younger patients with COPD who have comorbidities such as
chronic heart or lung disease.[1] [83] The indications and benefits of vaccination against influenza
virus, and Streptococcus pneumoniae , should be discussed with the patient.[85] [86] [91]
Pharmacotherapy
• Once the patient has stabilised following treatment for an exacerbation, the patient’s maintenance
medications should be reviewed and consideration should be given to adjusting the medications
following exacerbations, with the goal of reducing the risk and/or severity of future episodes,[83]
and use of medications according to evidence-based guidelines.[1] The use of long-acting beta-2
agonists and long-acting anticholinergic medicines has been associated with a decreased frequency
of exacerbations.[92] [93] [94] [95] [96] [97] [98] [99] [100] [101] [102] [103] [104] [105] [106] [107]
[108] The long-acting anticholinergic agent tiotropium bromide may be more effective than the long-
acting beta-2-agonist salmeterol in preventing exacerbations,[109] particularly among people with
moderate-severity airflow obstruction.[110] The novel Respimat mist delivery system for tiotropium
must, however, be used with caution, given that its use has been associated with a higher mortality
rate.[111] The once-daily long-acting inhaled beta-2 agonist indacaterol is also effective in improving
health status and reducing symptoms and exacerbations in COPD.[112] [113] [114] Another once-daily
beta-2-agonist, olodaterol, has been approved for use in some countries.[115] Aclidinium bromide,
a novel long-acting muscarinic antagonist, is also an effective bronchodilator that improves lung
function, reduces symptoms, and reduces severe exacerbations requiring hospitalisation.[116] [117]
[118] Neither class of agent poses substantial increased risk of adverse cardiovascular events.[106]
Combination dual-class bronchodilator therapy confers greater benefits on lung function than either
individual class (long-acting beta-2-agonist or long-acting anticholinergic) alone.[119] However, it
remains unclear whether a combination of dual-class bronchodilator therapy is more effective than
long-acting antimuscarinic agents alone for reducing exacerbations.[120] Novel combinations of a
long-acting beta-2 agonist with a long-acting muscarinic antagonist (i.e., vilanterol/umeclidinium)[121]
[122] are currently under investigation, but their efficacy in reducing the frequency and/or severity
of exacerbations is as yet unknown.[123] Inhaled corticosteroids have been shown to decrease the
frequency of exacerbations and decrease healthcare utilisation for respiratory illnesses.[124] [125]
[126] [127] [128] Inhaled corticosteroids should not be used as monotherapy in COPD; their use
should be considered as additional therapy for people with exacerbations not controlled with long-
acting bronchodilators alone.[1]
7
disease Prevention
• The combination of inhaled corticosteroids and long-acting beta-2 agonists appears more effective
than either agent alone to decrease the frequency of episodes in people with more severe COPD.[93]
[129] [130] In patients with moderate to severe COPD, treatment with salmeterol plus fluticasone
propionate reduces the rate of exacerbations and slows the progressive worsening of FEV1.[131]
[132] [133] Importantly, withdrawal of the inhaled corticosteroid component of combination therapy
led to deterioration in lung function and worsened symptoms among patients who had two or more
exacerbations in the previous year.[134] A subsequent large parallel group study among patients
with severe COPD and history of previous exacerbation showed similar risk of moderate or severe
exacerbation among people who withdrew the inhaled corticosteroid from triple combination treatment
gradually over a 12-week period, compared with controls who did not; inhaled corticosteroid withdrawal
was, however, associated with a greater reduction in trough FEV1 at 18 weeks of follow-up.[135] Also,
an increased risk of pneumonia has been reported following long-term use of inhaled corticosteroids
and inhaled corticosteroid/beta-2 agonist combination therapy.[93] [136] [137] [138] [139] [140] This
increased risk of pneumonia is not accompanied by a clear increase in mortality risk.[140] Currently,
there are limited but encouraging data on the concurrent use of inhaled corticosteroids, long-acting
beta-2 agonists, and long-acting anticholinergic medicines.[98] [126] [141] [142] [143] [144] [145] [146]
[147]While long-acting beta-2 agonists, anticholinergics, and inhaled corticosteroids are all helpful,
the optimal choice of medications to reduce exacerbations while minimising potential adverse events
remains somewhat uncertain,[136] [148] [149] and the impact of triple-class therapy as compared
with dual-agent combination therapy or anticholinergic therapy alone on long-term outcomes such
PREVENTION
as mortality or hospitalisations is as yet unclear.[147] [150] Novel combination therapies including

fluticasone/vilanterol and indacaterol/glycopyrronium bromide are emerging, and their impact on
exacerbations of COPD is currently being studied.
• Treatment of patients with intermittent doses of macrolide,[151] [152] the fluoroquinolone
moxifloxacin,[153] [154] phosphodiesterase inhibitors[155] [156] such as roflumilast, or statins[157]
[158] [159] can also decrease the frequency, severity, and/or duration of COPD exacerbations. The
short-term use of prophylactic antibiotics can reduce the rate and number of exacerbations of COPD
or chronic bronchitis,[160] and preventative treatment with macrolides can lead to healthcare cost
savings.[152] Daily azithromycin therapy was most effective in reducing exacerbations requiring both
antibiotic and steroid treatment, and risk reduction was greatest among people of older age and
milder GOLD grade; notably, no significant reduction of exacerbation risk was found among current
smokers.[161] The impact of long-term use of intermittent (e.g., three-times weekly) macrolides
or other prophylactic antibiotics on the development of antibiotic-resistant pathogens and related
COPD exacerbations is as yet unknown but is of potential concern. Phosphodiesterase-4 (PDE4)
inhibitor therapy is commonly associated with gastrointestinal upset, abdominal pain, weight loss, and
other side effects; individual patient tolerance of these agents varies. Importantly, existing studies
suggest that the PDE4 inhibitor roflumilast reduced exacerbations among patients with severe airflow
obstruction with clinical features of chronic bronchitis (including sputum production and cough), but not
among those with a predominance of emphysema without chronic bronchitis features.[162] [163]
• Oral mucolytics such as N-acetylcysteine may offer benefit in exacerbation reduction, particularly
among people with moderate to severe COPD and or history of two or more exacerbations in the
previous 2 years, but their role remains controversial.[83] [164] [165]
• Alpha-1-antitrypsin augmentation therapy may reduce the frequency of exacerbations for selected
people with documented alpha-1-antitrypsin deficiency as the aetiology of their COPD.[166]
• Beta-blockers are often withheld from patients with COPD due to concerns regarding precipitation
of exacerbations and bronchospasm. However, cardiovascular disease is a common comorbidity of
COPD, and many patients have cardiovascular indications for beta-blocker therapy. Current data
suggest that cardioselective beta-blockers are not only safe and effective in patients with COPD, but
may reduce exacerbation risk and mortality.[167] [168] Therefore, beta-blockers should not be withheld
from patients with COPD who have cardiovascular indications for their use.
• Some data suggest that an oral Haemophilus influenzae vaccine may help reduce recurrent
exacerbations of chronic bronchitis in selected patients;[169] however, one Cochrane review analysis
demonstrated that oral H influenzae vaccine did not significantly reduce the number or severity of
exacerbations.[170]
• Oral Haemophilus vaccines are not formally recommended in existing guidelines.[31] Prophylactic
antibiotics to prevent exacerbations are also not recommended.
• Although retrospective studies suggested that statins might decrease the rate and severity of
exacerbations, one large prospective randomised controlled trial of simvastatin versus placebo did
not show a reduction in exacerbation rates or time to first exacerbation among people with history of
disease Prevention
COPD exacerbation requiring accident and emergency department visit or hospitalisation in the year
prior to study enrolment.[171]
Secondary prevention
Pulmonary rehabilitation and disease-management programmes
• Patients who are non-compliant with their medicine regimens may develop worsening of signs
and symptoms associated with COPD. It is important to discuss and determine adherence with
medications in patients presenting with acute exacerbations.[292] Failure to adhere to prescribed
medications may be associated with increased healthcare costs.[293] Moreover, healthcare providers
do not always adhere to existing guidelines for management of stable COPD or acute COPD
exacerbations.[294] This, in turn, may impact COPD exacerbation outcomes.
• Also, patients with COPD are less physically active than healthy adults and low physical activity levels
are associated with a faster rate of decline in lung function and increased hospitalisations for COPD
exacerbations over time.[285] [295] [296] Pulmonary rehabilitation programmes provide exercise
reconditioning and education focused on health-enhancing behaviours that can improve patients’
physical activity levels and knowledge regarding management of their disease.[232] [297] As such,
patients’ participation in pulmonary rehabilitation programmes can play an important role in prevention
PREVENTION
of subsequent exacerbations,[292] [296] [298] particularly when undertaken within a month following
an exacerbation.[83] [238]
• Outpatient follow-up of patients within 30 days of hospital discharge following acute exacerbations
also helps prevent readmissions and relapse of disease.[289] Action plans can help patients recognise
worsening symptoms, initiate earlier treatment, and reduce overall impact of exacerbations.[83]
[299] Enrolment of patients in disease-management and integrated-care programmes can also be
effective in reducing emergency visits and/or hospitalisations for COPD exacerbations.[231] [272]
[273] However, their use remains somewhat controversial given that some trials have not shown any
increase in time to hospital readmission,[300] and one randomised controlled trial had to be stopped
early due to a noted increase in mortality in the patient group randomised to comprehensive care
management compared with the control group receiving guideline-based routine clinical care.[88]
[275] Self-management programmes offered immediately after acute exacerbations are associated
with positive effects on patients’ knowledge, but based on existing evidence it is not possible to draw
firm conclusions regarding their efficacy for other outcomes.[301] Education with case management
that includes direct access to a healthcare specialist at least monthly is recommended by evidence-
based guidelines for patients with previous or recent exacerbations to reduce subsequent severe
exacerbations requiring hospitalisation.[83] The benefits of disease management programmes
likely vary depending on programme content and structure, the healthcare system in which they are
implemented, and the patient population being studied. The role of hospital-at-home programmes in
the management of COPD exacerbations is being studied.[88] [277]
• Tele-health has been used for home-based disease monitoring and management intervention.[302]
Randomised controlled trials have suggested that the use of nurse-centred tele-assistance may
decrease the occurrence of exacerbations of COPD, urgent care visits, and hospitalisation.[302]
The use of such programmes may be cost-saving.[278] Other analyses have suggested that home
tele-monitoring may prolong the time free of hospitalisations or accident and emergency department
visits,[88] but the total number of hospitalisations may not be affected and another randomised
controlled trial showed no clear beneficial effects.[279] Heterogeneity of existing studies precludes
development of any firm generalisable conclusions regarding the role of tele-health in the prevention or
treatment of exacerbations at the present time,[303] and as such it is not currently recommended for
exacerbation prevention.[1] [83]
9
disease Diagnosis
Case history
Case history #1
A 67-year-old woman with a history of COPD presents with 3 days of worsening dyspnoea and increased
frequency of coughing. Her cough is now productive of green, purulent sputum. The patient has a 100-
pack-year history of smoking. She has had intermittent, low-grade fever of 37.7°C (100°F) for the past
3 days and her appetite is poor. She has required increased use of rescue bronchodilator therapy in
addition to her maintenance medications to control symptoms.
Other presentations
COPD often goes unrecognised. By the time that COPD is diagnosed, patients typically experience
dyspnoea with only mild to moderate exertion and may have a chronic productive cough, and FEV1 is
often already <50% of predicted level. Many patients are diagnosed with COPD for the first time when
they require hospitalisation for an acute exacerbation of disease.[2] Exacerbations may be triggered by
an infection or exposure to an airborne pollutant or other change in environmental conditions. Patients
commonly present with a complaint of increased dyspnoea, a change in the intensity and frequency
of chronic cough and/or wheezing, and a change in the colour and/or volume of sputum produced.
Patients experiencing an exacerbation may have a low-grade fever, but the presence of a fever, especially
>38.5°C (>101.3°F), should increase suspicion for an alternate diagnosis such as pneumonia.
Step-by-step diagnostic approach

Many definitions for acute exacerbations of COPD have been proposed and include many of the same
components. Episodes may be diagnosed in people with a history of COPD who experience any of the
following: worsening respiratory symptoms and physiological status;[11] or worsening of degree of cough,
their level of dyspnoea, and/or the volume and character of sputum,[63] particularly if these changes are
DIAGNOSIS
acute in onset, sustained over time, beyond the normal day-to-day variation, or lead to a change in the
patient's baseline medicine regimens.[1] [172] [173] [174]
Clinical evaluation
Most patients presenting with a potential acute exacerbation are stable enough that they may be
evaluated and managed in the outpatient setting. Clinical evaluation should include determination of the
following: vital signs (including SaO2 via pulse oximetry), mental status, severity of the level of dyspnoea
and airflow obstruction, history of symptoms associated with the patient's chief complaints, and the ability
to continue to provide self-care at home. The risk of exacerbations should also be assessed: people
with severe or very severe airflow obstruction, those with a history of two or more exacerbations in the
preceding year, or those with history of hospitalisation due to exacerbation in the previous year are
considered at high risk of subsequent exacerbations.[1] Patients should be questioned regarding changes
in their baseline level of dyspneoa, cough, wheeze, or sputum production; character of the sputum;
presence of fever; any other focal complaints (e.g., chest pain, signs/symptoms of an upper respiratory
tract infection, palpitations, light-headedness, or leg swelling); as well as their understanding and
adherence with their current medical regimen for COPD, including the use of supplemental oxygen and
any change in their requirement for rescue inhaler use. On examination, auscultation may reveal wheeze,
disease Diagnosis
and it is important to observe patients for signs of respiratory failure (e.g., tachypnoea, accessory muscle
use, chest retractions, paradoxical movements of the abdomen, and/or cyanosis) and/or signs of cor
pulmonale, haemodynamic instability, or worsened mental status.
Laboratory evaluation and imaging

Diagnostic tests are typically reserved for those with moderate to severe exacerbations. Features may
include but are not limited to unstable vital signs, severe symptoms, or low SaO2 on pulse oximetry,
evidence of ventilatory failure, or mental status change (e.g., confusion, lethargy, coma). Diagnostic
testing should also be considered if the diagnosis of an episode is uncertain.
Diagnostic tests for people with moderate to severe exacerbations may include:
• Pulse oximetry
• Chest x-ray
• ECG
• ABG
• FBC with platelets
• Electrolytes
• Creatinine
• Urea levels
• Sputum analysis.
In severe disease, a sputum Gram stain and culture should be obtained, and, if hospitalisation is being
considered and where feasible, tests for respiratory viruses should be conducted, to prevent healthcare-
associated transmission of the pathogen (e.g., influenza, respiratory syncytial virus, and parainfluenza
virus).
Emerging investigation
Procalcitonin is emerging as a promising biomarker for the diagnosis of bacterial infections as it tends to
be higher in severe bacterial infections and low in viral infections. The US Food and Drug Administration
DIAGNOSIS
has approved procalcitonin as a test for guiding antibiotic therapy in patients with acute respiratory tract
infections. A Cochrane review of the use of procalcitonin to guide initiation and duration of antibiotic
treatment in people with acute respiratory tract infections found it lowered the risk of mortality, and lead to
lower antibiotic consumption, and lower risk for antibiotic-related side effects in all patients including those
with acute exacerbation of COPD.[175] Further research is required to establish its use in clinical practice.
[VIDEO: How to perform an ECG animated demonstration ]
[VIDEO: Radial artery puncture animated demonstration ]
Risk factors
Strong
bacterial infection
• Bacterial pathogens are thought to be responsible for the majority of acute exacerbations of COPD.
Evidence suggests that the presence of purulent sputum is frequently associated with a bacterial lower
11
disease Diagnosis
respiratory tract infection.[58] Because the lower respiratory tract in people with COPD is not sterile,
the interpretation of culture results of both upper and lower respiratory tract specimens must be made
with caution. There is mixed evidence as to whether greater bacterial colony counts over baseline
levels are present in patients with an acute exacerbation of COPD.[59] [60]
• The most frequently identified bacterial pathogens include Haemophilus influenzae , Streptococcus
pneumoniae , and Moraxella catarrhalis .[31] [51] The role of other gram-positive pathogens such
as Staphylococcus aureus and gram-negative pathogens such as Pseudomonas aeruginosa in the
pathogenesis of acute exacerbations of COPD is less certain, but patients with more severe COPD
and greater frequency and/or severity of exacerbations, or those who have been hospitalised recently
or had recent (within 2 weeks) daily use of systemic corticosteroids (i.e., >10 mg/day of prednisolone)
are more likely colonised with these pathogens.[31] [61]
• Of note, it has been shown that acquisition of a new strain of bacteria by people with COPD is a risk
for an acute exacerbation.[62] Alterations in the innate and/or adaptive immune response may result in
cyclical perpetuation of inflammation and infection.[42]
• Concurrent infection with both bacterial and viral respiratory tract pathogens has been associated
with more severe episodes.[50] Treatment of moderate to severe exacerbations with antibiotics has
been associated with improved outcomes.[63] [64] Influenza vaccination may have protective effect in
reducing risk of Pseudomonas aeruginosa infection.[31]
gastro-oesophageal reflux and/or swallowing dysfunction

