Module B: ANNOTATIONS

---

Annotation P     Patient with Acute Exacerbation of COPD Presenting to Primary Care

---

9 Definition of Acute Exacerbation

DEFINITON

An exacerbation is a sustained worsening of the patient’s respiratory symptoms and function from his or her usual stable state that is beyond normal day-to-day variations, and is acute in onset. Commonly reported symptoms are worse breathlessness, cough, increased sputum production, and change in sputum color. The change in the patient’s condition often necessitates a change in medication.

10 Referral to the Emergency Department

Annotation Q      Are there Indications for Referral to the Emergency Department

---

10.1 Criteria for Referring to the Emergency Department/Hospital

BACKGROUND

Most patients with an exacerbation of COPD can be evaluated in an outpatient clinic setting and managed at home. However, certain conditions may require referral of the patient to a higher care facility (emergency department/hospital).

ACTION STATEMENT

More severe exacerbation or inadequate resources in the outpatient setting may require evaluation and management of the patient in the emergency department or a hospital setting. [I]

RECOMMENDATIONS

1. Patients evaluated for acute exacerbation of COPD should be considered for referral to the emergency department or admission to the hospital if they present with any of the following indications [I]:
   1. Unstable vital signs
   2. Impaired level of consciousness or altered mental status
   3. Severe breathlessness
   4. New or worsening hypoxemia (SaO₂ < 90 percent)
   5. Inadequate disease management resources at home
   6. Lack of appropriate resources to evaluate or manage the patient in a clinic setting.

---

Annotation R      Arrange for Transfer to the Hospital

---

10.2 Initiation of Short-Acting Bronchodilator and/or Oxygen Therapy if Necessary

BACKGROUND

Increased breathlessness is a common feature of an exacerbation of COPD. This is usually managed with increased doses of short-acting bronchodilators. Hypoxemia can develop or worsen with an exacerbation and can be life-threatening. This hypoxemia can be readily alleviated with low flow oxygen. Patients referred for further evaluation and management to an emergency department or hospital should receive these therapies promptly, if available.

ACTION STATEMENT

Early initiation of bronchodilator therapy and oxygen (in hypoxemic patients) is appropriate prior to full assessment and treatment in the emergency department or hospital.

RECOMMENDATIONS

1. Initial treatment for patients experiencing an initial acute exacerbation of COPD who have been referred to the emergency department or admitted directly to the hospital should include [I]:
   1. Short-acting bronchodilator, by nebulizer or metered dose inhaler, if readily available
   2. Low flow oxygen therapy to maintain SAO₂ at 90 percent.

---

Annotation S      Management of Exacerbation in the Emergency Department

---

10.3 Assessment of Acute Exacerbation in the Emergency Department

In the emergency department, patients experiencing an acute exacerbation of COPD should be evaluated for the potential factors that contribute to the exacerbation. Assessment and treatment should proceed simultaneously in these patients. The emergency department should have the ability to perform these evaluations and treatments in a timely fashion. Increased respiratory symptoms in COPD can be due to a number of cardiac or pulmonary causes. Appropriate management mandates knowledge of the cause while simultaneously treating the severely ill patient.

All patients with possible COPD acute exacerbations who either present directly to the emergency department or who are referred from outpatient settings should have the following differential diagnoses considered, assessed, and treated as necessary:

• Congestive heart failure
• Pneumonia
• Pneumothorax
• Pulmonary embolism
• Cardiac ischemia
• Cardiac arrhythmia
• Upper airway infection; e.g., acute sinusitis
• Upper airway obstruction
• Pleural effusion
• Recurrent aspiration
• Noncompliance with medications
• Inappropriate oxygen therapy which may produce hypercapnia
• Adverse effects of medications; e.g., sedatives.

