CAT 1

 

CAT

After completing your assigned readings, can anyone answer the following questions from Chapter 232 in our Hospital Medicine text?

1.     What conditions mimic an acute exacerbation of COPD and require different diagnostic and treatment modalities?

2.     What impatient therapeutic modalities reduce mortality or length of stay for patients with exacerbation of COPD?

3.     What are the indications for noninvasive ventilation for patients with an acute exacerbation of COPD?

4.     Explain the therapeutic interventions that you would consider and discuss with a patient at the time of discharge following an acute exacerbation of COPD?

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CHAPTER 232
Chronic Obstructive Pulmonary Disease

Gerald W. Staton, MD

Christopher D. Ochoa, MD

Key Clinical Questions

What conditions mimic an acute exacerbation of chronic obstructive pulmonary
disease (COPD) and require different diagnostic and treatment modalities?

What inpatient therapeutic modalities reduce mortality or length of stay for
patients with exacerbation of COPD?

What are the indications for noninvasive

ventilation

for patients with an acute
exacerbation of COPD?

Explain the therapeutic interventions that you would consider and discuss with a
patient at the time of discharge following an acute exacerbation of COPD?

INTRODUCTION
DEFINITION AND BACKGROUND

Chronic obstructive pulmonary disease (COPD) is a group of clinical and pathological
pulmonary disorders that are preventable and treatable and are characterized by airflow

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limitation that is not fully reversible. The most common phenotypes of COPD are
emphysema and chronic bronchitis. Emphysema is generally defined as irreversible
enlargement of the airways and loss of elastic recoil. Clinically, emphysema presents with
dyspnea along with clinical findings of an expanded chest, decreased breath sounds,
radiographic lucency, and flattening of the diaphragms. Chronic bronchitis is defined by
the finding of cough and sputum production on most days of at least 3 months per year
for two consecutive years. Pathologically, the hallmarks of chronic bronchitis are large
airway inflammation and the hypertrophy and hyperplasia of the mucous-secreting goblet
cells. COPD is diagnosed after demonstrating airflow limitation by spirometry (at a time
free of exacerbation) that is not fully reversible in patients who exhibit cough, sputum
production, dyspnea or other appropriate risk factors. The severity of COPD is classified by
the degree of limitation in the forced expiratory volume in 1 second (FEV1) as well as by
the frequency of exacerbations (0-1 vs ≥ 2 per year) and patient reported symptoms using
validated questionnaires (Tables 232-1 and 232-2).

TABLE 232-1 GOLD Spirometry Criteria for Chronic Obstructive Pulmonary Disease
Severity

GOLD Stage Severity Spirometry
I Mild FEV1/FVC < 0.7 and FEV1 80% predicted II Moderate FEV1/FVC < 0.7 and 50% FEV1 < 80%

predicted
III Severe FEV1/FVC < 0.7 and 30% FEV1 < 50%

predicted
IV Very severe FEV1/FVC < 0.7 and FEV1 < 30% predicted

or
FEV1 < 50% predicted with respiratory failure or signs of right heart failure

FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; GOLD, Global Initiative for Chronic
Obstructive Lung Disease.

TABLE 232-2 GOLD Grading Criteria for Chronic Obstructive Pulmonary Disease

Grade Spirometry Yearly Exacerbation Rate Symptom Score
A Stage 1 or 2 ≤1 exacerbation not

leading to a
hospitalization

CAT <10 or mMRC 0-1

B Stage 1 or 2 ≤1 exacerbation not
leading to a
hospitalization

CAT ≥10 or mMRC ≥2

C Stage 3 or 4 ≥2 exacerbations or
≥1 exacerbation leading
to hospitalization

CAT < 10 or mMRC 0-1

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D Stage 3 or 4 ≥2 exacerbations or
≥1 exacerbation leading
to hospitalization

CAT ≥10 or mMRC ≥2

Severity is determined by a combination of symptom scores and either number of yearly
exacerbations or spirometry stage. CAT, COPD assessment test; mMRC, modified Medical Research
Council questionnaire for assessing the severity of breathlessness.

Hospitalists often manage patients presenting with new symptoms consistent with
COPD, patients with acute exacerbations of underlying COPD, and patients whose COPD
complicates the course of other medical conditions. In this chapter, we will review best
practices for each of these scenarios and solutions for optimizing care of these patients
as they transition out of the acute care setting.

RISK FACTORS

Tobacco smoking is the single most important risk factor for the development of COPD.
Cigarette, pipe, and cigar smoking account for more than 90% of cases of COPD; yet,
clinically important disease is only found in 10% to 20% of smokers. Clearly there are other
predisposing factors because dose-dependent exposure to tobacco does not wholly
determine the onset or severity of disease in COPD. Additional factors that lead to the
onset (or accelerate the progression) of COPD include exposure to second-hand smoke,
environmental irritants and pollutants (including biomass), occupational exposures,
malnutrition, childhood pulmonary infections, HIV infection, and genetic predisposition.
The role of genetics is incompletely understood, but COPD is more common in the
relatives of those with COPD.

PATHOGENESIS

Tobacco smoke and other exposures trigger inflammatory, biochemical and anatomic
changes that account for the symptoms, limitations, and complications of COPD (Figure
232-1). These airway irritants activate the airway epithelium as well as alveolar
macrophages to release chemokines that attract a host of inflammatory cells into the
airway including neutrophils and monocytes. Production of IL-6 and TNF-α magnify this
inflammatory response. These cells, in concert with the airway epithelium produce
metalloproteinases responsible for the degradation of elastin resulting in emphysema.
Neutrophil elastase stimulates mucous hypersecretion while epithelial cells produce TGF-β
and fibroblast growth factors causing small airway fibrosis. When taken together, these
insults lead to loss of elastic recoil, airflow limitation and impaired gas exchange
characteristic of COPD.

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Figure 232-1 Pathogenesis of chronic obstructive pulmonary disease. (From Barnes PJ.
Immunology of asthma and chronic obstructive pulmonary disease. Nat Rev Immunol.
2008;8[3]:183-192. Reprinted by permission from Macmillan Publishers Ltd.)

EPIDEMIOLOGY

PREVALENCE AND EXACERBATIONS

Estimates of the incidence of COPD in the United States and worldwide vary, but data are
consistent that the disease burden is large and COPD is underdiagnosed. COPD is the third
leading cause of death in the United States. An estimated 12.7 million adults carried the
diagnosis of COPD in 2011. COPD was listed as the leading diagnosis in 715,000 hospital
discharges in 2010 and accounted for 133,965 deaths in 2009 according to the American
Lung Association.