• Gastro-oesophageal reflux and swallowing dysfunction with associated aspiration are common
triggers for exacerbations of COPD.[65] [66] No available studies guide whether the treatment of reflux
improves exacerbations of COPD.
viral infection
• It has been estimated that respiratory viruses are responsible for 22% to 50% of acute
exacerbations.[33]
• The rhinovirus has been isolated from patients with acute exacerbations of COPD more often than
other viruses.[67]
• Influenza, respiratory syncytial virus, parainfluenza, coronavirus, adenovirus, and human
DIAGNOSIS
metapneumovirus have also been associated with episodes.[31] [34] [35] [68]
• Exacerbations associated with respiratory viruses have been shown to be more severe and take longer
to resolve compared with those attributed to other triggers.[67] [69] Co-infection with viruses and
bacterial pathogens is not uncommon.
• It has been hypothesised that the chronic presence of respiratory viruses in the lower respiratory tract
may play a role in the pathogenesis of COPD.[70]
pollutants
• Increasing levels of pollutants, specifically nitrogen dioxide (NO2), sulphur dioxide (SO2), ozone (O3),
and black smoke particulates, including wood smoke, have been associated with a greater rate of
acute exacerbations and hospital admissions for people with COPD.[71] [72] [73] Peaks of air pollution
can also increase hospitalisations and mortality.[74]
• Exposure to many of these pollutants has been found to induce an inflammatory response in the
respiratory tract.[28]
Weak
disease Diagnosis
atypical bacterial infection
• Atypical organisms ( Mycoplasma pneumoniae , Chlamydia pneumoniae , and Legionella species)
have been associated with acute exacerbations though with conflicting results.[75] [76] [77] There is
insufficient evidence to suggest that antimicrobial coverage of atypical bacterial pathogens improves
outcomes.
change in weather
• Changes in temperature and humidity are associated with increased risk for acute exacerbations of
COPD.[28] [78] However, it remains unclear whether changes in ambient temperature and/or humidity
or changes in risk for infection due to respiratory viruses and/or other pathogens account for this
association.
• Exacerbation rates and all-cause mortality tend to be higher during winter months.[19]
History & examination factors

Key diagnostic factors
dyspnoea (common)
• A sustained increase from the baseline level of dyspnoea beyond day-to-day variation is usually
observed in patients with an acute exacerbation.[11]
cough (common)
• A change in the character and frequency of cough is often identified.[11] This change should be
beyond day-to-day variations of the patient's typical cough.[1]
wheeze (common)
• All patients with COPD have expiratory flow limitation, and this may lead to wheezing. Patients
experiencing an acute exacerbation may be found to have greater severity of wheezing and
prolongation of the expiratory phase of breathing on examination. However, wheezing is not identified
DIAGNOSIS
in many patients.
changes in sputum volume/colour/thickness (common)

• Changes in either the volume or the character (thickness, colour) or both are frequently observed. The
presence of purulent sputum appears to be sensitive and specific for high bacterial loads and may help
to identify subsets of patients who may most benefit from therapy with antibiotics.[177] [178]
tachypnoea (common)
• Tachypnoea is frequently seen and may be severe. It is important to observe the patient for signs of
respiratory failure.
cyanosis (uncommon)
• Possible sign of impending respiratory failure.
Other diagnostic factors

past medical hx COPD (common)
13
disease Diagnosis
• A past medical history of COPD should be sought, as well as of other conditions that may impact
the likelihood of another acute problem considered in the differential diagnosis. People with a history
of two or more exacerbations in the preceding year or those with history of hospitalisation due to
exacerbation in the previous year are considered at high risk of subsequent exacerbations.[1]
tobacco use (common)

• It is important to determine if patients have a history of significant exposure to tobacco smoke and
whether they are currently smoking.
past medical hx of gastro-oesophageal reflux and/or swallowing dysfunction

(common)
• It is important to determine if patients have a history of heartburn, bitter taste in the mouth, coughing
or choking after eating, hiatal hernia, and/or gastro-oesophageal reflux or difficulty swallowing.[65]
[66] However, gastro-oesophageal reflux should be considered as a potential cause of recurrent
exacerbations even if the patient lacks the above-noted typical symptoms and signs of gastro-
oesophageal reflux.
• No available studies guide whether the treatment of reflux improves exacerbations of COPD.
malaise and fatigue (common)

• These symptoms and other non-specific symptoms such as insomnia, decreased activity level, and
loss of appetite are commonly identified in people with an acute exacerbation of COPD.[173] [176]
• While these symptoms have great impact on the quality of life of the patient, they are generally not
used to determine whether an exacerbation is present.
chest tightness (common)

• This may result from worsened airflow limitation and chest hyperinflation.[14] However, the possibility
of a myocardial infarction or pneumothorax should be considered if marked chest tightness or other
chest discomfort is present.
features of cor pulmonale (common)

DIAGNOSIS
• This may develop as a result of increased hypoxic vasoconstriction due to exacerbation-induced

hypoxaemia. The resulting increase in pulmonary vascular resistance and/or pulmonary artery
pressure can lead to acute right heart failure. Elevated jugular venous pressure, hepatojugular reflux,
peripheral oedema, and relative hypotension may be present
environmental/occupational exposure to pollutants or dust (uncommon)

• It should be determined whether the patient has a history of significant exposure to black smoke, such
as wood smoke, dust and/or other pollutants.
change in mental status (uncommon)

• Including drowsiness, confusion, and/or personality change
fever (uncommon)
• Signs of a bacterial infection (based on increased sputum purulence and/or volume) may be
considered an indication for antimicrobial therapy.[1] In general, <50% of people with acute
exacerbations experience fever.[31] [35] [58]
• The presence of a high and/or persistent fever should lead to consideration the presence of bacterial
pneumonia or influenza virus infection.
disease Diagnosis
accessory muscle use (uncommon)
• Sign of impending respiratory failure.
paradoxical movements of abdomen (uncommon)

• Sign of impending respiratory failure.
Diagnostic tests
1st test to order
Test Result
SaO2 on pulse oximetry depressed below the
patient's baseline level
• Recommended to be performed for all patients with a possible acute
exacerbation of COPD, when available. It should be performed
when vital signs are obtained. During an episode, SaO2 is frequently
depressed below the patient's baseline level, and supplemental
oxygen and arterial blood gas testing should be considered if the
level is <90%.
CXR hyperinflation, flat tened
diaphragms, increased
• Rarely diagnostic; principal purpose is to exclude alternate
retro-sternal air space,
diagnoses. A CXR should be performed in people with moderate to
bullae, and a small,
severe disease and where pneumonia or other potential diagnoses
(e.g., pneumothorax, congestive heart failure, pleural effusion) are vertical heart
being considered.
ECG may be right heart
enlargement, arrhythmia,
• Cardiovascular disease is common in people with COPD.[179]
Additionally, the possibility of a myocardial infarction or pneumothorax ischaemia
should be considered if chest tightness or other chest discomfort is
present. Patients with COPD are at higher risk to develop cardiac
ischaemia and/or arrhythmias that can also lead to dyspnoea.
DIAGNOSIS
[VIDEO: How to perform an ECG animated
demonstration ]
Arterial blood gas respiratory acidosis and
compensatory metabolic
• Arterial blood gas (ABG) testing should be performed for people with
alkalosis
a moderate to severe acute exacerbation of COPD, to detect chronic
hypercapnia and assess for acute respiratory acidosis. Comparison
of results to prior baseline ABG is crucial (when available). Acute
respiratory acidosis may be a sign of impending respiratory failure.
Venous blood gas sampling is not considered a reliable alternative
measure.[180]
• PaO2 <60 mmHg indicates potential respiratory failure. PaO2 <50
mmHg, PaCO2 ≥45 mmHg, or pH <7.35 indicate a potentially life-
threatening illness that requires consideration for intensive care and
initiation of assisted ventilation.[181]
FBC with platelets may show elevated
haematocrit, elevated
• Should be considered for patients with moderate to severe
WBC count or anaemia
exacerbations, to screen for abnormalities that may suggest
additional medical disorders such as infection or anaemia.
15
disease Diagnosis
Test Result
electrolytes, urea, + creatinine usually normal
• Should be considered for patients with moderate to severe
exacerbations. An abnormal result may suggest additional medical
disorders. Patients with COPD exacerbations may have decreased
oral intake and may become volume depleted.
Other tests to consider
Test Result
sputum culture + Gram stain may suggest bacterial
infection
• In severe disease, and if hospitalisation is being considered, a
sputum Gram stain and culture should be obtained to assess for
potential bacterial pathogens that may have triggered the episode.
respiratory virus diagnostics may confirm viral
infection
• In severe disease and, if hospitalisation is being considered, testing
for respiratory virus pathogens (where feasible) should be considered
both to identify any treatable agent (e.g., influenza), and in case of
hospitalisation, to identify the need for use of expanded infection
control precautions.
cardiac troponin normal if no myocardial
injury
• Elevations in cardiac troponin can occur due to unrecognised
myocardial injury resulting from COPD exacerbation. Elevations in
troponin may be associated with increased mortality.[182]
CT scan of chest normal if no pneumonia,
pleural effusion,
• May be useful to exclude alternate diagnoses, especially pulmonary
malignancy, or
embolus, if the diagnosis and basis of respiratory decompensation
pulmonary embolus
remains uncertain after routine CXR.
present
DIAGNOSIS
Emerging tests
Test Result
procalcitonin may be elevated
• Emerging as a promising biomarker for the diagnosis of bacterial
infections as it tends to be higher in severe bacterial infections
and low in viral infections. The US Food and Drug Administration
has approved procalcitonin as a test for guiding antibiotic therapy
in patients with acute respiratory tract infections. A Cochrane
review of the use of procalcitonin to guide initiation and duration of
antibiotic treatment in poeple with acute respiratory tract infections
found it lowered the risk of mortality, and lead to lower antibiotic
consumption, and lower risk for antibiotic-related side effects in all
patients including those with acute exacerbation of COPD.[175]
Further research is required to establish its use in clinical practice.
disease Diagnosis
Differential diagnosis
Condition Differentiating signs / Differentiating tests

symptoms
Congestive heart failure • Patients with systolic left- • Chest imaging may show an
sided or biventricular enlarged heart, pulmonary
congestive heart failure will vascular congestion, and/
often have a history of heart or pleural effusions. An
failure. Underlying diastolic elevated B-type natriuretic
heart failure is often under- peptide is often present.[184]
recognised. [185] An echocardiogram
• Physical examination may may be used to determine
note signs consistent with cardiac function.
heart failure, such as an
elevated jugular venous
pressure, extra heart
sounds, coarse breath
sounds with crackles above
the lung bases, wheezing,
and dependent pitting
oedema.[183] It may be
difficult to distinguish heart
failure, particularly left-sided
heart failure, from an acute
exacerbation of COPD.
DIAGNOSIS
17
disease Diagnosis
symptoms
Pneumonia • Many aspects of acute • Chest imaging in patients
exacerbations including with pneumonia should
dyspnoea, cough, and identify changes consistent
sputum production may with an infiltrative process in
be found in patients with the lung parenchyma.
pneumonia and it is often
not possible to differentiate
without chest imaging.
• About 10% to 15% of
patients presenting
with an apparent acute
exacerbation are found to
have pneumonia, or other
abnormalities, defined
by chest imaging.[186]
[187] [188] Patients with
pneumonia have in general
been found to experience
higher fevers, more acute
onset of illness, and
somewhat greater severity of
acute illness when compared
with COPD patients without
pneumonia.[186] [189] The
presence of pneumonia
as a cause of respiratory
decompensation in a
patient with COPD does
not necessarily imply
the presence of a COPD
exacerbation per se (i.e.,
the presence of worsened
airflow limitation related to
DIAGNOSIS
airways inflammation and/

or bronchoconstriction),
and as such careful
consideration should be
given as to whether systemic
corticosteroids are warranted
in such patients.
Pleural effusion • Pleural effusions may • Chest imaging is

exacerbate dyspnoea recommended.
in patients with COPD.
Physical examination may
demonstrate decreased
or absent breath sounds
with dullness to percussion
related to a pleural effusion.
disease Diagnosis
symptoms
Pneumothorax • Patients with COPD found • Chest imaging is
to have pneumothoraces recommended to exclude a
may or may not have possible pneumothorax in
additional signs or symptoms patients with more than mild
suggestive of a respiratory episodes.[190]
tract infection, but their
presentation may closely
mirror that of an acute
exacerbation. Decreased
breath sounds may be
identified on the affected
side and tracheal deviation
away from the affected side
and/or hypotension may be
present in patients with a
tension pneumothorax.
Pulmonary embolism • Clinically, pulmonary • Pulmonary embolus may be

embolism may present with diagnosed using D-dimer
signs and symptoms similar assay, spiral computed
to an acute exacerbation tomography angiogram, or
of COPD, and the two are pulmonary angiography in
difficult to distinguish.[191] patients with COPD. Test
Pulmonary embolism should selection should be based
be considered as a cause on local expertise. Dopplers
of the acute symptoms if of the lower extremities may
no other identifiable trigger be considered to evaluate for
for the exacerbation is deep vein thrombosis.
evident. People with prior
thrombo-embolic disease or
underlying malignancy may
be at particular risk.[191]
• A low systolic blood pressure
DIAGNOSIS
and/or the inability to
increase the PaO2 >60
mmHg with oxygen may
indicate the presence of a
pulmonary embolism.
Cardiac ischaemia • Clinically, may be difficult • An electrocardiogram should

to distinguish. Chest pain be performed, especially for
may be more apparent, with patients who may require
radiation down left side. hospitalisation for care of
Nausea, jaw pain, and/or an acute exacerbation of
diaphoresis may be present. COPD, to identify possible
cardiac ischaemia and
arrhythmias.[1]
19
disease Diagnosis
symptoms
Cardiac arrhythmia • Differentiating features • An electrocardiogram should
may include palpitations, be performed, especially for
light-headedness, loss patients who may require
of consciousness, and/or hospitalisation for care
collapse. of an acute exacerbation
of COPD or who are
experiencing palpitations
or dizziness, to identify
possible cardiac ischaemia
and arrhythmias.[1]
DIAGNOSIS
disease Diagnosis
symptoms
Upper airway obstruction • Large airway obstruction • Spirometry with flow
typically presents with volume loop can identify
dyspnoea and wheeze the presence of upper
(particularly during exertion airway obstruction; when
and with forced exhalation tracheobronchomalacia is
manoeuvre), and it is suspected, CT scanning
commonly mistaken for with inspiration and
refractory exacerbations of expiration views or direct
COPD; variable intrathoracic bronchoscopic airway
upper airway obstruction inspection can be diagnostic.
is often caused by
tracheobronchomalacia, an
aspirated object, or central
airway tumour; variable
extrathoracic upper airway
obstruction is commonly
caused by vocal cord
paralysis, as well as by
inflammation and swelling
of the perilaryngeal soft
tissues and intermittent
vocal cord spasm associated
with GORD, undiagnosed
or untreated obstructive
sleep apnoea, and chronic
post nasal drip; fixed upper
airway obstruction may be
caused by tracheal stenosis
(e.g., due to prior intubation
for mechanical ventilation),
extrinsic compression
of central airways (e.g.,
lymphadenopathy or
DIAGNOSIS
mass), or large airway
tumour; auscultation over
the larynx, trachea, and
main bronchi during both
quiet breathing and forced
exhalation or hyperpnoea
manoeuvre should be done
to evaluate for the presence
of upper airway obstruction;
complete resolution of
wheezing during resting
quiet breathing that is
present during exertion
or a forced exhalation
manoeuvre argues
against the presence of
bronchoconstriction related
to COPD exacerbation.
21
disease Diagnosis
symptoms
Inappropriate ox ygen • While oxygen therapy • An ABG should be
therapy is clearly indicated for performed for patients
many patients with COPD who are hypoxaemic or
and acute exacerbations, are receiving oxygen
excessive oxygen leads therapy who present with an
to further degradation of apparent acute exacerbation
the patient's respiratory of COPD.
physiology. Exposure to
oxygen leads to decrease
of hypoxic vasoconstriction
of arteries supplying poorly
ventilated spaces, increasing
the degree of V/Q mismatch
and/or intrapulmonary
shunt.[192] [193] An excess
of oxygen may also decrease
the capacity of erythrocytes
to carry CO2 (Haldane
effect).[194] These changes
may then result in worsening
of the patient's hypercarbia
and respiratory acidosis.
Selected patients with
impaired respiratory drive
may also develop worsening
hypercarbia.
Diagnostic criteria
Assessment of severe exacerbations
DIAGNOSIS
Severity depends on patient's prior status and any changes to previous baseline investigation (based
on symptoms, examination, lung function, ABG). Use of accessory respiratory muscles, paradoxical
respirations, cyanosis, new peripheral oedema, haemodynamic instability, and/or worsened mental status
(e.g., confusion, lethargy, coma) are important indicators of severity of exacerbation.[1]
disease Treatment
Step-by-step treatment approach
The overall goals of therapy are to alleviate the patient's symptoms of dyspnoea, to stabilise and improve
respiratory status, and where possible, to remove the ongoing trigger. Short-acting beta-2 agonists and
anticholinergic medicines are considered first-line therapy, and may provide benefit within 15 and 30 minutes,
respectively. If the patient remains symptomatic, repeat doses may be given. There are as yet no clinical
trials to guide whether long-acting bronchodilators should be continued during acute COPD exacerbation.
Although discontinuation of a maintenance therapy might potentially contribute to worsening symptoms
and/or lung function, regular frequent administration of short-acting bronchodilators in addition to long-
acting bronchodilators of the same class has the potential to increase the risk of medication-related adverse
effects. Supplemental oxygen may be needed if the patient is hypoxic, although oxygen should be applied
with caution to prevent further hypercarbia. Careful titration of supplemental oxygen even in the pre-hospital
setting (e.g., en route to the hospital) is important to prevent worsening respiratory acidosis, which may
increase mortality.[195]
Systemic corticosteroids decrease airway inflammation and have been shown to be beneficial for patients
with acute exacerbation of COPD.[196] [197] [198] [199] They enhance early (within 3 days) improvements
in symptoms and lung function, reduce treatment failures and early (within 1 month) relapses, and reduce
hospital length of stay.[197] Systemic corticosteroids should be initiated after the first treatment of short-
acting inhaled bronchodilators. However, studies examining the role of systemic corticosteroids have been
primarily performed among people presenting to accident and emergency departments and those who are
hospitalised. The shortest duration of systemic corticosteroids that confers clinical benefit while minimising
adverse effects remains unclear.[200] The balance of risks and benefits of corticosteroids for people with
milder exacerbations is uncertain. Moreover, the benefit of systemic corticosteroid therapy for people with
acute exacerbations of COPD with associated respiratory failure requiring mechanical ventilatory support is
also unclear. One randomised controlled trial found no difference in ICU mortality, duration of mechanical
ventilation, or ICU length of stay between patients who received prednisolone versus the control group who
did not, yet those who received prednisolone had a higher risk of hyperglycaemia.[201]
The presence of pneumonia as a cause of respiratory decompensation in a patient with COPD does not
necessarily imply the presence of a COPD exacerbation per se (i.e., the presence of worsened airflow
limitation related to airways inflammation and/or bronchoconstriction), and as such careful consideration
should be given as to whether systemic corticosteroids are warranted in such patients.
Nebulised corticosteroids have been used with some success, but their utility in acute exacerbations of
COPD and relative efficacy compared with systemic corticosteroids is not fully clear.[181] [202]
While methylxanthine medicines may provide benefit to some people with COPD,[203] [204] this class of
medicines has a narrow therapeutic window and there does not appear to be a role for use in patients with
acute exacerbations.[205]
The use of mucolytics, expectorants, and/or physical mucus-clearing techniques does not appear to provide
any clear proven benefit,[206] [207] although some patients do experience symptomatic relief.
TREATMENT
COPD patients and their exacerbations are highly heterogeneous. While many aspects of their care are
amenable to protocols, those who may require hospitalisation, those who may benefit from pulmonary
rehabilitation, or those who have a less- versus more-severe acute exacerbation vary greatly according to the
comorbidities and other characteristics of the individual patient.
23
disease Treatment
Hospitalisation should be considered for people with marked or sudden increase in symptom severity, severe
underlying COPD, or new physical signs (such as peripheral oedema or cyanosis); those who have a history
of frequent exacerbations or comorbid illness; those who are of older age; or those who fail to respond to
initial outpatient management or have suboptimal home support.[1]
Exacerbations with suspected bacterial aetiology