Clinical evaluation and diagnostic workup for patients admitted to the emergency department for acute exacerbation of COPD will cover the following:

1. Clinical evaluation:
   
   • Vital signs including oximetry
   • Mental status
   • Clinical evidence of impending respiratory failure (tachypnea, accessory muscle use, abdominal paradox, and cyanosis)
   • Clinical signs and symptoms (e.g., cardiovascular disease, pulmonary embolism).
2. Diagnostic testing may include:
   • Chest X-ray
   • Arterial blood gases
   • Complete blood count and differential
   • Bun, creatinine, and electrolytes
   • ECG
   • Theophylline level, if patient is on theophylline
   • Sputum cultures if pseudomonas is suspected (when there is underlying structural lung disease, chronic oral glucocorticoid use, recurrent antibiotic therapy, and malnutrition).
3. Patients in acute respiratory distress should receive nebulized bronchodilator therapy, systemic glucocorticoids, and antibiotics and oxygen, if indicated, while simultaneously being assessed for the need for non-invasive or invasive ventilation.

11 Management of Acute Exacerbation in the Outpatient Setting

---

Annotation T     Obtain Medical History, Physical Examination, and Laboratory Tests to Assess Severity,
                          Rule Out Alternatives, and Confirm Diagnoses

---

11.1 Assessment, Testing, and Diagnosis

BACKGROUND

The diagnosis of an exacerbation is usually based on clinical evaluation and subjective parameters. A careful and comprehensive clinical evaluation is therefore critical to the appropriate diagnosis and management of exacerbations of COPD. Patients with COPD frequently suffer from other comorbid conditions that may impact upon the treatment of an acute exacerbation. Other cardiorespiratory conditions prevalent in patients with COPD can present with symptoms similar to an acute exacerbation and need to be clinically excluded.

ACTION STATEMENT

Patients with COPD with acute exacerbation should be assessed to confirm the diagnosis, rule out other causes for worsening symptoms and determine the severity of the exacerbation, and the priorities for treatment.

RECOMMENDATIONS

Clinical assessment should include:

1. The diagnosis of acute exacerbation of COPD should be confirmed and other causes excluded based upon clinical evaluation with additional diagnostic tests in selected cases. [I]
2. The severity of an exacerbation of COPD should be determined based upon medical history, symptoms, physical examination, and pulmonary function tests. [I]
3. Medical history with a patient with acute exacerbation should include:
   1. Onset, duration, and type of symptoms (cough, sputum production, dyspnea, fever, decreased exercise tolerance, confusion, or acute mental status changes)
   2. Current medication use
   3. History of prior COPD exacerbations or hospitalizations (frequency, ICU admissions, and prior intubation)
   4. The severity of the underlying COPD
   5. Presence of comorbid conditions; e.g., heart disease.
4. Physical examination with a patient with acute exacerbation should include:
   1. Vital signs
   2. Level of consciousness
   3. A careful pulmonary examination
   4. Cardiovascular examination
   5. Oxygenation.
5. Laboratory testing that may be considered with a patient with acute exacerbation:
   1. Oximetry (in all patients with moderate or worse COPD)
   2. Arterial blood gas in patients with deteriorating clinical status
   3. Spirometry, if available, in patients who are able to perform the test and for whom there is baseline data available for comparison
   4. Chest X-ray to exclude other causes if clinically suspected
   5. ECG if clinically indicated.
6. Alternative causes of increased symptoms that need to be clinically excluded include:
   1. Congestive heart failure
   2. Pneumonia
   3. Pneumothorax
   4. Pulmonary embolism
   5. Cardiac ischemia
   6. Cardiac arrhythmia
   7. Upper airway infection; e.g., acute sinusitis
   8. Upper airway obstruction
   9. Pleural effusion
   10. Recurrent aspiration
   11. Noncompliance with medications
   12. Inappropriate oxygen therapy
   13. Adverse effects of medications; e.g., sedatives.

RATIONALE

• Patients with COPD often have other medical comorbid problems. Worsening respiratory symptoms in patients with COPD may result from cardiovascular or respiratory conditions other than acute COPD exacerbation. Proper diagnosis of these events will help to better manage this syndrome.

12 Pharmacotherapy for Acute Exacerbation in Outpatient Settings

---

Annotation U      Initiate Drug Therapy with Bronchodilators

---

12.1 Bronchodilators

BACKGROUND

Pharmacotherapy should be initiated in the acute exacerbation to hasten resolution of the signs/symptoms of the exacerbation and prevent complications. This treatment may include antibiotics, systemic glucocorticoids, and bronchodilators. Patients who present with acute exacerbations of COPD need immediate relief of dyspnea. The approach is to provide inhaled short-acting bronchodilators delivered either by a metered dose inhaler or aerosol nebulization. These are provided until the patient’s dyspnea is sufficiently reduced, which may take as few as one treatment or many treatments over a number of hours or days.