COPD COMPLICATING OTHER DISEASES

There is increasing evidence that patients with COPD have high rates of morbidity and
mortality caused by extrapulmonary conditions. Patients with COPD have been found to
have higher rates of cardiovascular, gastrointestinal and psychiatric illnesses, among
others. It is estimated that COPD is a primary or contributing cause of almost 10% of all
admissions to the hospital. Cardiovascular morbidity and mortality might be even higher
than that of lung disease and respiratory failure.

COPD EXACERBATION: DIFFERENTIAL AND EVALUATION

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An acute exacerbation of COPD (AECOPD) is defined as a change in the baseline
symptoms of dyspnea, cough and/or sputum color or volume that necessitates a change
in management. When a patient with COPD or risk factors for COPD presents with any of
these complaints, the diagnosis of AECOPD must be considered against a number of other
diagnoses that may mimic an AECOPD. Once a diagnosis of AECOPD is reached, issues of
causation of the exacerbation and level of severity need to be addressed. There is no
single agreed-upon system to rank severity of exacerbations, but broadly categorizing
among three levels has been suggested: (1) home management, (2) hospital
management, and (3) respiratory failure.

ETIOLOGY AND DIFFERENTIAL DIAGNOSIS OF AECOPD

AECOPD has many different potential causes and the specific trigger for any one event is
sometimes never elucidated. It is commonly agreed, however, that various triggers cause
acute inflammation superimposed on the chronic inflammation of the underlying disease.
During an AECOPD, inflammatory cells of many inflammatory pathways can be found in
sputum and blood. Together, all infectious agents (bacteria, virus, and other) account for
up to 80% of acute exacerbations.

The differential diagnoses to consider as triggers in patients that have underlying
COPD and an acute respiratory decompensation are extensive (Table 232-3). Many of
these triggers incite the inflammatory pathway at the root of an AECOPD, but they may
also require other specific therapy. When a trigger is not immediately obvious from history
and physical examination, there are certain other diagnoses that must be considered. An
autopsy study of patients that were diagnosed as having an AECOPD and that died within
24 hours of admission showed that 37% of these deaths were due to heart failure and 21%
due to pulmonary embolism. Patients admitted with otherwise unexplained exacerbations
of COPD are often found to have pulmonary emboli when this diagnosis is pursued.

TABLE 232-3 Precipitants of Acute Exacerbation of Chronic Obstructive Pulmonary
Disease: Differential Diagnosis

Pneumonia
Upper respiratory tract infection
Pulmonary embolism
Reactive airways disease or allergens
Congestive heart failure
Pneumothorax (trauma, rib fracture)
Arrhythmia
Myocardial infarction
Upper airway obstruction
Sleep disordered breathing
Sedating medications
Medication nonadherence
Environmental irritants (smoke, smog, workplace irritants)

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Thickened bronchial secretions (eg, dehydration)

DIAGNOSTIC EVALUATION
For patients with known or suspected COPD, any complaint consistent with a COPD
exacerbation warrants thorough investigation. The degree of diagnostic evaluation should
be determined by the patient’s subjective degree of discomfort, physical examination
abnormalities, alterations in vital signs and/or diagnostic studies. Careful consideration of
any conditions in the differential diagnosis of AECOPD (Table 232-3) must be undertaken.

KEY HISTORY AND PHYSICAL EXAMINATION

Questions regarding dyspnea, cough, sputum volume or color and rescue bronchodilator
use may establish a change in symptoms from the patient’s baseline. The history may
also provide clues to other diagnoses or triggers (Table 232-3) for patients suspected of
having an AECOPD.

AECOPD is associated with increased dyspnea, sputum purulence, wheezing,
constitutional symptoms (fever, malaise, myalgias), and cough. Other past medical history
and comorbid conditions can affect overall mortality and may influence patient triage for
monitoring and therapy.

For patients with suspected AECOPD, but without a diagnosis of COPD, questioning
regarding age, smoking status, exercise tolerance and other respiratory exposures can help
increase or decrease the suspicion of COPD as the underlying disease.

The physical examination may help identify undiagnosed COPD, exclude other
diagnoses in patients with known COPD, and help triage the severity of a diagnosed
AECOPD. For evaluating the severity of an exacerbation, ominous physical examination
findings portending higher risk and poorer outcomes include altered mentation (agitation
and/or obtundation), respiratory muscle retraction, paradoxical abdominal movement,
cyanosis and diaphoresis. These findings necessitate higher levels of monitoring and
expedited care. Other findings that are consistent with an AECOPD include wheezing,
cough, hyper-resonance to percussion and diffusely decreased breath sounds.

LABORATORY EVALUATION

In the initial evaluation of AECOPD, pulse oximetry O2 saturation > 89% is evidence of
acceptable oxygenation.

PRACTICE POINT

An arterial blood gas should be rapidly obtained to evaluate any patient with an
AECOPD considered for hospital admission, as recommended by international
guidelines.

Arterial blood gases (ABGs) are able to more accurately determine the derangement of
gas exchange by calculating an alveolar-arterial gradient, and may detect worse hypoxia
than expected or evidence of hypercarbia. Importantly, the pH from the ABG may also
provide valuable information helping direct management (eg, consideration of

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noninvasive ventilation). Arterial blood gas interpretation must take into account the
patient’s baseline status. Patients with more severe disease are likely to have elevated
partial pressure of carbon dioxide (PCO2) with a relatively preserved pH as the kidneys
compensate for chronic hypoventilation. Ominous findings include elevated PCO2 with a
decreased pH (indicating an acute onset or worsening of hypoventilation), low partial
pressures of oxygen, and a severely elevated PCO2.

Guidelines recommend hematology and basic chemistry panels in the evaluation of
COPD. These tests may show polycythemia associated with chronic COPD, or conversely,
anemia. These basic labs are most valuable in identifying other diagnoses to be
considered or comorbid conditions that may require parallel treatment. Patients receiving
theophylline therapy should have the serum level measured.

Routine collection of sputum for Gram stain and culture is not recommended in the
management of COPD exacerbation. Sputum Gram stain and culture may play a role in
the laboratory evaluation of patients that do not respond to initial therapy and/or have
evidence of pneumonia.