Bacterial infections are thought to be a common trigger.[62] Multiple randomised placebo-controlled
trials have shown that antibiotics are beneficial for the treatment of patients with acute exacerbation of
COPD.[63] [208] [209] Antibiotics should be given to patients suspected of having a bacterial trigger.[13] A
bacterial trigger may be present in people with two or more of the following: increased sputum purulence,
increased sputum volume, or worsening dyspnoea.[46] [177] [210] The Global Initiative for Chronic
Obstructive Lung Disease (GOLD) guidelines recommend antibiotics for people with a combination of
increased dyspnoea, increased sputum volume, and increased sputum purulence, or for those with
increased sputum purulence combined with one of the other two criteria noted above.[1] Patients with
more severe exacerbations, particularly those requiring treatment in the intensive care unit (ICU), have
been shown to derive greater benefit from antibiotic therapy;[63] [211] antibiotics should be given to
patients with severe exacerbations requiring mechanical ventilation (invasive or noninvasive).[1] However,
patients who receive antibiotics are at increased risk for antibiotic-associated diarrhoea.[211] Antibiotic
choice and duration of therapy is an unresolved issue, but in general should be based on local resistance
patterns and patient characteristics.[210] The NHLBI/WHO (US National Heart, Lung and Blood Institute/
World Health Organization) workshop recommended choosing specific antibiotics based on local
susceptibility patterns of common bacteria associated with exacerbations: Streptococcus pneumoniae ,
Haemophilus influenzae , and Moraxella catarrhalis .[46] It has been recommended that more narrow-
spectrum antibiotics (e.g., amoxicillin, amoxicillin/clavulanic acid, doxycycline, tetracycline, second-
generation cephalosporins, macrolides, trimethoprim/sulfamethoxazole) be considered for patients at less
risk for a poor outcome and with an exacerbation of lesser severity. Patients with more severe underlying
COPD and those with greater exacerbation severity are more often colonised with gram-negative bacteria
such as Pseudomonas aeruginosa or other enteric gram-negative organisms and/or Staphylococcus
aureus (including methicillin-resistant Staphylococcus aureus ).[61] Therefore, extended-spectrum beta-
lactam combination drugs, fluoroquinolones, and vancomycin are considered for patients at greater risk
for a poor outcome or with an episode of greater severity, such as people with recent history of antibiotic
use, treatment failure, prior antibiotic resistance, or risk factors for healthcare-associated infections, or
critically ill patients in the ICU.[210] Studies have suggested that the use of a respiratory fluoroquinolone,
amoxicillin/clavulanic acid, second- or third-generation cephalosporins, or macrolides may be associated
with fewer treatment failures or recurrent exacerbations.[212] [213] [214] [215] [216] [217] There is
currently insufficient evidence to guide use of antibiotics based on serum procalcitonin levels in patients
with COPD.[210]
Severe exacerbations of COPD

Severity depends on patient's prior status and any changes to previous baseline investigation (based
on symptoms, examination, lung function, ABG). Use of accessory respiratory muscles, paradoxical
respirations, cyanosis, new peripheral oedema, haemodynamic instability, and worsened mental status
TREATMENT
(e.g., confusion, lethargy, coma) are important indicators of severity of exacerbation.[1]
In addition to the general measures, patients with severe exacerbations who do not appear to respond
sufficiently to the initial interventions should be considered for non-invasive positive-pressure ventilation
(NPPV). The use of NPPV for patients with acute exacerbations of COPD and respiratory failure has been
disease Treatment
shown to decrease the rate of invasive mechanical ventilation and mortality.[218] [219] [220] [221] [222]
[223] NPPV use should be considered for patients with one or more of the following:[1]
• Respiratory acidosis (PaCO2 ≥ 6.0 kPa or 45 mmHg and arterial pH ≤ 7.35)

• Severe dyspnoea with clinical signs suggestive of respiratory muscle fatigue, increased work
or breathing, or both, such as use of respiratory accessory muscles, paradoxical motion of the
abdomen, or retraction of the intercostal spaces
• Persistent hypoxaemia despite supplemental oxygen therapy.
In some patients, NPPV may fail. Invasive mechanical ventilation via endotracheal intubation should be
considered for patients who have outright respiratory or cardiac arrest, are in or have signs of impending
acute respiratory failure despite NPPV, have impaired mental status or cardiovascular instability, are at
high risk for aspiration, or for whom NPPV cannot be appropriately applied (e.g., craniofacial trauma,
recent gastro-oesophageal surgery, copious secretions, anxiety disorder, facial discomfort, or severe skin
breakdown).[224] Physiological criteria for invasive mechanical ventilation include the following: severe
hypoxia, inability to tolerate NPPV or failure of NPPV, respiratory or cardiac arrest, irregular breathing with
gasping or loss of consciousness, massive aspiration or persistent vomiting, inability to clear respiratory
secretions, heart rate <50 beats per minute with diminished alertness, severe haemodynamic instability
not responsive to medical treatment, or severe ventricular or supraventricular arrhythmias.[1] [225] The
risk for mortality is significant (11% to 49%) for people with severe disease in whom invasive mechanical
ventilation is indicated.[13] [226] Complications of mechanical ventilation include ventilator-associated
pneumonia and barotrauma. Weaning patients with severe COPD from mechanical ventilation can be
difficult.[224] Use of NPPV to assist weaning from mechanical ventilation can reduce weaning failure and
nosocomial pneumonia, and may reduce mortality.[223] [227]
[VIDEO: Tracheal intubation animated demonstration ]
[VIDEO: Bag-valve-mask ventilation animated demonstration ]
Pulmonary rehabilitation
Pulmonary rehabilitation is a multidisciplinary programme of care that involves physical rehabilitation as
well as guidance on disease management, nutrition, and other lifestyle issues (e.g., smoking cessation,
medicine compliance and inhaler technique, supplemental oxygen, and maintenance of physical
activity).[231] [232] [233]
• Selected forms of exercise rehabilitation initiated during a hospitalisation for COPD exacerbation,
including resistance strength training and transcutaneous electrical muscle stimulation, are well
tolerated and can prevent muscle function decline and hasten functional status recovery .[234]
[235] [236]
• Pulmonary rehabilitation initiated early during the recovery phase of an exacerbation is safe
and effective, and leads to improvements in exercise tolerance, physical abilities, the degree of
symptoms due to COPD, and quality of life.[237] [238] [239] [240] [241]
• Comprehensive supervised pulmonary rehabilitation in the outpatient setting in the post-
exacerbation period decreases the risk for future hospitalisation and may reduce mortality.[232]
TREATMENT
[238] [241] [242] Unsupervised home-based exercise training following exacerbations does not
appear to confer the same benefits.[243]
25
disease Treatment
Treatment details overview
Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
Acute ( summary )
at presentation
1st short-acting bronchodilator
plus systemic corticosteroid
adjunct airway clearance techniques
adjunct ox ygen
suspected bacterial adjunct narrow-spectrum antibiotic

aetiology (exacerbation of
lesser severity)
suspected bacterial adjunct broad-spectrum antibiotic

greater severity)
respiratory insufficiency adjunct non-invasive positive-pressure ventilation
adjunct invasive positive-pressure ventilation
Ongoing ( summary )
after stabilisation
1st pulmonary rehabilitation and disease-

management programmes
TREATMENT
disease Treatment
Treatment options
Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
Acute
at presentation
1st short-acting bronchodilator

Primary options
» salbutamol inhaled: 2.5 to 5 mg nebulised

every 20 minutes for up to 2 hours or until
clinical improvement, followed by 4-6 hourly
dosing; (100 micrograms/dose inhaler)
100-200 micrograms (1-2 puffs) every 20
minutes for up to 2 hours or until clinical
improvement, followed by 4-6 hourly dosing
-and/or-
» ipratropium inhaled: 0.25 to 0.5 mg
nebulised every 20 minutes for up to 2 hours
or until clinical improvement, followed by 4-6
hourly dosing; (20 micrograms/dose inhaler)
40 micrograms (2 puffs) every 20 minutes for
up to 2 hours or until clinical improvement,
followed by 4-6 hourly dosing
» Short-acting bronchodilators include beta-2

agonists and anticholinergic bronchodilators.
These medicines are delivered either by
nebulisation or metered-dose inhaler,[244]
and both reduce symptoms of dyspnoea;
improve airflow, possibly by decreasing lung
hyperinflation;[245] and are provided acutely
to patients with an acute exacerbation as the
initial treatment.[207] A systematic review did
not find significant differences in FEV1 when
short-acting bronchodilators were delivered
by nebuliser as compared with metered-dose
inhaler.[244] Severely dyspnoeic patients with
low inspiratory flow rates may have difficulty
achieving proper technique and medication
delivery from the metered-dose inhaler devices;
nebuliser treatment may be easier to use
for such patients. Administration should be
observed and a spacer should be used.
There is insufficient evidence to determine
whether metered-dose inhalers or the aerosol
nebuliser technique is the optimal method of
delivering bronchodilators to adults with COPD
exacerbation who are receiving mechanical
TREATMENT
ventilation via endotracheal tube.[246]
» Beta-2 agonists are typically favoured as

first-line as they function more rapidly than
anticholinergic bronchodilators. Initial therapy
with beta-2 agonists may lead to a transient
27
disease Treatment
Acute
reduction in PaO2.[247] If the initial dose of
short-acting bronchodilator does not provide
sufficient benefit, the frequency of dosing
may be increased and an anticholinergic
bronchodilator may be added.[248] [249]
Nebulised ipratropium may be given in
combination with nebulised salbutamol.
Ipratropium may be used in lieu of salbutamol for
patients developing significant adverse effects
due to beta-2 agonist use.
» It is not clear whether the combination

of a beta-2 agonist plus an anticholinergic
bronchodilator provides additional benefit.[248]
[250] [251] While there is no definitive evidence
that the combination improves outcomes,
patients may derive symptomatic benefit and
additional bronchodilation because these agents
work by different mechanisms. Combination
therapy is generally recommended for patients
who are not improving promptly on a beta-2
agonist alone.[1]
» After clinical improvement, the time between

doses may be increased as tolerated.
» Optimal dosing of bronchodilators in

acute exacerbations of COPD is yet to be
determined; however, guidelines generally
recommend increasing the dose or frequency of
administration. The doses recommended below
are a guide only and local protocols should be
consulted.
plus systemic corticosteroid
Treatment recommended for ALL patients in
selected patient group
Primary options
» prednisolone: 30-40 mg orally once daily for

5-7 days
OR
» methylprednisolone: 40-60 mg/day orally

given once daily or in 2 divided doses for 5-7
days
OR
TREATMENT
» methylprednisolone sodium succinate: 0.5

to 2 mg/kg intravenously every 6 hours for up
to 72 hours, followed by taper or change to
oral dosing
disease Treatment
Acute
» The use of systemic corticosteroids for the
treatment of acute exacerbation of COPD has
been associated with greater early improvement
in FEV1, improved oxygenation, faster recovery
time, decreased duration of hospitalisation,
and decreased rate of treatment failure and
relapsed disease.[1] [126] [196] [197] [198]
However, there is no evidence that the use
of corticosteroids has effect on rates of
mortality,[197] and the benefits for people with
acute exacerbations associated with respiratory
failure and the need for mechanical ventilation
are less clear.[197] [201]
» Studies identifying benefit in the use

of corticosteroids have used a range of
dose amounts and treatment durations.
Previous national and international guidelines
recommended that patients receive 30 to 40
mg prednisolone, or equivalent, for 7 to 14
days.[210] [248] It is not known whether tapering
systemic corticosteroids provides clinical
benefit apart from likely avoidance of adrenal
insufficiency. One randomised controlled trial
showed that 5 days’ treatment with 40 mg/day
of prednisolone was non-inferior to 14 days’
treatment in regard to risk of exacerbations
in the subsequent 6 months.[252] This 5-
day regimen is recommended in the Global
Initiative for Chronic Obstructive Lung Disease
(GOLD) guidelines.[1] The Department of
Veterans’ Affairs in the US recommends a similar
dose of 30 to 40 mg/day of prednisolone for
5 to 7 days.[210] An equivalent oral dose of
methylprednisolone may also be used. One
systematic review found no difference in risk
of treatment failure or relapse, likelihood of
an adverse event, length of hospital stay, or
lung function at the end of short (approximately
5 days) and longer (10-14 days) courses of
systemic corticosteroids.[197]
» Systemic corticosteroids should be initiated

after the first treatment of short-acting inhaled
bronchodilators.
» Diabetes is common in patients with COPD,

and the need for treatment of hyperglycaemia
is more frequently encountered when patients
receive systemic corticosteroids.[196] [197]
» For patients able to take oral medications,

TREATMENT
intravenous corticosteroids do not appear to

provide any significant benefit over those taken
orally.[197] [199] [253] [254]
29
disease Treatment
Acute
» The shortest duration of systemic
corticosteroids that confers clinical benefit while
minimising adverse effects remains unclear.[200]
adjunct airway clearance techniques
Treatment recommended for SOME patients in
» Selected airway clearance techniques such
as mechanical vibration and non-oscillating
positive expiratory pressure may improve
sputum clearance in some patients with copious
secretions, or concurrent bronchiectasis, and
may slightly reduce short-term risk of need for
ventilatory assistance,[255] but are not uniformly
helpful.[206] Other clearance techniques such
as manual chest wall percussion are also either
not routinely helpful or may have detrimental
effects.[256] [257] [258] There is no proven
benefit of airway clearance techniques on long-
term outcomes following COPD exacerbation,
such as reduction in subsequent exacerbation
risk.[255]
adjunct ox ygen
» Oxygen therapy is recommended for patients
with acute exacerbations who are hypoxic
(PaO2 <60 mmHg, SaO2 ≤90%). Oxygen is
best administered in a controlled fashion via a
high-flow Venturi mask to deliver 24% to 28%
oxygen.[181] The goal of oxygen therapy is
to increase PaO2 to ≥60 mmHg and SaO2
≥90%.[13] [46] For patients with hypercarbia
and more severe episodes, an ABG analysis is
recommended 30 to 60 minutes after initiating
oxygen therapy. Oxygen therapy may lead to
worsening hypercarbia, acidosis, and respiratory
failure due to worsening V/Q mismatch and
decreased CO2-carrying capacity of oxygenated
erythrocytes (Haldane effect). For this reason,
oxygen delivery via a high-flow Venturi mask
is favoured over nasal prongs as nasal prongs
are less accurate and deliver higher inspired
oxygen concentrations.[259] Careful titration
of supplemental oxygen even in the pre-
hospital setting (e.g., en route to the hospital)
is important to prevent worsening respiratory
acidosis and may impact mortality.[195] Oxygen
therapy may be discontinued when the patient is
TREATMENT
able to maintain PaO2 ≥60 mmHg and/or SaO2