ACTION STATEMENT

Provide relief of symptoms and improve FEV1 with short-acting inhaled bronchodilator therapy. [B]

RECOMMENDATIONS

1. A short-acting bronchodilator (short-acting anticholinergic or short-acting beta 2-agonist) or a combination of both, using a metered dose inhaler with a spacer or aerosol mobilization, should be administered as soon as possible and as frequently as necessary. The choice of agent should be made on the basis of individual assessment and initial response to therapy. [B]
2. Methylxanthines should be avoided either orally or systemically since these agents may lead to side effects and have no proven efficacy in the setting of an acute exacerbation of COPD. [D]

RATIONALE

• Short-acting bronchodilators are necessary in the early treatment of dyspnea and respiratory distress in a patient with an exacerbation of COPD. Such agents act quickly (albuterol more quickly than ipratropium, but both provide relief within a few minutes (albuterol within 15 minutes; ipratropium within 30 minutes). Since albuterol acts more rapidly, it is almost always used alone or in combination with ipratropium unless there is a contraindication to the use of beta 2-agonist such as an unstable arrhythmia or angina. Of note, albuterol has more side effects including tremor, vomiting, palpitations, and transient reductions in PaO 2, and rarely abnormal cardiac rhythm and changes in the electrocardiogram. These have not been reported when ipratropium has been used alone.

EVIDENCE TABLE

	Evidence	Source	QE	OQ	Net Effect	R
1	Ipratropium and albuterol, alone and in combination demonstrated improvement in FEV1, with no difference between therapies.	Bach et al., 2001	I	Fair	Substantial	B
2	A methyxanthine (such as aminophylline) added to ipratropium and albuterol, alone and in combination, increased side effects.	Bach et al., 2001	I	Fair	Substantial	D
QE = Quality of Evidence; Net Effect = Size of Intervention Effect; R = Strength of Recommendation (See Appendix A)

 

 

---

Annotation V      Is there Evidence of Respiratory Infection?

---

12.2 Antibiotics

BACKGROUND

Up to half of COPD exacerbations are related to bacterial infection of the airways. Treatment of COPD exacerbations that are due to bacteria with antibiotics hastens resolution and could prevent complications. Identification of exacerbations that are more likely to be related to bacterial infection can guide appropriate antibiotic therapy. Stratification of patients with exacerbation into uncomplicated (see Table 13) and complicated patients with readily assessable clinical criteria can guide antibiotic choice.

ACTION STATEMENT

Prescribe a course of antibiotics for acute exacerbation of COPD if symptoms indicate bacterial infection; choice of antibiotic agent may be based on the degree of complication (number of exacerbations, FEV1, previous exposure to antibiotics, and cardiac disease).

RECOMMENDATIONS

1. COPD patients with acute exacerbation of COPD with at least two of the following will most likely benefit from antibiotic therapy [A]:
   1. Increased sputum purulence (change in sputum color)
   2. Increased sputum volume
   3. Increased dyspnea.
2. Choice of antibiotic agents may be determined based on local bacterial resistance patterns. [C]
3. Choice of antibiotic agents may be determined based on the frequency of exacerbations in the past 12 months, severity of underlying COPD, presence of cardiac disease, and recent (within 3 months) antibiotic exposure for each patient. [B]
4. For uncomplicated exacerbations of COPD, consider doxycycline, trimethoprim/ sulfamethoxazole, second generation cephalosporin. [C]
5. For complicated exacerbations of COPD, consider beta-lactam/beta-lactamase inhibitor or fluoroquinolone. [C]

Stratifying the patient as complicated or uncomplicated may be helpful in determining the choice of antibiotic and is summarized in Table 13.