RADIOGRAPHY AND ELECTROCARDIOGRAPHY

Chest radiography is indicated for evaluation of AECOPD. Findings on the radiograph may
influence the type of care if there are findings such as pneumothorax, atelectasis, focal
infiltrate or pulmonary edema. About 20% of patients thought to have an AECOPD have
chest radiograph findings that influence management.

PRACTICE POINT

About 20% of patients thought to have an AECOPD have chest radiograph findings
that influence management.

Patients with dyspnea and other chest complaints need electrocardiography (ECG)
evaluation to identify relevant findings including coronary ischemia or arrhythmias. The
irregular rhythm of multifocal tachycardia (MAT) that is found frequently in COPD patients
may be difficult to distinguish from atrial fibrillation without ECG. MAT responds to the
treatment of the underlying lung disease and rate control whereas atrial fibrillation
requires additional therapeutic approaches.

SPIROMETRY

Spirometry, while a core diagnostic tool for the evaluation of outpatient stable COPD, does
not have a role in the evaluation of COPD exacerbations. In fact, national and international
guidelines recommend against the use of spirometry in the setting of AECOPD.

TRIAGE: DETERMINING SEVERITY, INDICATIONS FOR ADMISSION, AND LEVEL
OF CARE
DETERMINING SEVERITY OF AN EXACERBATION

No single system exists to classify patient severity of illness once they are identified as
having an AECOPD. The American Thoracic Society and European Respiratory Society

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(ATS/ERS) guidelines define severity based upon where the exacerbation is managed
(home versus inpatient versus ICU) requiring clinicians evaluating patients for AECOPD to
rely on previously mentioned risk factors for mortality and clinical acumen to best triage
patients.

CRITERIA FOR ADMISSION

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) and ATS/ERS
guidelines for management of COPD provide criteria for hospitalization in AECOPD (Table
232-4). Certain findings may predict the success or failure of outpatient management.
Older age, lower baseline FEV1, hypoxemia, previous recent exacerbations and extensive
comorbidities can increase risk of mortality or relapse exacerbation.

TABLE 232-4 Indications for Hospitalization of Patients with Acute Exacerbation of
Chronic Obstructive Pulmonary Disease

1. High-risk comorbid conditions (heart failure, renal disease, liver failure, pneumonia)
2. Failure of outpatient management
3. Inability to perform activities of daily living (eating, sleeping, etc)
4. Unremitting dyspnea
5. Worsening hypercapnea, hypoxemia
6. Altered mental status
7. Diagnostic uncertainty

CRITERIA FOR INTENSIVE CARE UNIT ADMISSION

The best location to manage any patient with an AECOPD will vary based on individual
hospital resources and staffing, with differences in the availability of specified inpatient
respiratory units, step-down or intermediate care units and personnel. Therefore, criteria for
intensive care unit (ICU) admission are often institution specific. Nonetheless, some
guidelines suggest criteria for ICU admission (Table 232-5).

TABLE 232-5 Indications for Intensive Care Unit Admission of Patients with Acute
Exacerbation of Chronic Obstructive Pulmonary Disease

1. Severe dyspnea that responds inadequately to initial emergency therapy
2. Confusion, lethargy, or respiratory muscle fatigue (the last characterized by

paradoxical diaphragmatic motion)
3. Impending respiratory failure
4. Hemodynamic instability
5. Persistent or worsening hypoxemia despite supplemental oxygen or severe/worsening

respiratory acidosis (pH < 7.30) 6. Assisted mechanical ventilation, either intubation or noninvasive positive pressure

ventilation

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MANAGEMENT OF AN ACUTE EXACERBATION OF COPD
INITIAL HOSPITAL TREATMENT

Bronchodilators

Short-acting β-agonists such as albuterol are a mainstay of outpatient management of
stable COPD and play a key role in the treatment of AECOPD for improving symptoms and
FEV1. β-agonists induce airway smooth muscle relaxation via increased cyclic adenosine
monophosphate and have their largest effect on peripheral airways. Their onset of action
occurs within minutes, peak at 30 minutes, and last for several hours. β-agonists should
be given every 2 hours for initial treatment of a patient being admitted to a general
medical floor, but may be given as frequently as every 20 minutes or continuously for
patients in extremis. Levalbuterol, a pure R isomer of albuterol (albuterol is a 1:1 mixture
of the R and S isomers) may produce better bronchodilation in asthma exacerbations, but
this effect has not been shown in COPD. There is also some thought that levalbuterol may
cause less tachycardia when compared to racemic albuterol, but scarce evidence supports
this effect or its clinical significance. Based on the multitude of conflicting data
surrounding the use of levalbuterol, it is difficult to recommend its routine use, but it may
be reasonable in patients that appear to have an adverse effect from albuterol or for a
short time while frequent dosing of a β-agonist is needed.

Short-acting anticholinergics, including ipratroprium, should be used in concert with β-
agonists to treat acute exacerbations. They bronchodilate via inhibition of muscarinic
pulmonary acetylcholine esterase receptors and have their largest effects on central
airways. The onset of action is slower than that of β-agonist with an onset of
approximately 15 minutes, a peak effect at 60 to 90 minutes, and duration of 4 to 6 hours.

The optimal dose of albuterol is 2.5 to 5.0 mg via nebulizer or six to eight puffs (90
mcg each) via metered dose inhaler (MDI). For ipratroprium, the optimal dose is 0.5 mg via
nebulizer or four to eight puffs of an MDI (at 17 mcg per puff). Inhalational technique
varies widely from patient to patient, especially in times of respiratory distress. However,
evidence supports delivery of drug via MDI with a spacer for equivalent results at a lower
cost compared to a nebulizer. Long-acting bronchodilators, including long-acting β-
agonists (eg, salmeterol) and long-acting anticholinergics (eg, tiotropium) have no role in
the management of AECOPD. Oral and injection bronchodilators are not as effective as
inhaled route and should be avoided.

Corticosteroids

Systemic steroids are indicated for the treatment of AECOPD requiring hospitalization.
More controversial, however, is the optimal route of administration and dose.

PRACTICE POINT

Systemic steroids have been shown to speed recovery of FEV1, lower the number of
treatment failures and shorten hospital length of stay. A 5-day course of oral steroids
has been shown to be noninferior to longer durations.