≥90% on room air.
suspected bacterial adjunct narrow-spectrum antibiotic
lesser severity)
disease Treatment
Acute
Primary options
» amoxicillin: 500 mg orally three times daily
OR
» doxycycline: 100 mg orally twice daily
OR
» trimethoprim/sulfamethoxazole: 160/800 mg
orally twice daily
OR
» azithromycin: 500 mg orally once daily on

day 1, followed by 250 mg once daily for 4
days
Secondary options
» cefuroxime: 250-500 mg orally twice daily;

750 mg intravenously every 8 hours
OR
» amoxicillin/clavulanate: 875 mg orally twice

daily
Dose refers to amoxicillin component.
OR
» clarithromycin: 500 mg orally twice daily
» The severity depends on patient's prior

status and any changes to previous baseline
investigation (based on symptoms, examination,
lung function, ABG).
» Antibiotics should be given to patients

with severe exacerbations requiring assisted
ventilation, and those suspected of having a
bacterial trigger for their acute exacerbations,[13]
[31] [260] including in an acute exacerbation with
increased sputum purulence, increased sputum
volume, and/or worsening dyspnoea.[1] [177]
[210]
» It has been recommended that more narrow-

spectrum antibiotics (e.g., amoxicillin, amoxicillin/
TREATMENT
clavulanate, doxycycline, tetracycline, second-

generation cephalosporins, macrolides,
trimethoprim/sulfamethoxazole) be considered
for patients at less risk for a poor outcome and
with an exacerbation of lesser severity.[210]
31
disease Treatment
Acute
» It has been shown that short courses (e.g.,
5 days) of antibiotics are equally effective
as courses >5 days for patients with mild to
moderate exacerbations of COPD,[261] [262]
and the recommended length of therapy is
usually 5 to 7 days.[1]
suspected bacterial adjunct broad-spectrum antibiotic
greater severity)
Primary options
» levofloxacin: 500 mg orally once daily for

3-10 days, or 750 mg orally once daily for 5
days
OR
» ciprofloxacin: 500 mg orally twice daily for

7-10 days
OR
» moxifloxacin: 400 mg orally/intravenously

once daily for 3-10 days
OR
» ampicillin/sulbactam: 1.5 to 3 g
intravenously every 6 hours
The 1.5 g dose consists of 1 g of ampicillin
and 0.5 g of sulbactam; the 3 g dose consists
of 2 g of ampicillin and 1 g of sulbactam.
OR
» ticarcillin/clavulanic acid: 3.2 g

Dose consists of 3 g of ticarcillin and 0.2 g of
clavulanic acid.
OR
» piperacillin/tazobactam: 2.25 to 4.5 g

Dose consists of 2 or 4 g of piperacillin and
0.25 or 0.5 g of tazobactam.
OR
TREATMENT
» vancomycin: 500-1000 mg intravenously

every 12 hours
» Severity depends on patient's prior status and

any changes to previous baseline investigation
disease Treatment
Acute
(based on symptoms, examination, lung function,
ABG). Use of accessory muscles, paradoxical
respirations, cyanosis, new peripheral oedema,
haemodynamic instability, and worsened
mental status (e.g., confusion, lethargy,
coma) are important indicators of severity of
exacerbation.[1]
» Antibiotics should be given to patients

with severe exacerbations requiring assisted
ventilation, and those suspected of having a
bacterial trigger for their acute exacerbations,[1]
[13] [31] [260] including in an acute exacerbation
with increased sputum purulence, increased
sputum volume, and/or worsening dyspnoea.[1]
[177] [210]
» It has been recommended that broad-spectrum

antibiotics such as extended-spectrum beta-
lactam combination drugs, fluoroquinolones, and
vancomycin are reserved for patients at greater
risk for a poor outcome, people with more severe
baseline COPD, or patients with an episode
of greater severity,[61] [210] including people
who require hospitalisation. Agents with activity
against Pseudomonas aeruginosa are indicated
for people at risk of this infection.[31]
» The choice of antibiotic should also be based

in part on local bacterial resistance patterns.
Sputum cultures or endotracheal aspirates (in
patients who are intubated) are recommended
for assessment of bacterial infection in patients
with severe lung function impairment, those with
history of frequent exacerbations, and patients
hospitalised with COPD exacerbations or who
require mechanical ventilation.[1] [31]
respiratory insufficiency adjunct non-invasive positive-pressure ventilation
(based on symptoms, examination, lung
function, ABG). Use of accessory respiratory
muscles, paradoxical respirations, cyanosis, new
peripheral oedema, haemodynamic instability,
and worsened mental status (e.g., confusion,
lethargy, coma) are important indicators of
severity of exacerbation.[1]
TREATMENT
» Respiratory failure is often seen in patients

with severe acute exacerbations of COPD. The
application of non-invasive positive-pressure
ventilation (NPPV) has been shown to improve
gas exchange, reduce dyspnoea, decrease
the need for endotracheal intubation, reduce
33
disease Treatment
Acute
complications such as pneumonia, and decrease
length of hospitalisation and mortality in these
patients.[1] [174] [221] [222] [263] [264] [265]
» NPPV use should be considered for patients

with one or more of the following: respiratory
acidosis (PaCO2 ≥ 6.0 kPa or 45 mmHg and
arterial pH ≤ 7.35); severe dyspnoea with
clinical signs suggestive of respiratory muscle
fatigue, increased work or breathing, or both,
such as use of respiratory accessory muscles,
paradoxical motion of the abdomen, or retraction
of the intercostal spaces; persistent hypoxaemia
despite supplemental oxygen therapy.[1]
» Improvements in patient's level of dyspnoea

and their physiological state are typically seen
within 1 to 4 hours.[266] However, NPPV is
not successful for all patients, and clinicians
should discuss the risks and benefits of invasive
mechanical ventilation with patients receiving
NPPV to determine their desired course of
treatment.
adjunct invasive positive-pressure ventilation
(based on symptoms, examination, lung
function, ABG). Use of accessory respiratory
muscles, paradoxical respirations, cyanosis, new
peripheral oedema, haemodynamic instability,
and worsened mental status (e.g., confusion,
lethargy, coma) are important indicators of
severity of exacerbation.[1] [46]
» Non-invasive positive-pressure ventilation

(NPPV) may fail. Invasive mechanical ventilation
should be considered for patients with outright
respiratory or cardiac arrest, who are in or have
signs of impending acute respiratory failure
despite NPPV, have impaired mental status or
cardiovascular instability, are at high risk for
aspiration, or have thick or copious secretions,
or for whom NPPV cannot be appropriately
applied (e.g., craniofacial trauma, recent gastro-
oesophageal surgery, anxiety disorder).[224]
TREATMENT
disease Treatment
Acute
[VIDEO: Tracheal intubation
animated demonstration ]
[VIDEO: Bag-valve-mask ventilation

animated demonstration ]
» Physiological criteria for invasive mechanical
ventilation include the following: severe hypoxia,
inability to tolerate NPPV or failure of NPPV,
respiratory or cardiac arrest, irregular breathing
with gasping or loss of consciousness, massive
aspiration or persistent vomiting, inability to clear
respiratory secretions, heart rate <50 beats
per minute with diminished alertness, severe
haemodynamic instability without response to
therapy, or severe ventricular or supraventricular
arrhythmias.[1] [225]
» The risk for mortality is significant (11% to

49%) for people with severe disease in whom
invasive mechanical ventilation is indicated.[13]
[226] Complications of mechanical ventilation
include ventilator-associated pneumonia and
barotrauma.
» Weaning patients with severe COPD from

mechanical ventilation can be difficult.[224] Use
of NPPV to assist weaning from mechanical
ventilation can reduce weaning failure and
nosocomial pneumonia, and may reduce
mortality.[223] [227]
Ongoing
after stabilisation
1st pulmonary rehabilitation and disease-

management programmes
» Patients with COPD who experience acute

exacerbations of COPD often have skeletal
muscle dysfunction, potentially due to limited
physical activity, nutritional disturbances,
corticosteroid use, and/or systemic inflammatory
factors.[267] [268]
» Pulmonary rehabilitation is a multidisciplinary

programme of care that involves physical
rehabilitation as well as guidance on disease
management, nutrition, and other lifestyle issues
TREATMENT
(e.g., smoking cessation, medication compliance

and inhaler technique, supplemental oxygen,
and maintenance of physical activity). [232] [233]
» Exercise training, particularly resistance

training and transcutaneous electrical muscle
35
disease Treatment
Ongoing
stimulation initiated during hospitalisation for
COPD exacerbation are well tolerated and can
prevent muscle function decline and hasten
functional status recovery.[234] [235] [236]
» Pulmonary rehabilitation initiated early during

the recovery phase of an exacerbation is safe
and effective, and leads to improvements
in exercise tolerance, physical abilities, the
degree of symptoms due to COPD, and
quality of life.[237] [238] [239] [241] [269] [270]
[271] Comprehensive supervised pulmonary
rehabilitation in the outpatient setting in the
post-exacerbation period also decreases the
risk for future hospitalisation and may reduce
mortality.[232] [238] [242] As COPD patients and
their exacerbations are highly heterogeneous,
determining who may benefit from respiratory
rehabilitation varies greatly according to the
comorbidities and other characteristics of
individual patients.
» Disease management programmes can be

helpful,[231] [272] [273] [274] but their use
remains controversial given a randomised
controlled trial had to be stopped early due to a
noted increase in mortality in the comprehensive
care management group as compared with
control patients who were receiving guideline-
based routine medical care.[275] Another study
involving unsupervised home-based exercise
training following hospitalisation for acute COPD
exacerbation also showed a mortality signal at
the 6-month post-hospitalisation time point.[243]
» Some data are emerging that hospital-at-home

care with support from respiratory nurses may
be appropriate for selected people with moderate
exacerbations of COPD.[276] However, this
approach is not yet considered the standard of
care,[88] [277] and people with unstable vital
signs, decompensated gas exchange, acute
respiratory acidosis, worsened hypoxaemia,
change in mental status, or significant comorbid
illness are not suitable for this approach.
» A randomised controlled trial has suggested

that the use of nurse-centred tele-assistance
may decrease the occurrence of exacerbations
of COPD and hospitalisation. The use of
such programmes may be cost-saving.[278]
However, another randomised controlled trial
TREATMENT
demonstrated that telemonitoring integrated

into existing clinical services did not reduce
hospital admissions or improve patients’ quality
of life.[279]
disease Follow up
Recommendations
Monitoring
FOLLOW UP
Patients experiencing an acute exacerbation of COPD should be followed closely to ensure continued
improvement and resolution of the associated signs and symptoms. When possible, people hospitalised
with COPD exacerbation should be seen by a healthcare provider within 30 days of hospital
discharge.[289] Clinicians should consider the potential need for adjustment of each patient's medicine
regimen for COPD, as patients experiencing an acute exacerbation occasionally do not return rapidly
to their baseline level of health. Efforts should be made to ensure that patients are educated regarding
compliance with their medicine regimens and that they have received appropriate vaccinations (e.g.,
influenza, pneumococcus).
Patient instructions
Patients often under-report symptoms of acute exacerbation.[290] Patients should be asked regularly
at clinic visits about escalation of symptoms, and educated about the difference between the expected
day-to-day variation in symptoms, symptoms of 'dyspnoea crisis' (related to dynamic hyperinflation), and
symptoms heralding a COPD exacerbation. 'Dyspnoea crisis' is defined as a sustained and severe resting
breathing discomfort that occurs in patients with advanced, often life-limiting illness and overwhelms the
patient and caregivers’ ability to achieve symptom relief.[291]
Patients should be advised to contact their clinician if they experience fever, worsening of their respiratory
status beyond usual day-to-day variation, and/or a significant increase in their production of purulent
sputum. If patients are receiving systemic corticosteroids and are known to be diabetic, they should be
advised to closely monitor their blood glucose and contact their clinician if it is outside the prescribed
range. If patients are prescribed antibiotics, they should be advised to contact their clinician if they
develop diarrhoea, as antibiotic-associated colitis, which may be due to Clostridium difficile , is a
recognised complication of exposure to antibiotics.
Complications
Complications Timeframe Likelihood

mechanical ventilation and ventilator-associated short term high
pneumonia
Patients who are ventilated are at high risk of infection. May be due to aspiration following intubation and/
or related to bypassing normal anatomical structures involved in host defense.
antibiotic-related diarrhoea short term high
Antibiotic-associated colitis, which may be due to Clostridium difficile , is a recognised complication of

exposure to antibiotics.
mechanical ventilation and ventilator-associated short term medium

barotrauma
Occurs due to mechanical ventilation, and is the development of extra-alveolar air. Careful use of
ventilator settings, including use of lower tidal volumes, faster inspiratory flow rates, and monitoring airway
pressures may help prevent the occurrence of this complication.
37
disease Follow up
Complications Timeframe Likelihood
cor pulmonale long term high
FOLLOW UP
This may develop as a result of increased hypoxic vasoconstriction due to exacerbation-induced

hypoxaemia. The resulting increase in pulmonary vascular resistance and/or pulmonary artery pressure
can lead to acute right heart failure. Elevated jugular venous pressure, hepatojugular reflux, peripheral
oedema, and relative hypotension may be present.
hypotension due to mechanical ventilation variable low
Occurs due to increased intrathoracic pressure and increased dynamic hyperinflation, leading to
decreased venous return to the heart, often in conjunction with relative volume depletion and/or use of
anxiolytic and/or narcotic medications.
Prognosis
There is a broad spectrum of severity of disease encompassed by people with COPD. Likewise, acute
exacerbations range from very mild to severe and life-threatening. Morbidity and mortality among people with
COPD occurs most often in the context of exacerbations. Older studies have estimated mortality rates of 4%
to 30% among patients hospitalised for acute exacerbations. A study based on data available from the 1996
Nationwide Inpatient Sample (Agency for Healthcare Research and Quality, Rockville, Maryland, US) found
in-hospital mortality for patients with an acute exacerbation to be 2.5% overall.[280] In this study, the median
duration of hospitalisation was 5 days and 70% of patients were discharged to home without additional in-
home health services. People who died during hospitalisation were shown to be older, had greater levels
of underlying comorbidities, and were hospitalised for longer periods. Not surprisingly, a greater rate of
mortality was shown for patients who were mechanically ventilated compared with those who were not (28%
versus 1.7%). Another study identified an approximately 50% 5-year mortality following hospitalisation for
COPD exacerbation.[281] Re-hospitalisation and/or mortality have been associated with lower FEV1, higher
PaCO2, lower PaO2, greater APACHE II score, lower BMI, older age, comorbidities, and low physical activity
levels.[226] [282] [283] [284] [285] [286] [287] The multidimensional CODEX (comorbidity, obstruction,
dyspnoea, previous severe exacerbations) index can predict readmission and survival at 3 months and 1
year after hospitalisation for COPD exacerbation.[288]
disease Guidelines
Diagnostic guidelines
Europe
Chronic obstructive pulmonary disease in over 16s: diagnosis and

management
Published by: National Institute for Health and Care Excellence Last published: 2019
International
Global strategy for the diagnosis, management, and prevention of chronic

obstructive pulmonary disease
Published by: Global Initiative for Chronic Obstructive Lung Disease Last published: 2017
GUIDELINES
North America
Veterans Affairs/Department of Defense clinical practice guideline: the

management of chronic obstructive pulmonary disease
Published by: US Department of Veterans Affairs and US Department Last published: 2014
of Defense
Diagnosis and management of stable chronic obstructive pulmonary

disease
Published by: American College of Physicians; American College of Last published: 2011
Chest Physicians; American Thoracic Society; European Respiratory
Society
Treatment guidelines
Europe
Chronic obstructive pulmonary disease in over 16s: diagnosis and

management
Chronic obstructive pulmonary disease (acute exacerbation): antimicrobial

prescribing
British Thoracic Society guideline on pulmonary rehabilitation in adults

Published by: British Thoracic Society Last published: 2013
39
disease Guidelines
Europe
Guidelines for the management of adult lower respiratory tract infections

Published by: European Respiratory Society; European Society for Last published: 2011
Clinical Microbiology and Infectious Diseases
Non-invasive ventilation in chronic obstructive pulmonary disease:

management of acute type 2 respiratory failure
Published by: Royal College of Physicians Last published: 2008
International
Global strategy for the diagnosis, management, and prevention of chronic

obstructive pulmonary disease
Published by: Global Initiative for Chronic Obstructive Lung Disease Last published: 2017
GUIDELINES
An Official American Thoracic Society/European Respiratory Society Policy