Table 13. Determine Level of Patient Complication and Antibiotic Agents

Patient Characteristics	Antibiotic Agents
Uncomplicated Patients Have experienced less than 3 exacerbations in the past 12 months Have a baseline FEV1 of > 50% predicted Do not have cardiac disease Have not been exposed to antibiotics in the past 3 months	Doxycycline Trimethoprim/Sulfamethoxazole Second or third generation cephalosporin Extended spectrum macrolide
Complicated Patients Have experienced 3 or more exacerbations in the past 12 months Have a baseline FEV1 of < 50% predicted Have cardiac disease Have been exposed to antibiotics in the past 3 months	Beta-lactam/beta-lactamase inhibitor Fluoroquinolone (a)
(a) By explicitly defining the patient that would benefit from the use of quinolone, the use of these drugs in uncomplicated exacerbations is discouraged.

RATIONALE

• Bacterial infection is one of the major causes of COPD exacerbation. Treatment of the patient with acute exacerbation of COPD with antibiotics is helpful when evidence of bacterial infection is present. Since sputum cultures and resistance patterns are only rarely available, resistance patterns are not suggested for criteria for antibiotic choice in outpatient care. Presence of symptoms is adequate and sputum culture is not recommended for outpatient management of acute COPD exacerbation. Haemophilus influenzae, streptococcus pneumoniae, moraxella catarrhalis, pseudomonas spp, and enterobacteriaceae spp are the major bacteria causing acute exacerbation of COPD.
• The current approach to treatment of exacerbations is clearly suboptimal. Relapse rates after ambulatory treatment of acute exacerbation of COPD may be as high as 20 to 25 percent of cases. Relapses are associated with significant morbidity and increased costs. The greatest part of costs derives from therapeutic failures, particularly those that end in hospitalization (Miravitlles et al., 2002).
• Evidence indicates that the number of patients with pathogenic bacteria in respiratory secretions and the bronchial bacterial load increases during exacerbations. Furthermore, the local inflammatory response of the host parallels the increase in bacterial load. It can be speculated, that for symptoms of acute exacerbation to appear, there must be a minimal bacterial load in the airways; i.e., the threshold above which the inflammatory reaction is severe enough to elicit clinical symptoms of exacerbation. This threshold may vary from patient to patient due to different modifying factors. Some of these factors may be the recognized risk factors for relapse, such as increasing age, impairment of lung function, comorbid conditions, or frequent exacerbations in the past.
• Though not proven, it is very likely that appropriate treatment of selected patients with more effective antibiotics could actually reduce hospitalizations and costs of care. Early aggressive treatment of exacerbations as outpatients has the potential for decreasing hospitalizations, resulting in overall less in-hospital antibiotic use and emergence of resistance.