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Steroids have significant side effects, including hyperglycemia, which is the most
common acute side effect. Higher doses and longer duration of exposure increase these
risks. The initial dose and route of administration of steroids should be tailored to the
patient. Patients requiring hospitalization but without impending respiratory failure may
be started at a dose of prednisone 30 to 40 mg (or equivalent) daily to maximize benefit
and minimize risk, whereas use of higher doses and IV route should be considered for
patients in acute distress or respiratory failure. Recent literature has shown that a 5-day
course of oral prednisone (40 mg) is noninferior to 2 weeks of therapy. No data supports
use of inhaled steroids in AECOPD.

Antibiotics

Bacterial infections play an important role in AECOPD. Guideline recommendations
encourage the use of empiric antibiotics for patients with moderate to severe AECOPD that
have suspected infection. Antibiotics should be tailored to the patient risk factors as well
as to community and hospital specific microbial patterns, but should always include
coverage for the most common causal pathogens (ie, Haemophilus influenzae,
Streptococcus pneumonia, and Moraxella catarrhalis). For patients with very severe
airflow limitation, extended spectrum coverage should be considered as more resistant
bacteria (ie, Pseudomonas, other Gram-negative rods) can cause exacerbations.

Oxygen and noninvasive ventilation

Oxygen level monitoring and supplemental oxygen provision are often necessary for
patients with AECOPD (Figure 232-2). Early and frequent assessment of blood oxygen
levels (via arterial blood gases or pulse oximetry) is critical for patients with an AECOPD.
Oxygen can be supplied via nasal cannula, simple face masks, nonrebreather masks or
high-flow oxygen masks. For patients with respiratory distress and increased work of
breathing, rapid inspiration may overcome the reservoir of a nonrebreather mask. In this
situation, oxygen delivered by high-flow masks yields the greatest percentage of inspired
oxygen. The goal of oxygen supplementation should be to achieve a goal SpO2 of 88% to
92% and/or a PaO2 of > 60. Care must also be taken to provide adequate but not excessive
levels of oxygen for patients that have baseline hypercapnea to avoid exacerbating carbon
dioxide retention. Carbon dioxide binds reversibly to reduced hemoglobin, but oxygen
drives the reaction to release carbon dioxide, a phenomenon known as the Haldane effect.
Patients receiving supplemental oxygen need frequent assessment of blood oxygen and
carbon dioxide levels in addition to a clinical assessment of alertness. The GOLD
guidelines recommend rechecking an arterial blood gas 30 to 60 minutes after initiation of
oxygen therapy.

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Figure 232-2 Algorithm for oxygen and carbon dioxide assessment during an acute
exacerbation of chronic obstructive pulmonary disease. ABG, arterial blood gas; O2,
oxygen; PaCO2, partial pressure of carbon dioxide in arterial blood; PaO2, partial pressure of
oxygen in arterial blood; SaO2, saturation level of oxygen in hemoglobin.

Positive pressure ventilation

Noninvasive positive pressure ventilation (NIPPV) has been shown to benefit some
patients with an AECOPD and should be considered for patients with mild to moderate
acidemia, increased work of breathing and hypercapnea. Special consideration should be
given for patients with a pH between 7.2 and 7.35, as this patient population has the most
evidence supporting benefit.

PRACTICE POINT

Positive pressure ventilation applied at two levels during the respiratory cycle (bi-level
ventilation) has been shown to decrease mortality, the need for intubation, and the
length of hospital stay for patients with an AECOPD.

Absolute contraindications to NIPPV include immediate need for intubation, untreated
tension pneumothorax and a comatose state. Relative contraindications for use of NIPPV
include severity of disease, likelihood of failure and anatomical risks (Table 232-6). If
NIPPV is selected, patients require frequent reassessment and close observation. An ABG

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should be rechecked 30 minutes to 1 hour from the time of NIPPV initiation. Within the
first 1 to 2 hours, there should be a clear trend toward improvement in clinical and
laboratory (pH, PCO2) parameters. Without rapid improvement, strong consideration must
be given to intubation and mechanical ventilation.

TABLE 232-6 Relative Contraindications for Use of Noninvasive Positive Pressure
Ventilation

1. Craniofacial abnormality or trauma
2. Respiratory arrest/apnea/refractory hypoxemia
3. Cardiac arrest/unstable cardiac arrhythmia
4. Hemodynamic instability
5. Inability to tolerate aerophagia (swallowing too much air), eg, recent gastrointestinal

surgery
6. Inability to cooperate or protect airway

a. Severe encephalopathy
b. Severe upper gastrointestinal bleed
c. High risk for aspiration

Invasive mechanical ventilation is sometimes required to treat severe exacerbations of
COPD. The decision to intubate and mechanically ventilate a patient with an AECOPD is
ultimately clinical, but guideline statements offer possible indications for intubation that
include severe dyspnea, respiratory rate > 35, somnolence, severe acidosis (pH < 7.25), refractory hypoxemia and complications of comorbidities. Predictors of poor outcomes with intubation and mechanical ventilation include a baseline FEV1 <30% predicted, nonrespiratory comorbidities and poor functional capacity prior to intubation.

OTHER THERAPIES

Methylxanthines such as theophylline and aminophylline have been used to treat COPD
(both stable and during exacerbations) for decades. A systemic review of methylxanthines
in AECOPD did not find significant benefits but did describe increased side effects,
including palpitations and arrhythmias. While guidelines do list methylxanthines as
alternate therapies for patients that do not respond to first-line therapies, they should be
considered later-line therapy. If methylxanthines are used, they require monitoring for side
effects and toxicity. Serum levels should be monitored every several days, and daily after a
dose change until levels are relatively stable. Acute illness and medication changes at the
time of admission can affect metabolism and serum levels of methylxanthines. If
theophylline is used, drug levels should be adjusted to 8 to 12 mg/mL.

Other therapies that have been used to treat AECOPD include mucolytic therapy,
postural drainage and chest physiotherapy. These modalities may improve symptoms, but
have not been shown to improve outcomes. Guidelines do not recommend pulmonary
rehabilitation during treatment for an AECOPD, but early ambulation and physical and/or
occupational therapy for patients that are not in respiratory failure is advisable (Table
232-7).