Statement: Enhancing Implementation, Use, and Delivery of Pulmonary
Rehabilitation
Published by: American Thoracic Society/European Respiratory Society Last published: 2015
An official American Thoracic Society/European Respiratory Society

statement: key concepts and advances in pulmonary rehabilitation
Published by: American Thoracic Society; European Respiratory Last published: 2013
Society
North America
Veterans Affairs/Department of Defense clinical practice guideline: the

management of chronic obstructive pulmonary disease
Published by: US Department of Veterans Affairs and US Department Last published: 2014
of Defense
ACR appropriateness criteria: acute respiratory illness in immunocompetent

patients
Published by: American College of Radiology Last published: 2013
Diagnosis and management of stable chronic obstructive pulmonary

disease
Published by: American College of Physicians; American College of Last published: 2011
Chest Physicians; American Thoracic Society; European Respiratory
Society
disease Guidelines
North America
Optimizing pulmonary rehabilitation in chronic obstructive pulmonary

disease - practical issues: a Canadian Thoracic Society clinical practice
guideline
Published by: Canadian Thoracic Society Last published: 2010
Canadian Thoracic Society recommendations for management of chronic

obstructive pulmonary disease: 2008 update - highlights for primary care
Published by: Canadian Thoracic Society Last published: 2008
Screening for chronic obstructive pulmonary disease: U.S. Preventive

Services Task Force recommendation statement
Published by: US Preventive Services Task Force, Agency for Last published: 2016
Healthcare Research and Quality
GUIDELINES
Pulmonary rehabilitation: joint ACCP/AACVPR evidence-based clinical
practice guidelines
Published by: American College of Chest Physicians; American Last published: 2007
Association of Cardiovascular and Pulmonary Rehabilitation
Nonpharmacologic airway clearance therapies: ACCP evidence-based clinical

practice guidelines
Published by: American College of Chest Physicians Last published: 2006
Cough suppressant and pharmacologic protussive therapy: ACCP evidence-

based clinical practice guidelines
Chronic cough due to chronic bronchitis: ACCP evidence-based clinical

practice guidelines
Nursing care of dyspnea: the 6th vital sign in individuals with chronic
obstructive pulmonary disease (COPD)
Published by: Registered Nurses Association of Ontario Last published: 2005
41
disease References
Key articles
• Cote CG, Dordelly LJ, Celli BR. Impact of COPD exacerbations on patient-centered outcomes. Chest.
REFERENCES
2007;131:696-704. Abstract
• Woodhead M, Blasi F, Ewig S, et al. Guidelines for the management of adult lower respiratory tract
infections - full version. Clini Microbiol Infect. 2011;17(suppl 6):E1-E59. Full text Abstract
• Anthonisen NR, Connett JE, Kiley JP, et al. Effects of smoking intervention and the use of an
inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA.
1994;272:1497-1505. Abstract
• Hanania NA, Crater GD, Morris AN, et al. Benefits of adding fluticasone propionate/salmeterol to
tiotropium in moderate to severe COPD. Respir Med. 2012;106:91-101. Abstract
• Vollenweider DJ, Jarrett H, Steurer-Stey CA, et al. Antibiotics for exacerbations of chronic obstructive
pulmonary disease. Cochrane Database Syst Rev. 2012;(12):CD010257. Full text Abstract
• Spruit MA, Singh SJ, Garvey C, et al. An official American Thoracic Society/European Respiratory
Society statement: key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care
Med. 2013;188:e13-e64. Abstract
• Celli BR, MacNee W, Agusti A, et al; ATS/ERS Task Force. Standards for the diagnosis and treatment
of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004;23:932-946.
Full text Abstract
• Tang CY, Blackstock FC, Clarence M, et al. Early rehabilitation exercise program for inpatients during
an acute exacerbation of chronic obstructive pulmonary disease: a randomized controlled trial. J
Cardiopulm Rehabil Prev. 2012;32:163-169. Abstract
References
1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management
and prevention of chronic obstructive pulmonary disease. November 2017 [internet publication] Full
text
2. Bastin AJ, Starling L, Ahmed R, et al. High prevalence of undiagnosed and severe chronic
obstructive pulmonary disease at first hospital admission with acute exacerbation. Chron Respir Dis.
2010;7:91-97. Abstract
3. Hanania NA, Marciniuk DD. A unified front against COPD: clinical practice guidelines from the
American College of Physicians, the American College of Chest Physicians, the American Thoracic
Society, and the European Respiratory Society. Chest. 2011;140:565-566. Full text Abstract
4. Jemal A, Ward E, Hao Y. Trends in the leading causes of death in the United States, 1970-2002.
JAMA. 2005;294:1255-1259. Full text Abstract
disease References
5. Mannino DM, Buist AS. Global burden of COPD: risk factors, prevalence, and future trends. Lancet.
2007;370:765-773. Abstract
REFERENCES
6. Mannino DM, Doherty DE, Sonia Buist A. Global Initiative on Obstructive Lung Disease (GOLD)
classification of lung disease and mortality: findings from the Atherosclerosis Risk in Communities
(ARIC) study. Respir Med. 2006;100:115-122. Abstract
7. Buist AS, McBurnie MA, Vollmer WM, et al. International variation in the prevalence of COPD (the
BOLD Study): a population-based prevalence study. Lancet. 2007;370:741-750. Abstract
8. Menezes AM, Perez-Padilla R, Jardim JR, et al. Chronic obstructive pulmonary disease in five Latin
American cities (the PLATINO study): a prevalence study. Lancet. 2005;366:1875-1881. Abstract
9. Soriano JB, Maier WC, Egger P, et al. Recent trends in physician diagnosed COPD in women and men
in the UK. Thorax. 2000;55:789-794. Full text Abstract
10. de Torres JP, Casanova C, Hernandez C, et al. Gender and COPD in patients attending a pulmonary
clinic. Chest. 2005;128:2012-2016. Abstract
11. Seemungal TA, Donaldson GC, Bhowmik A, et al. Time course and recovery of exacerbations
in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med.
2000;161:1608-1613. Abstract
12. Seemungal TA, Donaldson GC, Paul EA, et al. Effect of exacerbation on quality of life in patients with
chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998;157:1418-1422. Abstract
13. Rodriguez-Roisin R. COPD exacerbations.5: management. Thorax. 2006;61:535-544. Abstract
14. O'Donnell DE, Parker CM. COPD exacerbations. 3: Pathophysiology. Thorax. 2006;61:354-361.
Abstract
15. Barberà JA, Roca J, Ferrer A, et al. Mechanisms of worsening gas exchange during acute
exacerbations of chronic obstructive pulmonary disease. Eur Respir J. 1997;10:1285-1291. Full text
Abstract
16. Cote CG, Dordelly LJ, Celli BR. Impact of COPD exacerbations on patient-centered outcomes. Chest.
2007;131:696-704. Abstract
17. Spencer S, Jones PW; GLOBE Study Group. Time course of recovery of health status following an
infective exacerbation of chronic bronchitis. Thorax. 2003;58:589-593. Full text Abstract
18. Xu W, Collet JP, Shapiro S, et al. Negative impacts of unreported COPD exacerbations on health-
related quality of life at 1 year. Eur Respir J. 2010;35:1022-1030. Abstract
19. Rabe KF, Fabbri LM, Vogelmeier C, et al. Seasonal distribution of COPD exacerbations in the
Prevention of Exacerbations with Tiotropium in COPD trial. Chest. 2013;143:711-719. Abstract
20. Sutherland ER, Cherniack RM. Management of chronic obstructive pulmonary disease. N Engl J Med.
2004;350:2689-2697. Abstract
43
disease References
21. Ai-Ping C, Lee KH, Lim TK. In-hospital and 5-year mortality of patients treated in the ICU for acute
exacerbation of COPD: a retrospective study. Chest. 2005;128:518-524. Abstract
REFERENCES
22. Donaldson GC, Seemungal TA, Bhowmik A, et al. Relationship between exacerbation frequency and
lung function decline in chronic obstructive pulmonary disease. Thorax. 2002;57:847-852. Abstract
23. Seneff MG, Wagner DP, Wagner RP, et al. Hospital and 1-year survival of patients admitted to
intensive care units with acute exacerbation of chronic obstructive pulmonary disease. JAMA.
1995;274:1852-1857. Abstract
24. Soler-Cataluña JJ, Martínez-García MA, Román Sánchez P, et al. Severe acute exacerbations and
mortality in patients with chronic obstructive pulmonary disease. Thorax. 2005;60:925-931. Full text
Abstract
25. Zvezdin B, Milutinov S, Kojicic M, et al. A postmortem analysis of major causes of early death in
patients hospitalized with COPD exacerbation. Chest. 2009;136:376-380. Abstract
26. Donaldson GC, Hurst JR, Smith CJ, et al. Increased risk of myocardial infarction and stroke following
exacerbation of COPD. Chest. 2010;137:1091-1097. Abstract
27. Lundback B, Lindberg A, Lindstrom M, et al. Not 15 but 50% of smokers develop COPD?--Report from
the Obstructive Lung Disease in Northern Sweden Studies. Respir Med. 2003;97:115-122. Abstract
28. Sapey E, Stockley RA. COPD exacerbations.2: aetiology. Thorax. 2006;61:250-258. Abstract
29. Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive
pulmonary disease. N Engl J Med. 2004;350:2645-2653. Full text Abstract
30. Anzueto A. Primary care management of chronic obstructive pulmonary disease to reduce
exacerbations and their consequences. Am J Med Sci. 2010;340:309-318. Abstract
31. Woodhead M, Blasi F, Ewig S, et al. Guidelines for the management of adult lower respiratory tract
infections - full version. Clini Microbiol Infect. 2011;17(suppl 6):E1-E59. Full text Abstract
32. Lieberman D, Lieberman D, Ben-Yaakov M, et al. Infectious etiologies in acute exacerbation of COPD.
Diagn Microbiol Infect Dis. 2001;40:95-102. Abstract
33. Greenberg SB, Allen M, Wilson J, et al. Respiratory viral infections in adults with and without chronic
obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;162:167-173. Abstract
34. Beckham JD, Cadena A, Lin J, et al. Respiratory viral infections in patients with chronic obstructive
pulmonary disease. J Infect. 2005;50:322-330. Abstract
35. Martinello RA, Esper F, Weibel C, et al. Human metapneumovirus and exacerbations of chronic
obstructive pulmonary disease. J Infect. 2006;53:248-254. Abstract
36. Dennis RJ, Maldonado D, Norman S, et al. Woodsmoke exposure and risk for obstructive airways
disease among women. Chest. 1996;109:115-119. Abstract
disease References
37. Sunyer J, Saez M, Murillo C, et al. Air pollution and emergency room admissions for chronic
obstructive pulmonary disease: a 5-year study. Am J Epidemiol. 1993;137:701-705. Abstract
REFERENCES
38. Jones JG, Minty BD, Lawler P, et al. Increased alveolar epithelial permeability in cigarette smokers.
Lancet. 1980;1:66-68. Abstract
39. Sethi S, Murphy TF. Bacterial infection in chronic obstructive pulmonary disease in 2000: a state-of-
the-art review. Clin Microbiol Rev. 2001;14:336-363. Full text Abstract
40. Barnes PJ. Chronic obstructive pulmonary disease. N Engl J Med. 2000;343:269-280. Abstract
41. Stockley RA. Progression of chronic obstructive pulmonary disease: impact of inflammation,
comorbidities and therapeutic intervention. Curr Med Res Opin. 2009;25:1235-1245. Abstract
42. Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary
disease. N Engl J Med. 2008;359:2355-2365. Abstract
43. Barnes PJ. Mechanisms in COPD: differences from asthma. Chest. 2000;117(suppl 2):10S-14S.
Abstract
44. Hogg JC. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet.
2004;364:709-721. Abstract
45. Lougheed DM, Webb KA, O'Donnell DE. Breathlessness during induced lung hyperinflation in asthma:
the role of the inspiratory threshold load. Am J Respir Crit Care Med. 1995;152:911-920. Abstract
46. Pauwels RA, Buist AS, Calverley PM, et al. Global strategy for the diagnosis, management,
and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for
Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med.
2001;163:1256-1276. Abstract
47. Tashkin DP, Celli B, Decramer M, et al. Bronchodilator responsiveness in patients with COPD. Eur
Respir J. 2008;31:742-750. Full text Abstract
48. Belman MJ, Botnick WC, Shin JW. Inhaled bronchodilators reduce dynamic hyperinflation during
exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med.
1996;153:967-975. Abstract
49. Celli B, ZuWallack R, Wang S, et al. Improvement in resting inspiratory capacity and hyperinflation with
tiotropium in COPD patients with increased static lung volumes. Chest. 2003;124:1743-1748. Abstract
50. Papi A, Bellettato CM, Braccioni F, et al. Infections and airway inflammation in chronic obstructive
pulmonary disease severe exacerbations. Am J Respir Crit Care Med. 2006;173:1114-1121. Abstract
51. Wedzicha JA, Seemungal TA. COPD exacerbations: defining their cause and prevention. Lancet.
2007;370:786-796. Abstract
52. Hurst JR, Wedzicha JA. The biology of a chronic obstructive pulmonary disease exacerbation. Clin
Chest Med. 2007;28:525-536. Abstract
45
disease References
53. Giacomini M, DeJean D, Simeonov D, et al. Experiences of living and dying with COPD: a systematic
review and synthesis of the qualitative empirical literature. Ont Health Technol Assess Ser.
2012;12:1-47. Full text Abstract
REFERENCES
54. Burge S, Wedzicha JA. COPD exacerbations: definitions and classifications. Eur Respir J Suppl.
2003;41:46s-53s. Abstract
55. Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic obstructive pulmonary
disease. N Engl J Med. 2010;363:1128-1138. Full text Abstract
56. Niewoehner DE, Lokhnygina Y, Rice K, et al. Risk indexes for exacerbations and hospitalizations due
to COPD. Chest. 2007;131:20-28. Abstract
57. Foreman MG, DeMeo DL, Hersh CP, et al. Clinical determinants of exacerbations in severe, early-
onset COPD. Eur Respir J. 2007;30:1124-1130. Abstract
58. Soler N, Agusti C, Angrill J, et al. Bronchoscopic validation of the significance of sputum purulence in
severe exacerbations of chronic obstructive pulmonary disease. Thorax. 2007;62:29-35. Abstract
59. Wilkinson TM, Hurst JR, Perera WR, et al. Effect of interactions between lower airway bacterial and
rhinoviral infection in exacerbations of COPD. Chest. 2006;129:317-324. Abstract
60. Sethi S, Sethi R, Eschberger K, et al. Airway bacterial concentrations and exacerbations of chronic
obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;176:356-361. Abstract
61. Caramori G, Adcock IM, Papi A. Clinical definition of COPD exacerbations and classification of their
severity. South Med J. 2009;102:277-282. Abstract
62. Sethi S, Evans N, Grant BJ, et al. New strains of bacteria and exacerbations of chronic obstructive
pulmonary disease. N Engl J Med. 2002;347:465-471. Abstract
63. Anthonisen NR, Manfreda J, Warren CP, et al. Antibiotic therapy in exacerbations of chronic
obstructive pulmonary disease. Ann Intern Med. 1987;106:196-204. Abstract
64. Puhan MA, Vollenweider D, Latshang T, et al. Exacerbations of chronic obstructive pulmonary disease:
when are antibiotics indicated? A systematic review. Respir Res. 2007;8:30. Full text Abstract
65. Terada K, Muro S, Sato S, et al. Impact of gastro-oesophageal reflux disease symptoms on COPD
exacerbation. Thorax. 2008;63:951-955. Abstract
66. Terada K, Muro S, Ohara T, et al. Abnormal swallowing reflex and COPD exacerbations. Chest.
2010;137:326-332. Abstract
67. Seemungal TA, Harper-Owen R, Bhowmik A, et al. Detection of rhinovirus in induced sputum at
exacerbation of chronic obstructive pulmonary disease. Eur Respir J. 2000;16:677-683. Full text
Abstract
68. Falsey AR, Formica MA, Hennessey PA, et al. Detection of respiratory syncytial virus in adults with
disease References
69. Hurst JR, Donaldson GC, Wilkinson TM, et al. Epidemiological relationships between the common
cold and exacerbation frequency in COPD. Eur Respir J. 2005;26:846-852. Full text Abstract
REFERENCES
70. Hogg JC. Role of latent viral infections in chronic obstructive pulmonary disease and asthma. Am J
Respir Crit Care Med. 2001;164:S71-S75. Abstract
71. Anderson HR, Spix C, Medina S, et al. Air pollution and daily admissions for chronic obstructive
pulmonary disease in 6 European cities: results from the APHEA project. Eur Respir J.
1997;10:1064-1071. Abstract
72. Yang CY, Chen CC, Chen CY, et al. Air pollution and hospital admissions for asthma in a subtropical
city: Taipei, Taiwan. J Toxicol Environ Health A. 2007;70:111-117. Abstract
73. Pope CA, 3rd, Kanner RE. Acute effects of PM10 pollution on pulmonary function of smokers with
mild to moderate chronic obstructive pulmonary disease. Am Rev Respir Dis. 1993;147:1336-1340.
Abstract
74. Faustini A, Stafoggia M, Colais P, et al. Air pollution and multiple acute respiratory outcomes. Eur
Respir J. 2013;42:304-313. Full text Abstract
75. Diederen BM, van der Valk PD, Kluytmans JA, et al. The role of atypical respiratory pathogens in
exacerbations of chronic obstructive pulmonary disease. Eur Respir J. 2007;30:240-244. Abstract
76. Blasi F, Damato S, Cosentini R, et al. Chlamydia pneumoniae and chronic bronchitis: association with
severity and bacterial clearance following treatment. Thorax. 2002;57:672-676. Abstract
77. Seemungal TA, Wedzicha JA, MacCallum PK, et al. Chlamydia pneumoniae and COPD exacerbation.
Thorax. 2002;57:1087-1088. Abstract
78. Donaldson GC, Seemungal T, Jeffries DJ, et al. Effect of temperature on lung function and symptoms
in chronic obstructive pulmonary disease. Eur Respir J. 1999;13:844-849. Abstract
79. Chen CZ, Ou CY, Yu CH, et al. Comparison of global initiative for chronic obstructive pulmonary
disease 2013 classification and body mass index, airflow obstruction, dyspnea, and exacerbations
index in predicting mortality and exacerbations in elderly adults with chronic obstructive pulmonary
disease. J Am Geriatr Soc. 2015;63:244-250. Abstract
80. Anthonisen NR, Connett JE, Kiley JP, et al. Effects of smoking intervention and the use of an
inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA.
1994;272:1497-1505. Abstract
81. Thabane M; COPD Working Group. Smoking cessation for patients with chronic obstructive pulmonary
disease (COPD): an evidence-based analysis. Ont Health Technol Assess Ser. 2012;12:1-50. Full text
Abstract
82. Au DH, Bryson CL, Chien JW, et al. The effects of smoking cessation on the risk of chronic obstructive
pulmonary disease exacerbations. J Gen Intern Med. 2009;24:457-463. Full text Abstract
47
disease References
83. Criner GJ, Bourbeau J, Diekemper RL, et al. Prevention of acute exacerbations of COPD: American
College of Chest Physicians and Canadian Thoracic Society Guideline. Chest. 2015;147:894-942. Full
text Abstract
REFERENCES
84. McCrory DC, Brown C, Gelfand SE, et al. Management of acute exacerbations of COPD: a summary
and appraisal of published evidence. Chest. 2001;119:1190-1209. Abstract
85. Nichol KL, Baken L, Nelson A. Relation between influenza vaccination and outpatient visits,
hospitalization, and mortality in elderly persons with chronic lung disease. Ann Intern Med.
1999;130:397-403. Abstract
86. Wongsurakiat P, Maranetra KN, Wasi C, et al. Acute respiratory illness in patients with COPD and the
effectiveness of influenza vaccination: a randomized controlled study. Chest. 2004;125:2011-2020.
Abstract
87. Sehatzadeh S. Influenza and pneumococcal vaccinations for patients with chronic obstructive
pulmonary disease (COPD): an evidence-based review. Ont Health Technol Assess Ser.
88. OHTAC COPD Collaborative. Chronic obstructive pulmonary disease (COPD) evidentiary framework.
Ont Health Technol Assess Ser. 2012;12:1-97. Full text Abstract
89. Alfageme I, Vazquez R, Reyes N, et al. Clinical efficacy of anti-pneumococcal vaccination in patients
with COPD. Thorax. 2006;61:189-195. Abstract
90. Walters JA, Tang JN, Poole P, Wood-Baker R. Pneumococcal vaccines for preventing pneumonia in
chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2017 Jan 24;1:CD001390. Full
text Abstract
91. Seemungal T, Harper-Owen R, Bhowmik A, et al. Respiratory viruses, symptoms, and inflammatory
markers in acute exacerbations and stable chronic obstructive pulmonary disease. Am J Respir Crit
Care Med. 2001;164:1618-1623. Abstract
92. Rennard SI, Anderson W, ZuWallack R, et al. Use of a long-acting inhaled beta2-adrenergic agonist,
salmeterol xinafoate, in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care
Med. 2001;163:1087-1092. Abstract
93. Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in
chronic obstructive pulmonary disease. N Engl J Med. 2007;356:775-789. Abstract
94. Niewoehner DE, Rice K, Cote C, et al. Prevention of exacerbations of chronic obstructive pulmonary
disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial. Ann
Intern Med. 2005;143:317-326. Abstract
95. Mahler DA, Donohue JF, Barbee RA, et al. Efficacy of salmeterol xinafoate in the treatment of COPD.
Chest. 1999;115:957-965. Abstract
96. Casaburi R, Mahler DA, Jones PW, et al. A long-term evaluation of once-daily inhaled tiotropium in
chronic obstructive pulmonary disease. Eur Respir J. 2002;19:217-224. Full text Abstract
disease References
97. Brusasco V, Hodder R, Miravitlles M, et al. Health outcomes following treatment for six months
with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax.
REFERENCES
98. Tashkin DP, Celli B, Senn S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease.
N Engl J Med. 2008;359:1543-1554. Full text Abstract
99. Tashkin DP. Preventing and managing exacerbations in COPD--critical appraisal of the role of
tiotropium. Int J Chron Obstruct Pulmon Dis. 2010;5:41-53. Full text Abstract
100. Halpin D, Menjoge S, Viel K. Patient-level pooled analysis of the effect of tiotropium on COPD
exacerbations and related hospitalisations. Prim Care Respir J. 2009;18:106-113. Abstract
101. Cooper CB, Anzueto A, Decramer M, et al. Tiotropium reduces risk of exacerbations irrespective
of previous use of inhaled anticholinergics in placebo-controlled clinical trials. Int J Chron Obstruct
Pulmon Dis. 2011;6:269-275. Full text Abstract
102. Morice AH, Celli B, Kesten S, et al. COPD in young patients: a pre-specified analysis of the four-year
trial of tiotropium (UPLIFT). Respir Med. 2010;104:1659-1667. Abstract
103. Van den BA, Gailly J, Neyt M. Does tiotropium lower exacerbation and hospitalization frequency in
COPD patients: results of a meta-analysis. BMC Pulm Med. 2010;10:50. Full text Abstract
104. Wang J, Nie B, Xiong W, et al. Effect of long-acting beta-agonists on the frequency of COPD
exacerbations: a meta-analysis. J Clin Pharm Ther. 2012;37:204-211. Abstract
105. Yohannes AM, Willgoss TG, Vestbo J. Tiotropium for treatment of stable COPD: a meta-analysis of
clinically relevant outcomes. Resp Care. 2011;56:477-487. Full text Abstract
106. Decramer ML, Hanania NA, Lötvall JO, et al. The safety of long-acting β2-agonists in the treatment of
stable chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2013;8:53-64. Full
text Abstract
107. Mahler DA, Buhl R, Lawrence D, et al. Efficacy and safety of indacaterol and tiotropium in COPD
patients according to dyspnoea severity. Pulm Pharmacol Ther. 2013;26:348-355. Abstract
108. Kew KM, Mavergames C, Walters JA. Long-acting beta2-agonists for chronic obstructive pulmonary
disease. Cochrane Database Syst Rev. 2013;(10):CD010177. Full text Abstract
109. Vogelmeier C, Hederer B, Glaab T, et al. Tiotropium versus salmeterol for the prevention of
exacerbations of COPD. N Engl J Med. 2011;364:1093-1103. Abstract
110. Vogelmeier C, Fabbri LM, Rabe KF, et al. Effect of tiotropium vs. salmeterol on exacerbations: GOLD II
and maintenance therapy naïve patients. Respir Med. 2013;107:75-83. Abstract
111. Beasley R, Singh S, Loke YK, et al. Call for worldwide withdrawal of tiotropium Respimat mist inhaler.
BMJ. 2012;345:e7390. Abstract
49
disease References
112. Dahl R, Chung KF, Buhl R, et al. Efficacy of a new once-daily long-acting inhaled beta2-agonist
indacaterol versus twice-daily formoterol in COPD. Thorax. 2010;65:473-479. Abstract
REFERENCES
113. Chapman KR, Rennard SI, Dogra A, et al. Long-term safety and efficacy of indacaterol, a long-
acting beta2-agonist, in subjects with COPD: a randomized, placebo-controlled study. Chest.
114. Donohue JF, Fogarty C, Lotvall J, et al. Once-daily bronchodilators for chronic obstructive pulmonary
disease: indacaterol versus tiotropium. Am J Respir Crit Care Med. 2010;182:155-162. Full text
Abstract
115. van Noord JA, Smeets JJ, Drenth BM, et al. 24-hour bronchodilation following a single dose of the
novel β(2)-agonist olodaterol in COPD. Pulm Pharmacol Ther. 2011;24:666-672. Abstract
116. Jones PW, Rennard SI, Agusti A, et al. Efficacy and safety of once-daily aclidinium in chronic
obstructive pulmonary disease. Respir Res. 2011;12:55. Full text Abstract
117. Frampton JE. Aclidinium: in chronic obstructive pulmonary disease. Drugs. 2012;72:1999-2011.
Abstract
118. Ni H, Soe Z, Moe S. Aclidinium bromide for stable chronic obstructive pulmonary disease. Cochrane
Database Syst Rev. 2014;(9):CD010509. Full text Abstract
119. Wang J, Jin D, Zuo P, et al. Comparison of tiotropium plus formoterol to tiotropium alone in stable
chronic obstructive pulmonary disease: a meta-analysis. Respirology. 2011;16:350-358. Abstract
120. Wedzicha JA, Decramer M, Ficker JH, et al. Analysis of chronic obstructive pulmonary disease
exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium
(SPARK): a randomised, double-blind, parallel-group study. Lancet Respir Med. 2013;1:199-209.
Abstract
121. National Horizon Scanning Centre. Umeclidinium and vilanterol for chronic obstructive pulmonary
disease. February 2012. http://www.hsc.nihr.ac.uk (last accessed 28 December 2015). Full text
122. Bateman ED, Ferguson GT, Barnes N, et al. Dual bronchodilation with QVA149 versus single
bronchodilator therapy: the SHINE study. Eur Respir J. 2013;42:1484-1494. Full text Abstract
123. Donohue JF, Maleki-Yazdi MR, Kilbride S, et al. Efficacy and safety of once-daily umeclidinium/
vilanterol 62.5/25 mcg in COPD. Respir Med. 2013;107:1538-1546. Full text Abstract
124. Burge PS, Calverley PM, Jones PW, et al. Randomised, double blind, placebo controlled study of
fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the
ISOLDE trial. BMJ. 2000;320:1297-1303. Full text Abstract
125. Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary
function in chronic obstructive pulmonary disease. N Engl J Med. 2000;343:1902-1909. Full text
Abstract
disease References
126. Aaron SD, Vandemheen KL, Fergusson D, et al. Tiotropium in combination with placebo, salmeterol,
or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial.
Ann Intern Med. 2007;146:545-555. Full text Abstract
REFERENCES
127. Alsaeedi A, Sin DD, McAlister FA. The effects of inhaled corticosteroids in chronic obstructive
pulmonary disease: a systematic review of randomized placebo-controlled trials. Am J Med.
2002;113:59-65. Abstract
128. Spencer S, Karner C, Cates CJ, et al. Inhaled corticosteroids versus long-acting beta2-agonists for
chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2011;(12):CD007033. Full text
Abstract
129. Szafranski W, Cukier A, Ramirez A, et al. Efficacy and safety of budesonide/formoterol in the
management of chronic obstructive pulmonary disease. Eur Respir J. 2003;21:74-81. Abstract
130. Calverley PM, Boonsawat W, Cseke Z, et al. Maintenance therapy with budesonide and formoterol in
chronic obstructive pulmonary disease. Eur Respir J. 2003;22:912-919. Full text Abstract
131. Ferguson GT, Anzueto A, Fei R, et al. Effect of fluticasone propionate/salmeterol (250/50 microg) or
salmeterol (50 microg) on COPD exacerbations. Respir Med. 2008;102:1099-1108. Abstract
132. Celli BR, Thomas NE, Anderson JA, et al. Effect of pharmacotherapy on rate of decline of lung
function in chronic obstructive pulmonary disease: results from the TORCH study. Am J Respir Crit
133. Anzueto A, Ferguson GT, Feldman G, et al. Effect of fluticasone propionate/salmeterol (250/50) on
COPD exacerbations and impact on patient outcomes. COPD. 2009;6:320-329. Abstract
134. Wouters EF, Postma DS, Fokkens B, et al. Withdrawal of fluticasone propionate from combined
salmeterol/fluticasone treatment in patients with COPD causes immediate and sustained disease
deterioration: a randomised controlled trial. Thorax. 2005;60:480-487. Full text Abstract
135. Magnussen H, Disse B, Rodriguez-Roisin R, et al. Withdrawal of inhaled glucocorticoids and