EVIDENCE STATEMENTS

• Bacterial infection results in acute exacerbation of COPD (Sethi et al., 2002).
• Randomized controlled trials (stratified on steroid use) comparing quinolones to standard antibiotic treatment (i.e., amoxicillin, clarithromycin, or cefuroximeaxetil [250 mg bid for 7 days]) (Wilson et al., 2002, 2004) have shown more rapid resolution of symptoms, less failure of treatment, less need for additional antibiotics, and less frequency of recurrent exacerbation in the subsequent 6 months of patients treated with quinolones. Several clinically relevant outcomes such as less failure of treatment, less need for additional antibiotics, and less frequency of recurrent exacerbation in the subsequent 6 months have shown superiority of the quinolones.
• Antibiotics are helpful in patients with acute exacerbation of COPD and symptoms of bacterial infection (Allegra et al., 2001; Anthonisen et al., 1987; Nouira et al., 2001; Saint et al., 1995).
• Sputum culture is not recommended for determination of bacterial infection in outpatient management of acute exacerbation of COPD (NICE, 2004).
• Sputum purulence or increased sputum production accompanied with increased dyspnea indicates responsiveness of antibiotic therapy (Anthonisen et al., 1987; Stockley et al., 2000).
• Complicated patients are more likely to have antibiotic resistant pathogens and a worse outcome of the exacerbation (Martinez et al., 2005; Miravittles et al., 2001; O’Donnell et al., 2003). The baseline characteristics of the patients such as degree of dyspnea, coexisting ischemic heart disease, and number of previous visits for respiratory problems are strongly associated with increased risk of relapse after ambulatory treatment of acute exacerbations (Miravittles et al., 2001).
• A systematic review of 11 (917 patients) RCTs estimating the value of antibiotics in the management of acute COPD exacerbations (search period 1966 – 2005) shows that in COPD exacerbations with increased cough and sputum purulence antibiotics, regardless of choice, reduce the risk of short-term mortality by 77 percent, decrease the risk of treatment failure by 53 percent and the risk of sputum purulence by 44 percent; with a small increase in the risk of diarrhea. Antibiotics did not improve arterial blood gases and peak flow. These results should be interpreted with caution due to the differences in patient selection, antibiotic choice, small number of included trials, and lack of control for interventions that influence outcome, such as the use of systemic corticosteroids and ventilatory support. Nevertheless, this review supports antibiotics for patients with COPD exacerbations with increased cough and sputum purulence who are moderately or severely ill (Ram et al., 2006).
• A trial of 369 patients was included in an intent-to-treat population (187 treated with levofloxacin and 182 treated with amoxicillin/clavulanate). A total of 175 patients were microbiologically assessable (86 treated with levofloxacin and 89 treated with amoxicillin/clavulanate). At the on-treatment visit, a significantly higher proportion of the microbiologially accessible patients in the levofloxacin group resolved purulent sputum production (57.5% vs. 35.6%; P < 0.006), sputum production (65.4% vs. 45.3%; P < 0.013), and cough (60.0% vs. 44.0%; P < 0.045), compared with the amoxicillin/clavulanate group. However, no significant between-group differences were observed at posttreatment (Grossman et al., 2006).
• The MOSAIC study randomized patients with acute exacerbation to moxifloxacin and three other standard antibiotic treatments. Further exploratory analyses were performed to identify prognostic factors of short- and long-term clinical outcomes. Patients were assessed 7 to 10 days after study treatment, and followed monthly until a new acute exacerbation chronic bronchitis or for up to 9 months. The clinical cure was positively influenced by treatment with moxifloxacin (odds ratio (OR) 1.49; 95% CI 1.08 to 2.04) while cardiopulmonary disease (OR 0.59; 95% CI 0.38 to 0.90), FEV1 < 50 percent predicted (OR 0.48; 95% CI 0.35 to 0.67), and more than 4 exacerbations in the previous year (OR 0.68; 95% CI 0.48 to 0.97) predicted a poorer outcome. For clinical success, treatment with moxifloxacin had a positive influence (OR 1.57; 95% CI 1.03 to 2.41). The occurrence of the composite event was influenced by antibiotic treatment (hazard ratio=0.82) (Wilson et al., 2006).

EVIDENCE TABLE

	Evidence	Source	QE	OQ	R
1	Identify presence of symptoms that may indicate bacterial infection.	Anthonisen et al., 1987 Stockley et al., 2000	I	Good	A
2	Patients with COPD and acute exacerbation who have at least 2 of the following symptoms will benefit from antibiotic therapy: Increased dyspnea Increased sputum volume Increased sputum purulence.	Anthonisen et al., 1987 Ram et al., 2006	I	Good	A
3	Do not perform sputum culture in primary care (outpatient) setting for establishing the bacteriological cause of COPD exacerbation.	ATS/ERS, 2004 NICE, 2004	III	Good	D
4	Start a course of antibiotics in patients with acute exacerbation of COPD and symptoms indicative of bacterial infection.	Allegra et al., 2001 Anthonisen et al., 1987 Nouira et al., 2001 Ram et al., 2006 Saint et al., 1995	I	Good	A
5	Base antibiotic choice on the local bacterial resistance patterns (if available).	ATS/ERS, 2004 Grossman et al., 2006 NICE, 2004	I	Fair	C
6	Stratify patients into uncomplicated and complicated to assist in antibiotic choice.	Martinez et al., 2005 Miravittles et al., 2001 O’Donnell et al., 2003	I	Fair	B
7	For uncomplicated exacerbations of COPD, consider the following antibiotics: Doxycycline Trimethoprim/sulfamethoxazole Second generation cephalosporin Extended spectrum macrolide ketolide.	ATS/ERS, 2004 NICE, 2004	III	Fair	C
8	For complicated exacerbations of COPD, consider the following antibiotics: Beta-lactam/beta-lactamase inhibitor Fluoroquinolone.	Martinez et al., 2005 Wilson et al., 2002, 2004, 2006	I	Fair	B
QE = Quality of Evidence; OQ = Overall Quality; SR = Strength of Recommendation (See Appendix A)

 

---

Annotation W      Consider Oral Glucocorticoid Treatment

---

12.3 Oral Glucocorticoids

BACKGROUND

Airway inflammation is an integral part of stable COPD. Increased airway inflammation underlies exacerbations of COPD. Systemic glucocorticoids can decrease airway inflammation in exacerbations. Several placebo controlled trials in patients with exacerbations of COPD who were hospitalized or treated in the emergency department have shown significant benefit with glucocorticoids with better and more sustained clinical resolution and shorter hospitalizations.