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TABLE 232-7 Evidence for Specific Therapies in Acute Exacerbation of Chronic
Obstructive Pulmonary Disease

Therapy Outcomes Improved
Antibiotics Decreased treatment failure in the ICU

Decreased in-hospital mortality while in the ICU
Oral corticosteroids Decreased treatment failure

Decreased hospital LOS
Increased FEV1 after 3 d

Bronchodilators Increased FEV1
Noninvasive positive
pressure ventilation

Decreased need for intubation
Decreased in-hospital mortality
Decreased hospital LOS

Pulmonary rehabilitation
(following recovery)

Decreased readmissions
Decreased mortality in follow-up
Increased quality of life in questionnaires
Increased exercise capacity in 6MWT

6MWT, 6-minute walk test; FEV1, forced expiratory volume in 1 s; LOS, length of stay.

TRIGGERS FOR CONSULTATION

Management of an AECOPD may have varying levels of complexity. The decision to
consult a pulmonary or critical care specialist will be determined by hospital and referral
resources, as well as the experience level of clinicians caring for these patients. For the
inpatient management of an acute exacerbation, acuity of illness, hemodynamic
compromise and poor response to therapy should be the overriding considerations for
consultation. The ATS/ERS guidelines for the management of COPD list the following
factors as indication for outpatient specialist consultation: age of COPD onset < 40 years old, two or more exacerbations per year (despite adequate outpatient management), rapidly progressive disease, severe disease (FEV1 < 50% predicted), need for long-term oxygen therapy, onset of comorbid illness (osteoporosis, heart failure, bronchiectasis, lung cancer) and/or evaluation for surgery. A consultant may also help with discharge planning and follow-up care for patients after their acute illness. Outpatient specialty referral may be indicated for most patients once they have completed their inpatient treatment.

OUTPATIENT THERAPEUTICS AND REGIMEN AUGMENTATION
SUPPLEMENTAL OXYGEN

If patients remain hypoxemic at the time of discharge, they will require home oxygen
therapy. To meet the Centers for Medicare and Medicaid Services (CMS) criteria for 24
hours per day long-term home oxygen therapy, patients must have resting, room air PaO2
of 55 mm Hg or less or PaO2 of 59 mm Hg or less with coexisting congestive heart failure,
peripheral edema, hematocrit > 56%, or cor pulmonale (Table 232-8). Alterations of oxygen

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levels during sleep and/or exercise can also qualify patients for supplementation during
those activities. Hypoxemia at hospital discharge following AECOPD may represent a
prolonged recovery from an acute illness, a new baseline, or new recognition of a chronic
problem. Regardless, long-term oxygen therapy improves mortality for COPD patients
that have resting hypoxemia. Patients that have a new prescription for home oxygen
should be reassessed with an arterial blood gas within 3 months to determine the ongoing
need for supplemental oxygen.

TABLE 232-8 Centers for Medicare and Medicaid Services Criteria for Oxygen
Supplementation

Group I Coverage
• PaO2 ≤ 55 or SaO2 ≤ 88%

At rest
During sleep

• OR ↓ PaO2 > 10 mm Hg or ↓ SaO2 5% associated with symptoms or signs of hypoxemia
During activity

Group II Coverage
• SaO2 = 89% (not + 89%)
• Any of the following:

Dependent edema
Pulmonary hypertension or cor pulmonale
Hematocrit > 56%

Requires retesting between 61 and 90 d

PaO2, partial pressure of oxygen in arterial blood; SaO2, saturation level of oxygen in hemoglobin.

ORAL STEROIDS

Systemic oral steroids are indicated for the treatment of an AECOPD that requires
hospitalization. A 5-day course of oral steroids is supported by current evidence. Once the
patient has stabilized, there is no indication for long-term treatment with steroids.

INHALED THERAPIES

Inhaled long-acting bronchodilators (long-acting β-agonists and long-acting
anticholinergics) and inhaled corticosteroids (ICS) have a significant role in regimen
augmentation when a patient with AECOPD is being discharged. Strong evidence supports
that inhaled medications reduce deterioration in health status, improve lung function
(FEV1), and reduce the number of exacerbations per year. All patients who have been
hospitalized with AECOPD should be discharged on a combination of a long-acting
bronchodilator and ICS, as meta-analysis data suggest mortality reduction with this
regimen compared to placebo and other regimens. Additional data indicate that the
combination of LABA and ICS plus long-acting anticholinergic for patients with more
advanced COPD is associated with additional improvement in quality of life and a

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reduction in subsequent hospitalizations. Some evidence shows that chronic use of short-
acting anticholinergic agents may impart increased cardiovascular risk in COPD patients,
while mounting evidence suggests that long-acting anticholinergic agents may not have
significant cardiovascular risks. The decisions of which medications to utilize should be
made in light of clinical acumen, patient preferences, and patient-provider discussions
regarding treatment goals and potential adverse effects.

MUCOLYTIC AND MUCOKINETIC AGENTS

Mucolytic agents are sometimes used in the treatment of COPD though they are not
recommended in the guidelines. This is an area of active research.

COPD COMPLICATING ADMISSIONS FOR OTHER DIAGNOSES
Underlying COPD may complicate the care of patients admitted for other diagnoses.
Complications may result from the underlying compromise of the respiratory symptom or
because an exacerbation occurs at the time of, or shortly after, the onset of the original
stress. Also, patients hospitalized for any reason are exposed to iatrogenic risks such as
resistant microbes, painful procedures (causing splinting), sedative medications
(hypoventilation), and decreased physical activity (deconditioning).

The use of β-blockers in COPD has long been a controversial topic. A 2005 Cochrane
Review demonstrated that there was no short-term decrease in FEV1 or responsiveness to
inhaled β-agonists for patients that received cardioselective β-blockers, regardless of the
severity of COPD. Therefore, cardio-selective β-blocker prescription is reasonable for
chronic COPD patients who have a cardiac indication to receive this therapy.

While COPD may complicate any medical or surgical illness, there are certain
processes where this occurs more frequently. Patients with heart failure and COPD often
present complaining of shortness of breath. It is difficult to decipher if the worsening of
the baseline condition is because of cardiac decompensation, pulmonary exacerbation, or
both. Normal levels of serum brain natriuretic peptide (BNP) significantly decrease the
likelihood of cardiac decompensation, but elevated BNP is less specific and more difficult
to interpret. A full physical examination and workup is often necessary and occasionally
an empiric trial of treating both conditions is warranted. Patients recovering from surgical
procedures need to have special consideration of postoperative activity, pain control
(without oversedation) and abdominal processes (such as swelling or ileus).