exacerbations of COPD. N Engl J Med. 2014;371:1285-1294. Full text Abstract
136. Welsh EJ, Cates CJ, Poole P. Combination inhaled steroid and long-acting beta2-agonist versus
tiotropium for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013 May 31;
(5):CD007891. Full text Abstract
137. Crim C, Calverley PM, Anderson JA, et al. Pneumonia risk in COPD patients receiving inhaled
corticosteroids alone or in combination: TORCH study results. Eur Respir J. 2009;34:641-647. Full
text Abstract
138. Singh S, Loke YK. An overview of the benefits and drawbacks of inhaled corticosteroids in chronic
obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2010;5:189-195. Full text Abstract
139. Calverley PM, Stockley RA, Seemungal TA, et al. Reported pneumonia in patients with COPD: findings
from the INSPIRE study. Chest. 2011;139:505-512. Full text Abstract
51
disease References
140. Kew KM, Seniukovich A. Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary
disease. Cochrane Database Syst Rev. 2014;(3):CD010115. Full text Abstract
REFERENCES
141. Tashkin DP, Littner M, Andrews CP, et al. Concomitant treatment with nebulized formoterol and
tiotropium in subjects with COPD: a placebo-controlled trial. Respir Med. 2008;102:479-487. Abstract
142. Tashkin DP, Rennard SI, Martin P, et al. Efficacy and safety of budesonide and formoterol in one
pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive
pulmonary disease: results of a 6-month randomized clinical trial. Drugs. 2008;68:1975-2000. Abstract
143. Wedzicha JA, Calverley PM, Seemungal TA, et al. The prevention of chronic obstructive pulmonary
disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit
144. Welte T, Miravitlles M, Hernandez P, et al. Efficacy and tolerability of budesonide/formoterol added
to tiotropium in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med.
2009;180:741-750. Abstract
145. Gaebel K, McIvor RA, Xie F, et al. Triple therapy for the management of COPD: a review. COPD.
2011;8:206-243. Abstract
146. Karner C, Cates CJ. The effect of adding inhaled corticosteroids to tiotropium and long-acting
beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2011;
(9):CD009039. Full text Abstract
147. Rojas-Reyes MX, García Morales OM, Dennis RJ, Karner C. Combination inhaled steroid and long-
acting beta₂-agonist in addition to tiotropium versus tiotropium or combination alone for chronic
obstructive pulmonary disease. Cochrane Database Syst Rev. 2016 Jun 6;(6):CD008532. Full text
Abstract
148. Baker WL, Baker EL, Coleman CI. Pharmacologic treatments for chronic obstructive pulmonary
disease: a mixed-treatment comparison meta-analysis. Pharmacotherapy. 2009;29:891-905. Abstract
149. Rodrigo GJ, Castro-Rodriguez JA, Plaza V. Safety and efficacy of combined long-acting beta-agonists
and inhaled corticosteroids vs long-acting beta-agonists monotherapy for stable COPD: a systematic
review. Chest. 2009;136:1029-1038. Abstract
150. Hanania NA, Crater GD, Morris AN, et al. Benefits of adding fluticasone propionate/salmeterol to
tiotropium in moderate to severe COPD. Respir Med. 2012;106:91-101. Abstract
151. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl
J Med. 2011; 365: 689-698. Abstract
152. Simoens S, Laekeman G, Decramer M. Preventing COPD exacerbations with macrolides: a review
and budget impact analysis. Respir Med. 2013;107:637-648. Abstract
153. Sethi S, Jones PW, Theron MS, et al. Pulsed moxifloxacin for the prevention of exacerbations of
chronic obstructive pulmonary disease: a randomized controlled trial. Respir Res. 2010;11:10. Full
text Abstract
disease References
154. Miravitlles M, Marín A, Monsó E, et al. Efficacy of moxifloxacin in the treatment of bronchial
colonisation in COPD. Eur Respir J. 2009;34:1066-1071. Full text Abstract
REFERENCES
155. Rennard SI, Schachter N, Strek M, et al. Cilomilast for COPD:results of a 6-month, placebo-controlled
study of a potent, selective inhibitor of phosphodiesterase 4. Chest. 2006;129:56-66. Abstract
156. Rabe KF, Bateman ED, O'Donnell D, et al. Roflumilast - an oral anti-inflammatory treatment for chronic
obstructive pulmonary disease: a randomised controlled trial. Lancet. 2005;366:563-571. Abstract
157. Mortensen EM, Copeland LA, Pugh MJ, et al. Impact of statins and ACE inhibitors on mortality after
COPD exacerbations. Respir Res. 2009;10:45. Abstract
158. Blamoun AI, Batty GN, DeBari VA, et al. Statins may reduce episodes of exacerbation and the
requirement for intubation in patients with COPD: evidence from a retrospective cohort study. Int J Clin
Pract. 2008;62:1373-1378. Abstract
159. Janda S, Park K, FitzGerald JM, et al. Statins in COPD: a systematic review. Chest.
2009;136:734-743. Abstract
160. Lee JS, Park DA, Hong Y, et al. Systematic review and meta-analysis of prophylactic antibiotics in
COPD and/or chronic bronchitis. Int J Tuberc Lung Dis. 2013;17:153-162. Abstract
161. Han MK, Tayob N, Murray S, et al. Predictors of chronic obstructive pulmonary disease exacerbation
reduction in response to daily azithromycin therapy. Am J Respir Crit Care Med. 2014;189:1503-1508.
Full text Abstract
162. Rennard S, Calverley PM, Goehring PMA, et al. Reduction of exacerbations by the PDE4 inhibitor
roflumilast—the importance of defining different subsets of patients with COPD. Respir Res.
2011;12:18. Full text Abstract
163. Taegtmeyer AB, Leuppi JD, Kullak-Ublick GA. Roflumilast: a phosphodiesterase-4 inhibitor licensed for
add-on therapy in severe COPD. Swiss Med Wkly. 2012;142:w13628. Abstract
164. Davies L, Calverley PM. The evidence for the use of oral mucolytic agents in chronic obstructive
pulmonary disease (COPD). Br Med Bull. 2010;93:217-227. Full text Abstract
165. Poole P, Chong J, Cates CJ. Mucolytic agents versus placebo for chronic bronchitis or chronic
obstructive pulmonary disease. Cochrane Database Syst Rev. 2015;(7):CD001287. Full text Abstract
166. Kueppers F. The role of augmentation therapy in alpha-1 antitrypsin deficiency. Curr Med Res Opin.
2011;27:579-588. Abstract
167. Salpeter SR, Ormiston TM, Salpeter EE. Cardioselective beta-blockers for chronic obstructive
168. Rutten FH, Zuithoff NP, Hak E, et al. Beta-blockers may reduce mortality and risk of exacerbations in
patients with chronic obstructive pulmonary disease. Arch Intern Med. 2010;170:880-887. Full text
Abstract
53
disease References
169. Foxwell AR, Cripps AW, Dear KB. Haemophilus influenzae oral whole cell vaccination for preventing
acute exacerbations of chronic bronchitis. Cochrane Database Syst Rev. 2010;(10):CD001958.
Abstract
REFERENCES
170. Teo E, Lockhart K, Purchuri SN, et al. Haemophilus influenzae oral vaccination for preventing acute
exacerbations of chronic bronchitis and chronic obstructive pulmonary disease. Cochrane Database
Syst Rev. 2017 Jun 19;6:CD010010. Full text Abstract
171. Criner GJ, Connett JE, Aaron SD, et al. Simvastatin for the prevention of exacerbations in moderate-
to-severe COPD. N Engl J Med. 2014;370:2201-2210. Full text Abstract
172. Rodriguez-Roisin R. Toward a consensus definition for COPD exacerbations. Chest. 2000;117(suppl
2):398S-401S. Abstract
173. Pauwels R, Calverley P, Buist AS, et al. COPD exacerbations: the importance of a standard definition.
Respir Med. 2004;98:99-107. Abstract
174. Quon BS, Gan WQ, Sin DD, et al. Contemporary management of acute exacerbations of COPD: a
systematic review and metaanalysis. Chest 2008;133:756-766. Abstract
175. Schuetz P, Wirz Y, Sager R, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory
tract infections. Cochrane Database Syst Rev. 2017 Oct 12;10:CD007498. Full text Abstract
176. Bestall JC, Paul EA, Garrod R, et al. Usefulness of the Medical Research Council (MRC) dyspnoea
scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax.
1999;54:581-586. Abstract
177. Stockley RA, O'Brien C, Pye A, et al. Relationship of sputum color to nature and outpatient
management of acute exacerbations of COPD. Chest. 2000;117:1638-1645. Abstract
178. Gompertz S, O'Brien C, Bayley DL, et al. Changes in bronchial inflammation during acute
exacerbations of chronic bronchitis. Eur Respir J. 2001;17:1112-1119. Full text Abstract
179. Huiart L, Ernst P, Suissa S. Cardiovascular morbidity and mortality in COPD. Chest.
2005;128:2640-2646. Abstract
180. Lim BL, Kelly AM. A meta-analysis on the utility of peripheral venous blood gas analyses in
exacerbations of chronic obstructive pulmonary disease in the emergency department. Eur J Emerg
Med. 2010;17:246-248. Abstract
181. British Thoracic Society. BTS Guideline for oxygen use in healthcare and emergency settings. October
2017 [internet publication] Full text Abstract
182. Brekke PH, Omland T, Smith P, et al. Underdiagnosis of myocardial infarction in COPD - Cardiac
Infarction Injury Score (CIIS) in patients hospitalised for COPD exacerbation. Respir Med.
2008;102:1243-1247. Abstract
183. Gelow JM, Fang JC. Update in the approach to and management of heart failure. South Med J.
2006;99:1346-1355. Abstract
disease References
184. Doust J, Lehman R, Glasziou P. The role of BNP testing in heart failure. Am Fam Physician.
2006;74:1893-1898. Abstract
REFERENCES
185. Mueller C, Scholer A, Laule-Kilian K, et al. Use of B-type natriuretic peptide in the evaluation and
management of acute dyspnea. N Engl J Med. 2004 Feb 12;350(7):647-54. Full text Abstract
186. Dewan NA. COPD exacerbations: to X-ray or not to X-ray. Chest. 2002;122:1118-1121. Abstract
187. Emerman CL, Cydulka RK. Evaluation of high-yield criteria for chest radiography in acute exacerbation
of chronic obstructive pulmonary disease. Ann Emerg Med. 1993;22:680-684 Abstract
188. Sherman S, Skoney JA, Ravikrishnan KP. Routine chest radiographs in exacerbations of chronic
obstructive pulmonary disease. Diagnostic value. Arch Intern Med. 1989;149:2493-2496. Abstract
189. Lieberman D, Lieberman D, Gelfer Y, et al. Pneumonic vs nonpneumonic acute exacerbations of