ACTION STATEMENT

Consider a course of oral glucocorticoids in the treatment of an acute exacerbation of COPD to improve outcomes. [A]

RECOMMENDATIONS

1. A short course of oral glucocorticoids with a dose equivalent to 30 to 40 mg of prednisone per day (up to 14 days) should be considered for patients with COPD exacerbation. [A]

RATIONALE

• Oral glucocorticoids have been shown in several RCTs to be superior to placebo in the treatment of acute exacerbation.

EVIDENCE STATEMENTS

• There are 8 published clinical trials comparing systemic glucocorticoids to placebo in patients with acute exacerbation of COPD. Studies were conducted in patients who were either hospitalized or presented to the emergency department due to a COPD exacerbation. The dose and duration of glucocorticoids varied from study to study. Patients received concomitant bronchodilators +/- antibiotics.
• Use of systemic glucocorticoids resulted in greater improvement in FEV1 within the first 3 to 5 days compared to placebo in all studies except for the single-dose study by Emerman et al. (1989) (mean difference 140 mL [95%CI: 80, 200 mL]). One study found that dyspnea was improved while 2 others showed a trend favoring glucocorticoids.
• In those studies that were emergency department based, numerically fewer patients receiving glucocorticoids required hospital admission, except for the single-dose study by Emerman et al., (1989). In the studies of hospitalized patients, the duration of the hospitalization was approximately one to 2 days shorter in the glucocorticoid treated groups (Davies et al., 1999; Maltais et al., 2002; Niewoehner et al., 1999; Wood-Baker et al., 2005).
• Two studies evaluated 30-day relapse rate and found that the rate was lower in patients treated with glucocorticoids (Relative Risk=0.78; 95%CI: 0.63, 0.97) (Aaron et al., 2003; Niewoehner et al., 1999; Wood-Baker et al., 2005).
• There was no difference in mortality between glucocorticoid treated patients versus placebo (OR=0.85; 95%CI: 0.45, 1.59) (Wood-Baker et al., 2005).
• Hyperglycemia was more common in glucocorticoid treated patients compared to placebo (Albert et al., 1980; Davies et al., 1999; Maltais et al., 2002; Niewoehner et al., 1999; Wood-Baker et al., 2005).
• The optimal dose of glucocorticoids has not been clearly defined. The minimum dose used that showed benefit was prednisone 40 mg (prednisolone 30 mg) once daily.
• The optimal duration of glucocorticoid therapy has not been clearly defined. The majority of studies used a 9- to 10-day or 14-day course of therapy. One study showed there was no difference in outcomes between a 2-week versus an 8-week course of glucocorticoids (Niewoehner et al., 1999). A single-blind comparative trial (no placebo control) found that a 9-day course resulted in greater improvement in FEV1 and PaO 2 and fewer exacerbations compared to a 3-day course. There is no evidence to support the long-term use of oral glucocorticoids (Walters et al., 2005). No study has compared tapering of glucocorticoid dose to no taper. In the clinical trials, some tapered the glucocorticoid dose while others did not. Glucocorticoids were shown to be beneficial whether or not the dose was tapered.

EVIDENCE TABLE

---

Annotation X      Arrange for Follow-Up if Needed

---

13 Follow-Up

RECOMMENDATIONS

1. Patients should be instructed that if they have not improved with therapy over 48 to 72 hours or if they deteriorate at any time, they should seek attention from a healthcare provider. [I]

RATIONALE

There are no studies that have addressed a specific schedule that is more likely to result in positive outcomes, but patients with frequent exacerbations are more likely to relapse. The continuous evaluation of a patient with COPD should resume (see Annotation O).

---