PERIOPERATIVE EVALUATION

Large numbers of patients with recognized or unrecognized COPD may require surgery.
Hospitalists are often asked to determine which patients represent undue risk and if there
are any measures that can minimize these risks. In general, pulmonary complications are
equal (in prevalence, morbidity, mortality, and length of stay) when compared to cardiac
complications for moderate and high-risk surgeries. Perioperative care of COPD patients
includes identifying and managing any acute worsening from pulmonary baseline, risk
assessment, preoperative risk minimization (ensuring proper preoperative care and
medications) and postoperative risk minimization. Separate chapters describe
perioperative pulmonary care (Chapters 51 [Preoperative Pulmonary Risk Assessment and
Management] and 60 [Management of Postoperative Pulmonary Complications]).

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PROGNOSIS AND

END-OF-LIFE CARE

PROGNOSIS

COPD patients’ pulmonary function progressively declines over the course of the disease.
Tobacco cessation is the most important factor in slowing the progression of COPD, but
even those patients that stop smoking experience continued age-related decline in lung
function. Predicting the future health of a patient with COPD is important at the time of
discharge to ensure all appropriate treatment modalities are considered as well as
ensuring patients have the needed social support to meet the demands of daily life.

Once a patient is admitted for an AECOPD, morbidity and mortality are significantly
different when compared to COPD patients that have not been hospitalized previously.
The 1-year readmission rate for COPD patients discharged for AECOPD is as high as 59%
for patients with severe disease and the 1-year mortality rate is as high as 22%. Two-year
mortality approaches 50% for patients admitted with AECOPD and hypercapnea.

Increasing age, male sex, white race, prior hospitalization, weight loss, pulmonary
hypertension, hypoxemia, hypercapnea, decreased FEV1, and decreased diffusing capacity
of the lung for carbon monoxide (DLCO) have all been identified as risk factors for death
with COPD. Progressive decline in FEV1 has historically been used as the primary measure
of predicting the course of COPD, but it is being replaced by an indexed score, the BODE
score. The BODE score (Table 232-9) has the advantage of taking into account multiple
factors that have been shown to be predictive of respiratory and all-cause mortality. The
BODE index requires a (B) BMI, FEV1 as a measure of (O) obstruction, degree of (D)
dyspnea on the Medical Research Council dyspnea scale, and (E) exercise capacity as
measured by a 6-minute walk test. Patients who have a 5 or greater BODE score are
appropriate for evaluation for lung transplant and/or other advanced treatment
modalities.

TABLE 232-9 BODE Index Scoring System

0 1 2 3
FEV1 (% predicted) ≥ 65 50-64 36-49 ≤ 35
6MWT distance > 350 m 250-349 m 150-249 m ≤ 149 m
mMRC dyspnea scale 0-1 2 3 4
BMI > 21 < 21

6MWT, 6-minute walk test; BMI, body mass index; BODE, body mass index, airflow obstruction,
dyspnea and exercise capacity; FEV1, forced expiratory volume in 1 s; mMRC, modified Medical
Research Council.

END-OF-LIFE CARE

For patients that have not previously expressed their desires regarding invasive or life
supporting treatments, difficult decisions have to be made during the time of an acute
illness. It is preferable, however, to facilitate patient expression of their end-of-life wishes
in a stable and less stressed state. The time of discharge from the hospital can be a

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“teachable moment” and discussion of what the patient would or would not want in the
case of future illness and/or respiratory failure should occur.

For some patients, an emphasis on palliative care (formally or informally) and/or
hospice referral may be appropriate. Dyspnea is a key symptom that must be addressed
as a source of anxiety and discomfort for the patient. Oxygenation status, respiratory rate,
and other objective measures are not good indicators of a patient’s perception of
breathlessness. When underlying causes of dyspnea can be corrected, that should be the
focus of care. When the underlying causes are not reversible, opioids in low-to-moderate
doses have good effect in relieving dyspnea. For patients who have a significant
component of anxiety along with dyspnea, benzodiazepines may be added to relieve
symptoms.

DISCHARGE PLANNING
For the majority of patients admitted with an AECOPD, improvement is noted within a
short period from admission. For the minority of patients that do not improve, alternative
diagnoses, intensified therapies, and/or palliative measures must be considered. The latter
stages of an acute inpatient stay can focus on tapering the frequency of medication
dosing, transitioning care to an outpatient setting, patient education, and prevention of
future exacerbations.

The GOLD and ATS/ERS guidelines provide lists of criteria that should be met for
consideration of discharge home. These include controlling or reversing the reason for
admission, hemodynamic stability, return to oxygenation baseline, less frequent need for
inhaled bronchodilators, ability to resume ambulating, no parenteral therapy for 12 to 24
hours, ability to eat and sleep without being disturbed by dyspnea, understanding the use
of medications, and completion of arrangements for follow-up and/or home care. For
patients to meet all of these criteria, length of stay might increase beyond what is
reasonable or desirable. While the patient’s trend should be back toward baseline, full
recovery and baseline oxygenation status might take several weeks and strict adherence
to the guidelines may not be practical or feasible.

QUALITY IMPROVEMENT

SECONDARY PREVENTION

Smoking cessation

Counseling regarding tobacco cessation for active smokers is essential because tobacco
cessation is the best way to slow the decline in lung function. There is some limited data
that counseling during an inpatient stay might increase the chance of quitting and more
robust evidence that quit rates can be increased by inpatient counseling followed by
continued outpatient intervention. Also, several pharmacological strategies have been
shown to improve quit rates. Options include nicotine replacement, buproprion (which can
be used in conjunction with nicotine replacement) and varenicline. A Cochrane Review
compiled several trials of varenicline and found that relative risk of cessation was two to
three times greater when compared to placebo, approximately 1.5 times greater when
compared to buproprion, and approximately 1.3 times greater when compared to nicotine
replacement therapy.

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Vaccinations

All patients with COPD should have the 23-valent pneumococcal polysaccharide vaccine,
and those patients aged greater than 65 that have not had the vaccine in the last 5 years
should have it administered regardless of previous vaccination status. The CDC
recommends all adults over the age of 65 receive the pneumococcal conjugate vaccine
(PCV13). The PCV13 and 23-valent should not be administered during the same visit and
the minimum time between administration is 8 weeks. Also, all patients with COPD should
have the influenza vaccine annually.

PATIENT EDUCATION

Efforts toward education ar

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e also vital for improving the patient’s health after discharge and include education
regarding proper inhaler technique, and avoidance of second-hand smoke (and other
respiratory irritants). Patient education regarding the ability to recognize the symptoms of
an exacerbation should be emphasized.