COPD. Chest. 2002;122:1264-1270. Abstract
190. Slater A, Goodwin M, Anderson KE, et al. COPD can mimic the appearance of pneumothorax on
thoracic ultrasound. Chest. 2006;129:545-550. Abstract
191. Tillie-Leblond I, Marquette CH, Perez T, et al. Pulmonary embolism in patients with unexplained
exacerbation of chronic obstructive pulmonary disease: prevalence and risk factors. Ann Intern Med.
2006 Mar 21;144(6):390-6. Abstract
192. Robinson TD, Freiberg DB, Regnis JA, et al. The role of hypoventilation and ventilation-perfusion
redistribution in oxygen-induced hypercapnia during acute exacerbations of chronic obstructive
pulmonary disease. Am J Respir Crit Care Med. 2000;161:1524-1529. Abstract
193. Santos C, Ferrer M, Roca J, et al. Pulmonary gas exchange response to oxygen breathing in acute
lung injury. Am J Respir Crit Care Med. 2000;161:26-31. Abstract
194. Hanson CW, 3rd, Marshall BE, Frasch HF, et al. Causes of hypercarbia with oxygen therapy in patients
with chronic obstructive pulmonary disease. Crit Care Med. 1996;24:23-28. Abstract
195. Austin MA, Wills KE, Blizzard L, et al. Effect of high flow oxygen on mortality in chronic obstructive
pulmonary disease patients in prehospital setting: randomised controlled trial. BMJ. 2010;341:c5462.
Full text Abstract
196. Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations
of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group. N
Engl J Med. 1999;340:1941-1947. Abstract
197. Walters JA, Tan DJ, White CJ, et al. Systemic corticosteroids for acute exacerbations of chronic
198. Walters JA, Walters EH, Wood-Baker R. Oral corticosteroids for stable chronic obstructive pulmonary
disease. Cochrane Database Syst Rev. 2005;(3):CD005374. Abstract
55
disease References
199. de Jong YP, Uil SM, Grotjohan HP, et al. Oral or IV prednisolone in the treatment of COPD
exacerbations: a randomized, controlled, double-blind study. Chest. 2007;132:1741-1747. Abstract
REFERENCES
200. Walters JA, Tan DJ, White CJ, et al. Different durations of corticosteroid therapy for exacerbations of
chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014;(12):CD006897. Full text
Abstract
201. Abroug F, Ouanes-Besbes L, Fkih-Hassen M, et al. Prednisone in COPD exacerbation requiring