PULMONARY REHABILITATION

Pulmonary rehabilitation is an important part of outpatient COPD care after an admission
for AECOPD, and should be considered at the time of discharge for all patients with
chronic lung disease with the goal of alleviating symptoms and optimizing functional
capacity. Evidence supports that entering pulmonary rehabilitation within 10 days of
hospital discharge is safe. Furthermore, patients enrolled in early pulmonary rehabilitation
experienced improved exercise tolerance and health status at 3 months. Beyond
functional capacity, pulmonary rehabilitation programs often focus on establishing social
support and care networks that are most appropriate for the patient and can have quality-
of-life benefits beyond physical improvements.

PRACTICE POINT

Evidence supports that entering pulmonary rehabilitation within 10 days of hospital
discharge is safe, and patients enrolled in early pulmonary rehabilitation experience
improved exercise tolerance and health status at 3 months.

SURGICAL TREATMENT OPTIONS AND TRANSPLANT EVALUATION

Surgical treatment options for COPD include lung volume reduction surgery (LVRS),
bullectomy, lung transplantation and investigational approaches. LVRS involves bilateral
removal of 25% to 30% of total lung volume. The National Emphysema Treatment Trial,
published in 2003, demonstrated that LVRS improved exercise capacity but not survival
among all patients with severe emphysema. This trial did, however, identify subgroups
that had a survival advantage. The best candidates for LVRS are patients with
predominantly upper-lobe disease and a low exercise capacity after pulmonary
rehabilitation. Bullectomy has not been well studied in randomized trials, but it may be
considered for patients with at least one-third of the thorax occupied by bullae.

For patients with advanced disease another therapy to consider is lung
transplantation. Lung transplant referral is indicated for younger patients with COPD that
have progressive symptoms despite maximal medical therapy, including smoking
cessation. Lung transplant for COPD has been shown to improve quality of life, but effect
on mortality has not been clearly demonstrated and is more controversial. For further
analysis of trials addressing treatment strategies in COPD, please refer to the key
references (Table 232-10).

TABLE 232-10 Evidence-based Medicine: Key References for Chronic Obstructive
Pulmonary Disease

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Reference Methodology Results Limitations Bottom Line
Calverely P, et al.
N Engl J Med.
2007;356:775-
789.
TORCH trial

Randomized,
double-blind,
placebo-
controlled trial
of placebo vs
salmeterol alone
vs fluticasone
alone vs
salmeterol plus
fluticasone
inhaled twice
daily for 3 y.
6112 patients
were active or
former smokers
with diagnosis
of COPD, FEV1 < 60% predicted and no significant bronchodilator response

Comparing
combination
therapy to
placebo, there
was
nonstatistically
significant
reduction in
mortality (OR,
0.825; CI 0.681-
1.002).
Compared to
placebo,
combination
therapy reduced
exacerbations.
There were
higher levels of
pneumonia in
both groups
receiving
fluticasone
when compared
to placebo

There was a
large drop-out
rate (as might be
expected in a
COPD trial with
a placebo arm)

There is
insufficient data
to suggest that
inhaled
corticosteroids
decrease
mortality in
patients with
COPD, but
addition of
inhaled
corticosteroid
may reduce
exacerbations
for patients on
LABAs that have
recurrent
exacerbations.
For
monotherapy in
COPD, LABA
should be used
rather than an
ICS

Taskin DP, et al.
N Engl J Med.
2008;359:1543-
1554.
UPLIFT

Randomized,
double-blind,
placebo-
controlled trial
of tiotroprium vs
placebo to
decrease decline
in FEV1 over
time (before and
after
bronchodilation)
in 5993 patients

There was no
significant
difference in
decline in FEV1
over time in the
tiotroprium
group as
compared to
placebo.
Tiotroprium did
lead to increases
in FEV1 (but not
change over
time), improved
quality-of-life
scores, and
fewer
exacerbations

There was a
large drop-out
rate and short-
acting inhaled
anticholinergics
were stopped in
all patients

Tiotroprium may
be prescribed to
alleviate
symptoms of
COPD, but
should not be
expected to alter
progression of
disease

Anthonisen NR.
JAMA.

Randomized,
placebo-
controlled trial

Participants in
both smoking
cessation

There was
predictably low
adherence to

Smoking
cessation
counseling can

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1994;272:1497-
1505.
Lung Health
study

comparing no
intervention to
smoking
cessation
counseling plus
placebo to
smoking
cessation
counseling plus
inhaled short-
acting
anticholinergics
in 5887 patients

groups
experienced
smaller declines
in FEV1 over
time. Responses
to short-acting
anticholinergics
were not
cumulative over
time

prescribed
inhalers

lead to declines
in rates of
smoking, and
FEV1 decline
was mitigated
amongst
patients who
received
counseling, and
the effect was
strongest in
those who did
abstain

Bronchard L, et
al. N Engl J Med.
1995;333:817-
822.

Prospective
randomized trial
comparing use
of NIPPV vs
standard care
for treating 85
patients
admitted to ICU
with COPD
exacerbation

NIPPV
significantly
decreased rate
of endotracheal
intubation,
hospital LOS,
and in-hospital
mortality

Large
percentage of
patients
admitted to ICU
with COPD
exacerbation
were excluded,
limiting
population of
patients to
which data can
be applied

For selected
patients with
acute
exacerbations of
COPD,
application of
NIPPV can
prevent need for
endotracheal
intubation and
speed recovery

NETT Research
Group. N Engl J
Med.
2003;348:2059-
2073.
NETT trial

Randomized
trial of 1218
patients with
severe
emphysema to
receive lung
volume
reduction
surgery vs
continued
medical care.
Overall mortality
and maximal
exercise
capacity were
compared as
primary
outcomes

In entire study
group, there was
no difference in
overall mortality.
Surgery group
had significantly
higher
percentage of
patients who
improved
maximal
exercise
capacity when
compared to
nonsurgery
group. In
subgroup
analysis,
patients with
mostly upper-
lobe disease and
low exercise

No difference in
mortality overall.
Caution must be
used when
results of
subgroup
analysis are
applied

Lung volume
reduction
surgery may be
indicated for
specific group of
patients who
have
predominantly
upper-lobe
emphysema and
low exercise
capacity after
pulmonary
rehabilitation.
Risks and
benefits must be
weighed against
options of doing
nothing vs lung
transplant.
Patients with
FEV1 ≤ 20%

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capacity after
pulmonary
rehabilitation,
there was a
mortality benefit
from surgery.
Amongst
subgroup of
nonupper-lobe
emphysema and
high exercise
capacity,
mortality was
higher in surgery
group. Interim
analysis
identified group
of patients with
high risk of
surgical death

predicted and
either
homogenous
emphysema or
DLCO ≤ 20%
predicted are at
high risk of
death from lung-
volume
reduction
surgery

Leuppi JD.
JAMA.
2013;309:2223-
2231.
REDUCE trial

Randomized,
noninferiority
trial comparing
use of 5 d vs 14
d of
corticosteroids
in 314 patients
with COPD
exacerbation

No significant
difference in
rates of re-
exacerbation at
6 mo between
treatment arms
(37.2% in the
short term
treatment group
vs 38.4% in the
long-term
treatment group)

The study used
an absolute
difference of
15% to show
noninferiority
which may miss
smaller
treatment
differences
between
treatment arms

To reduce the
overall exposure
to steroids, limit
treatment to a
total of 5 d of
prednisone for
acute
exacerbations of
COPD

COPD, chronic obstructive pulmonary disease; DLCO, diffusing capacity of the lung for carbon
monoxide; FEV1, forced expiratory volume in 1 s; ICS, inhaled corticosteroid; ICU, intensive care unit;
LABA, long-acting beta-agonist; NIPPV, noninvasive positive pressure ventilation; OR, odds ratio.

TRANSITIONS OF CARE

Patients transitioning from inpatient to outpatient care, whether for an AECOPD or for
patients with underlying COPD admitted for other reasons, have many educational and
therapeutic needs. Education needs include smoking cessation, inhaler technique and
mobility prescriptions. For patients that might still have pain issues or decreased mobility,
education regarding incentive spirometry is imperative. Follow-up care should be arranged
with a primary care physician, a pulmonary specialist or both. For discharges after an
AECOPD, follow-up should be arranged at discharge for the patient to be seen within 2
weeks of discharge or sooner if requiring significant changes to their care regimen. Recent

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literature has suggested implementing a “COPD care bundle” prior to discharge. This
includes specialist notification of patient admissions, smoking cessation assistance,
referral to pulmonary rehab, educational literature and proper inhaler teaching. Preliminary
data have shown a significant reduction in readmissions for AECOPD following these
steps.

DISPARITIES IN HEALTH CARE

COPD has long been considered a disease of white, male smokers. Data, however, show
that the epidemic is increasing most rapidly for women and African Americans. For over a
decade, more women have died of COPD than men annually. The death rate is increasing
more rapidly for African Americans as well. To some degree, these changes represent
changes in the demographics of cigarette smoking over decades. However, some data
suggest that women and African Americans may actually be more susceptible to chronic
lung disease when compared to white men. In general, women have smaller caliber central
airways than similarly sized men and African Americans have smaller trunk/leg ratios
than whites. These differences may explain more clinically significant airflow limitation
after exposure to cigarettes or other respiratory toxins. Possible differences in specific
genes, proteases, and/or cytokines might also explain some differences in response to
exposures.

OUTCOMES TO MONITOR

There are many possible outcomes to monitor and measure regarding quality of care for
patients admitted with an AECOPD or for patients with COPD treated in the hospital for
other issues. The percentage of patients provided with smoking cessation counseling
would be appropriate for either group, as would vaccination rates.

For patients treated for an AECOPD, tracking the number of patients referred for
pulmonary rehabilitation is another option, as is the short-term readmission rate. Lastly,
the percentage of patients with severe COPD that are referred to hospice and/or palliative
services could be monitored.

COSTS AND RESOURCE UTILIZATION

While only smoking cessation and supplemental oxygen have been proven to have an
impact on chronic COPD mortality, there are many other modalities that may improve
quality of life and possibly decrease health care costs for patients with COPD.

Smoking cessation programs, health-maintenance caseworkers for patients with COPD
and pulmonary rehabilitation programs each offer ways in which large institutions might
decrease overall costs for the care of a population of COPD patients. Vaccinations have
been shown to have significant cost-savings as well.

Another area of focus for resource utilization is goals of care and end-of-life
discussions. A 2006 study found that COPD patients in the last 6 months of life were more
likely to be admitted to an ICU and have longer length of stay when compared to patients
in the last 6 months of life with lung cancer. Total health care costs were $4000 more per
patient during this time frame. Improved communication (preferably before admission, but
also possibly at the time of admission) regarding goals of care and realistic expectations
could prove to decrease these costs while hopefully improving quality of life for terminal
patients and their families.

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SUGGESTED READINGS
Almagro P, Balbo E, Ochoa de Echaguen A, et al. Mortality after hospitalization for COPD.

Chest. 2002;121:1441-1448.
Barnes P. Cellular and molecular mechanisms of chronic obstructive pulmonary disease.

Clin Chest Med. 2014;35:71-86.
Bronchard 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.

Celli BR, MacNee W, Augusti 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.

Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis,
Management, and Prevention of Chronic Obstructive Pulmonary Disease. Updated 2015.
Available at: http://www.goldcopd.com. Accessed March 30, 2015.

Hopkinson NS, Englebretsen C, Cooley N, et al. Designing and implementing a COPD
discharge care bundle. Thorax. 2012;67(1):90-92.

Nathan SD. Lung transplantation: disease-specific considerations for referral. Chest.
2005;127:1006-1016.

Ram FSF, Picot J, Lightowler J, Wedzicha JA. Non-invasive positive pressure ventilation for
treatment of respiratory failure due to exacerbations of chronic obstructive pulmonary
disease. Cochrane Database Syst Rev. 2004:Issue 3. Art. No.: CD004104.

Rigotti NA, Clair C, Munafo MR, et al. Interventions for smoking cessation in hospitalized
patients. Cochrane Database Syst Rev. 2012;Issue 5. Art. No.: CD001837.

Salpeter SS, Ormiston T, Salpeter E, et al. Cardioselective beta blockers for chronic
obstructive pulmonary disease (Cochrane Review). Cochrane Database Syst Rev.
2005(1);Issue 4. Art. No.:CD003566.

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.

Walters JAE, Tan DJ, White CJ, Wood-Baker R. Different durations of corticosteroid therapy
for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst
Rev. 2014;Issue 12. Art. No.: CD006897.

http://www.goldcopd.com/