ventilatory support: an open-label randomised evaluation. Eur Respir J. 2014;43:717-724. Abstract
202. Gaude GS, Nadagouda S. Nebulized corticosteroids in the management of acute exacerbation of
COPD. Lung India. 2010;27:230-235. Full text Abstract
203. Ram FS. Use of theophylline in chronic obstructive pulmonary disease: examining the evidence. Curr
Opin Pulm Med. 2006;12:132-139. Abstract
204. Zhou Y, Wang X, Zeng X, et al. Positive benefits of theophylline in a randomized, double-blind,
parallel-group, placebo-controlled study of low-dose, slow-release theophylline in the treatment of
COPD for 1 year. Respirology. 2006;11:603-610. Abstract
205. Barr RG, Rowe BH, Camargo CA, Jr. Methylxanthines for exacerbations of chronic obstructive
pulmonary disease: meta-analysis of randomised trials. BMJ. 2003;327:643. Full text Abstract
206. Osadnik CR, McDonald CF, Miller BR, et al. The effect of positive expiratory pressure (PEP) therapy
on symptoms, quality of life and incidence of re-exacerbation in patients with acute exacerbations
of chronic obstructive pulmonary disease: a multicentre, randomised controlled trial. Thorax.
2014;69:137-143. Abstract
207. Bach PB, Brown C, Gelfand SE, et al. Management of acute exacerbations of chronic obstructive
pulmonary disease: a summary and appraisal of published evidence. Ann Intern Med.
2001;134:600-620. Abstract
208. Saint S, Bent S, Vittinghoff E, et al. Antibiotics in chronic obstructive pulmonary disease
exacerbations. A meta-analysis. JAMA. 1995;273:957-960. Abstract
209. Llor C, Moragas A, Hernández S, et al. Efficacy of antibiotic therapy for acute exacerbations of mild to
moderate chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;186:716-723. Full
text Abstract
210. Veterans Affairs/Department of Defense. VA/DoD clinical practice guideline: the management of
chronic obstructive pulmonary disease. December 2014. http://www.healthquality.va.gov/ (last
accessed 28 December 2015). Full text
211. Vollenweider DJ, Jarrett H, Steurer-Stey CA, et al. Antibiotics for exacerbations of chronic obstructive
212. Wilson R, Allegra L, Huchon G, et al. Short-term and long-term outcomes of moxifloxacin compared to
standard antibiotic treatment in acute exacerbations of chronic bronchitis. Chest. 2004;125:953-964.
Abstract
disease References
213. Wilson R, Schentag JJ, Ball P, et al. A comparison of gemifloxacin and clarithromycin in acute
exacerbations of chronic bronchitis and long-term clinical outcomes. Clin Ther. 2002;24:639-652.
Abstract
REFERENCES
214. Wilson R, Jones P, Schaberg T, et al. Antibiotic treatment and factors influencing short and long term
outcomes of acute exacerbations of chronic bronchitis. Thorax. 2006;61:337-342. Abstract
215. Grossman RF, Ambrusz ME, Fisher AC, et al. Levofloxacin 750 mg QD for five days versus amoxicillin/
clavulanate 875 mg/125 mg BID for ten days for treatment of acute bacterial exacerbation of chronic
bronchitis: a post hoc analysis of data from severely ill patients. Clin Ther. 2006;28:1175-1180.
Abstract
216. Siempos II, Dimopoulos G, Korbila IP, et al. Macrolides, quinolones and amoxicillin/clavulanate for
chronic bronchitis: a meta-analysis. Eur Respir J. 2007;29:1127-1137. Abstract
217. Dimopoulos G, Siempos, II, Korbila IP, et al. Comparison of first-line with second-line antibiotics for
acute exacerbations of chronic bronchitis: a meta-analysis of randomized controlled trials. Chest.
2007;132:447-455. Abstract
218. Keenan SP, Kernerman PD, Cook DJ, et al. Effect of noninvasive positive pressure ventilation
on mortality in patients admitted with acute respiratory failure: a meta-analysis. Crit Care Med.
1997;25:1685-1692. Abstract
219. Brochard L, Mancebo J, Wysocki M, et al. Noninvasive ventilation for acute exacerbations of chronic
obstructive pulmonary disease. N Engl J Med. 1995;333:817-822. Abstract
220. Kramer N, Meyer TJ, Meharg J, et al. Randomized, prospective trial of noninvasive positive pressure
ventilation in acute respiratory failure. Am J Respir Crit Care Med. 1995;151:1799-1806. Abstract
221. Osadnik CR, Tee VS, Carson-Chahhoud KV, et al. Non-invasive ventilation for the management of
acute hypercapnic respiratory failure due to exacerbation of chronic obstructive pulmonary disease.
Cochrane Database Syst Rev. 2017 Jul 13;7:CD004104. Full text Abstract
222. Keenan SP, Sinuff T, Burns KE, et al. Clinical practice guidelines for the use of noninvasive positive-
pressure ventilation and noninvasive continuous positive airway pressure in the acute care setting.
CMAJ. 2011;183:E195-214. Full text Abstract
223. McCurdy BR. Noninvasive positive pressure ventilation for acute respiratory failure patients with
chronic obstructive pulmonary disease (COPD): an evidence-based analysis. Ont Health Technol
Assess Ser. 2012;12:1-102. Full text Abstract
224. Koh Y. Ventilatory management in patients with chronic airflow obstruction. Crit Care Clin.
2007;23:169-181. Abstract
225. Chandra D, Stamm JA, Taylor B, et al. Outcomes of noninvasive ventilation for acute exacerbations of
chronic obstructive pulmonary disease in the United States, 1998-2008. Am J Respir Crit Care Med.
57
disease References
226. Breen D, Churches T, Hawker F, et al. Acute respiratory failure secondary to chronic obstructive
pulmonary disease treated in the intensive care unit: a long term follow up study. Thorax.
REFERENCES
227. Udwadia ZF, Santis GK, Steven MH, et al. Nasal ventilation to facilitate weaning in patients with
chronic respiratory insufficiency. Thorax. 1992;47:715-718. Abstract
228. Perkins GD, Olasveengen TM, Maconochie I, et al. European Resuscitation Council guidelines for
resuscitation: 2017 update. Resuscitation. 2018 Feb;123:43-50. Abstract
229. Colquhoun MC, Handley AJ, Evans TR, eds. ABC of resuscitation. 5th ed. Wiley-Blackwell; 2004.
230. Soar J, Nolan JP, Böttiger BW, et al. European Resuscitation Council guidelines for resuscitation 2015:
Section 3. Adult advanced life support. Resuscitation. 2015;95:100-147. Abstract
231. Rice KL, Dewan N, Bloomfield HE, et al. Disease management program for chronic obstructive
pulmonary disease: a randomized controlled trial. Am J Respir Crit Care Med. 2010;182:890-896.
Abstract
232. Spruit MA, Singh SJ, Garvey C, et al. An official American Thoracic Society/European Respiratory
Society statement: key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care
Med. 2013;188:e13-e64. Abstract
233. British Thoracic Society. BTS guideline on pulmonary rehabilitation in adults. September 2013. https://
www.brit-thoracic.org.uk (last accessed 28 December 2015). Full text
234. Zanotti E, Felicetti G, Maini M, et al. Peripheral muscle strength training in bed-bound patients with
COPD receiving mechanical ventilation: effect of electrical stimulation. Chest. 2003;124:292-296.
Abstract
235. Troosters T, Probst VS, Crul T, et al. Resistance training prevents deterioration in quadriceps muscle
function during acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care
Med. 2010;181:1072-1077. Abstract
236. Reid WD, Yamabayashi C, Goodridge D, et al. Exercise prescription for hospitalized people with
chronic obstructive pulmonary disease and comorbidities: a synthesis of systematic reviews. Int J
Chron Obstruct Pulmon Dis. 2012;7:297-320. Full text Abstract
237. Man WD, Polkey MI, Donaldson N, et al. Community pulmonary rehabilitation after hospitalisation for
acute exacerbations of chronic obstructive pulmonary disease: randomised controlled study. BMJ.
2004;329:1209. Full text Abstract
238. Seymour JM, Moore L, Jolley CJ, et al. Outpatient pulmonary rehabilitation following acute
exacerbations of COPD. Thorax. 2010;65:423-428. Abstract
239. Marciniuk DD, Brooks D, Butcher S, et al. Canadian Thoracic Society COPD Committee Expert
Working Group. Optimizing pulmonary rehabilitation in chronic obstructive pulmonary disease practical
issues: a Canadian Thoracic Society Clinical Practice Guideline. Can Respir J. 2010;17:159-168.
Abstract
disease References
240. Clini EM, Crisafulli E, Costi S, et al. Effects of early inpatient rehabilitation after acute exacerbation of
COPD. Respir Med. 2009;103:1526-1531. Abstract
REFERENCES
241. Puhan MA, Gimeno-Santos E, Cates CJ, Troosters T. Pulmonary rehabilitation following exacerbations
of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2016 Dec 8;12:CD005305.
Full text Abstract
242. Puhan MA, Scharplatz M, Troosters T, et al. Respiratory rehabilitation after acute exacerbation of
COPD may reduce risk for readmission and mortality--a systematic review. Respir Res. 2005;6:54.
Full text Abstract
243. Greening NJ, Williams JE, Hussain SF, et al. An early rehabilitation intervention to enhance recovery
during hospital admission for an exacerbation of chronic respiratory disease: randomised controlled
trial. BMJ. 2014;349:g4315. Full text Abstract
244. Turner MO, Patel A, Ginsburg S, et al. Bronchodilator delivery in acute airflow obstruction. A meta-
analysis. Arch Intern Med. 1997;157:1736-1744. Abstract
245. Stevenson NJ, Walker PP, Costello RW, et al. Lung mechanics and dyspnea during exacerbations of
246. Holland A, Smith F, Penny K, et al. Metered dose inhalers versus nebulizers for aerosol bronchodilator
delivery for adult patients receiving mechanical ventilation in critical care units. Cochrane Database
Syst Rev. 2013;(6):CD008863. Full text Abstract
247. Karpel JP, Pesin J, Greenberg D, et al. A comparison of the effects of ipratropium bromide and
metaproterenol sulfate in acute exacerbations of COPD. Chest. 1990;98:835-839. Abstract
248. Celli BR, MacNee W, Agusti A, et al; ATS/ERS Task Force. Standards for the diagnosis and treatment
of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004;23:932-946.
Full text Abstract
249. Emerman CL, Cydulka RK. Effect of different albuterol dosing regimens in the treatment of acute
exacerbation of chronic obstructive pulmonary disease. Ann Emerg Med. 1997;29:474-478. Abstract
250. Moayyedi P, Congleton J, Page RL, et al. Comparison of nebulised salbutamol and ipratropium
bromide with salbutamol alone in the treatment of chronic obstructive pulmonary disease. Thorax.
1995;50:834-837. Abstract
251. Patrick DM, Dales RE, Stark RM, et al. Severe exacerbations of COPD and asthma: incremental
benefit of adding ipratropium to usual therapy. Chest. 1990;98:295-297. Abstract
252. Leuppi JD, Schuetz P, Bingisser R, et al. Short-term vs conventional glucocorticoid therapy in acute
exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA.
253. Zheng J, Lin J, Zhou X, et al. Nebulized budesonide in the treatment of acute exacerbations of chronic
obstructive pulmonary disease (AECOPD): a randomized, double blind, double dummy, parallel
controlled, multicenter trial. Chest. 2011;140:526A. Full text
59
disease References
254. Alía I, de la Cal MA, Esteban A, et al. Efficacy of corticosteroid therapy in patients with an acute
exacerbation of chronic obstructive pulmonary disease receiving ventilatory support. Arch Intern Med.
REFERENCES
255. Osadnik CR, McDonald CF, Jones AP, et al. Airway clearance techniques for chronic obstructive
256. Hill K, Patman S, Brooks D. Effect of airway clearance techniques in patients experiencing an acute
exacerbation of chronic obstructive pulmonary disease: a systematic review. Chron Respir Dis.
2010;7:9-17. Abstract
257. Cross J, Elender F, Barton G, et al. A randomised controlled equivalence trial to determine the
effectiveness and cost-utility of manual chest physiotherapy techniques in the management of
exacerbations of chronic obstructive pulmonary disease (MATREX). Health Technol Assess.
2010;14:1-147, iii-iv. Abstract
258. Tang CY, Taylor NF, Blackstock FC. Chest physiotherapy for patients admitted to hospital with an acute
exacerbation of chronic obstructive pulmonary disease (COPD): a systematic review. Physiotherapy.
2010;96:1-13. Abstract
259. Agusti AG, Carrera M, Barbe F, et al. Oxygen therapy during exacerbations of chronic obstructive
pulmonary disease. Eur Respir J. 1999;14:934-939. Abstract
260. Puhan MA, Vollenweider D, Steurer J, et al. Where is the supporting evidence for treating mild to
moderate chronic obstructive pulmonary disease exacerbations with antibiotics? A systematic review.
BMC Med. 2008;6:28. Full text Abstract
261. El Moussaoui R, Roede BM, Speelman P, et al. Short-course antibiotic treatment in acute
exacerbations of chronic bronchitis and COPD: a meta-analysis of double-blind studies. Thorax.
262. Falagas ME, Avgeri SG, Matthaiou DK, et al. Short- versus long-duration antimicrobial treatment for
exacerbations of chronic bronchitis: a meta-analysis. J Antimicrob Chemother. 2008;62:442-450. Full
text Abstract
263. Barreiro TJ, Gemmel DJ. Noninvasive ventilation. Crit Care Clin. 2007;23:201-222. Abstract
264. Roberts CM, Brown JL, Reinhardt AK, et al. Non-invasive ventilation in chronic obstructive pulmonary
disease: management of acute type 2 respiratory failure. Clin Med. 2008;8:517-521. Abstract
265. Smith TA, Davidson PM, Lam LT, et al. The use of non-invasive ventilation for the relief of dyspnoea
in exacerbations of chronic obstructive pulmonary disease; a systematic review. Respirology.
2012;17:300-307. Abstract
266. Anton A, Guell R, Gomez J, et al. Predicting the result of noninvasive ventilation in severe acute
exacerbations of patients with chronic airflow limitation. Chest. 2000;117:828-833. Abstract
267. Man WD, Soliman MG, Nikoletou D, et al. Non-volitional assessment of skeletal muscle strength in
patients with chronic obstructive pulmonary disease. Thorax. 2003;58:665-659. Abstract
disease References
268. Spruit MA, Gosselink R, Troosters T, et al. Muscle force during an acute exacerbation in hospitalised
patients with COPD and its relationship with CXCL8 and IGF-I. Thorax. 2003;58:752-756. Full text
Abstract
REFERENCES
269. Maltais F, Bourbeau J, Shapiro S, et al. Effects of home-based pulmonary rehabilitation in patients
with chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2008;149:869-878.
Abstract
270. Langer D, Hendriks E, Burtin C, et al. A clinical practice guideline for physiotherapists treating patients
with chronic obstructive pulmonary disease based on a systematic review of available evidence. Clin
Rehabil. 2009;23:445-462. Abstract
271. Tang CY, Blackstock FC, Clarence M, et al. Early rehabilitation exercise program for inpatients during
an acute exacerbation of chronic obstructive pulmonary disease: a randomized controlled trial. J
Cardiopulm Rehabil Prev. 2012;32:163-169. Abstract
272. Bourbeau J, Julien M, Maltais F, Rouleau M, et al. Reduction of hospital utilization in patients with
chronic obstructive pulmonary disease: a disease-specific self-management intervention. Arch Intern
Med. 2003;163:585-591. Full text Abstract
273. Casas A, Troosters T, Garcia-Aymerich J, et al. Integrated care prevents hospitalisations for
exacerbations in COPD patients. Eur Respir J. 2006;28:123-130. Full text Abstract
274. Kuo CC, Lin CC, Lin SY, et al. Effects of self-regulation protocol on physiological and psychological
measures in patients with chronic obstructive pulmonary disease. J Clin Nurs. 2013;22:2800-2811.
Abstract
275. Fan VS, Gaziano M, Lew R, et al. A comprehensive care management program to prevent chronic
obstructive pulmonary disease hospitalizations: a randomized, controlled trial. Ann Intern Med.
2012;156:673-683. Abstract
276. Jeppesen E, Brurberg KG, Vist GE, et al. Hospital at home for acute exacerbations of chronic
277. McCurdy BR. Hospital-at-home programs for patients with acute exacerbations of chronic obstructive
pulmonary disease (COPD): an evidence-based analysis. Ont Health Technol Assess Ser.
278. Vitacca M, Bianchi L, Guerra A, et al. Tele-assistance in chronic respiratory failure patients: a
randomised clinical trial. Eur Respir J. 2009;33:411-418. Abstract
279. Pinnock H, Hanley J, McCloughan L, et al. Effectiveness of telemonitoring integrated into existing
clinical services on hospital admission for exacerbation of chronic obstructive pulmonary disease:
researcher blind, multicentre, randomised controlled trial. BMJ. 2013;347:f6070. Full text Abstract
280. Patil SP, Krishnan JA, Lechtzin N, et al. In-hospital mortality following acute exacerbations of chronic
obstructive pulmonary disease. Arch Intern Med. 2003;163:1180-1186. Full text Abstract
61
disease References
281. Hoogendoorn M, Hoogenveen RT, Rutten-van Mölken MP, et al. Case fatality of COPD exacerbations:
a meta-analysis and statistical modelling approach. Eur Respir J. 2011;37:508-515. Full text Abstract
REFERENCES
282. Dewan NA, Rafique S, Kanwar B, et al. Acute exacerbation of COPD: factors associated with poor
treatment outcome. Chest. 2000;117:662-671. Abstract
283. Gunen H, Hacievliyagil SS, Kosar F, et al. Factors affecting survival of hospitalised patients with
COPD. Eur Respir J. 2005;26:234-241. Full text Abstract
284. Garcia-Aymerich J, Farrero E, Felez MA, et al. Risk factors of readmission to hospital for a COPD
exacerbation: a prospective study. Thorax. 2003;58:100-105. Full text Abstract
285. Garcia-Aymerich J, Lange P, Benet M, et al. Regular physical activity reduces hospital admission
and mortality in chronic obstructive pulmonary disease: a population based cohort study. Thorax.
286. Piquet J, Chavaillon JM, David P, et al. High-risk patients following hospitalisation for an acute
exacerbation of COPD. Eur Respir J. 2013;42:946-955. Full text Abstract
287. Singanayagam A, Schembri S, Chalmers JD. Predictors of mortality in hospitalized adults with acute
exacerbation of chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2013;10:81-89. Full text
Abstract
288. Almagro P, Soriano JB, Cabrera FJ, et al. Short- and medium-term prognosis in patients hospitalized
for COPD exacerbation: the CODEX index. Chest. 2014;145:972-980. Full text Abstract
289. Sharma G, Kuo YF, Freeman JL, et al. Outpatient follow-up visit and 30-day emergency department
visit and readmission in patients hospitalized for chronic obstructive pulmonary disease. Arch Intern
Med. 2010;170:1664-1670. Full text Abstract
290. Jones PW, Lamarca R, Chuecos F, et al. Characterisation and impact of reported and unreported
exacerbations: results from ATTAIN. Eur Respir J. 2014;44:1156-1165. Full text Abstract
291. Mularski RA, Reinke LF, Carrieri-Kohlman V, et al. An official American Thoracic Society workshop
report: assessment and palliative management of dyspnea crisis. Ann Am Thorac Soc. 2013;10:S98-
S106. Full text Abstract
292. Gross N, Levin D. Primary care of the patient with chronic obstructive pulmonary disease-part 2:
pharmacologic treatment across all stages of disease. Am J Med. 2008;121(suppl 7):S13-S24.
Abstract
293. Sorensen SV, Baker T, Fleurence R, et al. Cost and clinical consequence of antibiotic non-adherence
in acute exacerbations of chronic bronchitis. Int J Tuberc Lung Dis. 2009;13:945-954. Abstract
294. Lodewijckx C, Sermeus W, Vanhaecht K, et al. Inhospital management of COPD exacerbations: a

systematic review of the literature with regard to adherence to international guidelines. J Eval Clin
Pract. 2009;15:1101-1110. Abstract
disease References
295. Pitta F, Troosters T, Probst VS, et al. Physical activity and hospitalization for exacerbation of COPD.
Chest. 2006;129:536-544. Abstract
REFERENCES
296. Garcia-Aymerich J, Lange P, Benet M, et al. Regular physical activity modifies smoking-related lung
function decline and reduces risk of chronic obstructive pulmonary disease: a population-based cohort
study. Am J Respir Crit Care Med. 2007;175:458-463. Abstract
297. Cindy Ng LW, Mackney J, Jenkins S, et al. Does exercise training change physical activity in people
with COPD? A systematic review and meta-analysis. Chron Respir Dis. 2012;9:17-26. Abstract
298. COPD Working Group. Pulmonary rehabilitation for patients with chronic pulmonary disease (COPD):
an evidence-based analysis. Ont Health Technol Assess Ser. 2012;12:1-75. Full text Abstract
299. Howcroft M, Walters EH, Wood-Baker R, Walters JA. Action plans with brief patient education for
exacerbations in chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2016 Dec
19;12:CD005074. Full text Abstract
300. Bucknall CE, Miller G, Lloyd SM, et al. Glasgow supported self-management trial (GSuST) for patients
with moderate to severe COPD: randomised controlled trial. BMJ. 2012;344:e1060. Full text Abstract
301. Harrison SL, Janaudis-Ferreira T, Brooks D, et al. Self-management following an acute exacerbation of
COPD: a systematic review. Chest. 2015;147:646-661. Abstract
302. McLean S, Nurmatov U, Liu JL, et al. Telehealthcare for chronic obstructive pulmonary disease.
Cochrane Database Syst Rev. 2011 Jul 6;(7):CD007718. Full text Abstract
303. Franek J. Home telehealth for patients with chronic obstructive pulmonary disease (COPD): an
evidence-based analysis. Ont Health Technol Assess Ser. 2012;12:1-58. Full text Abstract
63
disease Disclaimer
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Contributors:
// Authors:
Carolyn L. Rochester, MD
Associate Professor
Yale University School of Medicine, New Haven, VA Connecticut Healthcare System, West Haven, CT
DISCLOSURES: CLR serves on the COPD scientific advisory board for GlaxoSmithKline Pharmaceuticals
but has no competing interests pertaining to this publication.
Richard A. Martinello, MD
Associate Professor
Yale University School of Medicine, New Haven, Veterans Health Administration, Office of Public Health,
West Haven, CT
DISCLOSURES: RAM declares that he has no competing interests.
// Peer Reviewers:
Sanjay Sethi, MD
Professor of Medicine
Division Chief, Pulmonary/Critical Care/Sleep Medicine, University at Buffalo, State University of New York,
Section Chief, Pulmonary/Critical Care/Sleep Medicine, VA Western New York Healthcare System, Buffalo,
NY
DISCLOSURES: SS declares that he has no competing interests.
Francis Thien, MD, FRACP, FCCP

Professor
Box Hill Hospital and Monash University, Victoria, Australia
DISCLOSURES: FT declares that he has no competing interests.

Acute COPD Exacerbation

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Acute COPD Exacerbation

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Acute exacerbation of

Last updated: Apr 12, 2018

◊ Treatment includes bronchodilators, systemic corticosteroids, and antibiotics.

abnormalities usually caused by significant exposure to noxious particles or gases."[1]

• GOLD 1 - mild: FEV1 ≥ 80% predicted

Trigger avoidance, smoking cessation, and immunisation

as mortality or hospitalisations is as yet unclear.[147] [150] Novel combination therapies including

Step-by-step diagnostic approach

Laboratory evaluation and imaging

[VIDEO: How to perform an ECG animated demonstration ]

[VIDEO: Radial artery puncture animated demonstration ]

gastro-oesophageal reflux and/or swallowing dysfunction

History & examination factors

changes in sputum volume/colour/thickness (common)

Other diagnostic factors

tobacco use (common)

past medical hx of gastro-oesophageal reflux and/or swallowing dysfunction

malaise and fatigue (common)

chest tightness (common)

features of cor pulmonale (common)

• This may develop as a result of increased hypoxic vasoconstriction due to exacerbation-induced

environmental/occupational exposure to pollutants or dust (uncommon)

change in mental status (uncommon)

paradoxical movements of abdomen (uncommon)

Other tests to consider

Condition Differentiating signs / Differentiating tests

airways inflammation and/

Pleural effusion • Pleural effusions may • Chest imaging is

Pulmonary embolism • Clinically, pulmonary • Pulmonary embolus may be

Cardiac ischaemia • Clinically, may be difficult • An electrocardiogram should

Exacerbations with suspected bacterial aetiology

Severe exacerbations of COPD

(e.g., confusion, lethargy, coma) are important indicators of severity of exacerbation.[1]

• Respiratory acidosis (PaCO2 ≥ 6.0 kPa or 45 mmHg and arterial pH ≤ 7.35)

[VIDEO: Tracheal intubation animated demonstration ]

[VIDEO: Bag-valve-mask ventilation animated demonstration ]

1st short-acting bronchodilator

plus systemic corticosteroid

adjunct airway clearance techniques

suspected bacterial adjunct narrow-spectrum antibiotic

suspected bacterial adjunct broad-spectrum antibiotic

respiratory insufficiency adjunct non-invasive positive-pressure ventilation

adjunct invasive positive-pressure ventilation

1st pulmonary rehabilitation and disease-

1st short-acting bronchodilator

» salbutamol inhaled: 2.5 to 5 mg nebulised

» Short-acting bronchodilators include beta-2

ventilation via endotracheal tube.[246]

» Beta-2 agonists are typically favoured as

» It is not clear whether the combination

» After clinical improvement, the time between

» Optimal dosing of bronchodilators in

» prednisolone: 30-40 mg orally once daily for

» methylprednisolone: 40-60 mg/day orally

» methylprednisolone sodium succinate: 0.5

» Studies identifying benefit in the use

» Systemic corticosteroids should be initiated

» Diabetes is common in patients with COPD,

» For patients able to take oral medications,