Exacerbations Of COPD

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6 Interesting Facts of Exacerbations of COPD

Episodic exacerbations—during which patients experience new or worsening dyspnea, cough, and wheezing—may punctuate periods of stable chronic obstructive pulmonary disease
- These episodes are often triggered by bacterial or viral infections and environmental pollutants, resulting in increased airway inflammation, sputum production, and gas trapping
- Greatest risk factor is the occurrence and number of previous exacerbations, particularly in the past year
- Particularly when exacerbations are severe or frequent (ie, more than 1 per year), they may be associated with progressive loss of lung function
Diagnosis is suggested by history and physical examination findings; laboratory studies and imaging serve to further assess severity of exacerbation, guide treatment, and provide baseline against which to measure response
Give all patients supplemental oxygen to achieve target oxygen saturation of 88% to 92%
- Noninvasive or invasive mechanical ventilation may be necessary in patients for whom supplemental oxygen alone is not sufficient (eg, hypoxemia, severe respiratory acidosis, inability to sustain the work of breathing)
Initial pharmacotherapy revolves around use of short-acting bronchodilators (usually a β₂-agonist), which can be started de novo in previously untreated patients or added temporarily to an existing regimen of long-acting agents
- A short course of systemic steroids (preferably oral) given in conjunction with bronchodilators results in earlier improvement, shorter hospital stays, and reduced relapse rates; more effective in patients who are not critically ill
- Antibiotic use is somewhat controversial but is generally recommended in patients with the following 3 criteria: purulent sputum, increase in sputum production, and worsening dyspnea
Pulmonary rehabilitation, if begun within 3 to 4 weeks of stabilization, improves quality of life and may prevent subsequent exacerbations
Other measures to prevent exacerbations include regular use of an optimal regimen of inhaled maintenance therapy, smoking cessation, and immunization against influenza and pneumococcal infection

Pitfalls

Repeated courses of antibiotics for exacerbations may increase the risk of antibiotic-resistant bacterial strains, making treatment of future exacerbations more difficult
Supplemental oxygen supplied at a high FIO₂ without ventilatory support may suppress the drive to breathe, resulting in CO₂ retention, hypercarbia, and respiratory arrest
Be aware that patients with this disease may have an advance directive incorporating end-of-life wishes. Failure to identify advance directives may lead to undesired emergency medical intervention and acute care admission during an acute exacerbation

Chronic obstructive pulmonary disease is a common, slowly progressive lung disease that may include components of emphysema and bronchitis ¹
Episodic exacerbations—during which patients experience new or worsening dyspnea, cough, and wheezing—may punctuate periods of stable disease ¹
- These episodes are often triggered by bacterial or viral infections and environmental pollutants, resulting in increased airway inflammation, sputum production, and gas trapping
- Particularly when exacerbations are severe or frequent (ie, more than 1 per year), they may be associated with progressive loss of lung function

Classification

Exacerbations may be classified by severity ¹ ⁸
- Level I is mild
  - Increased need for medication, which patients can manage in their own personal environments
  - Treated with short-acting bronchodilators
- Level II is moderate
  - Sustained worsening of respiratory status that requires treatment with short-acting bronchodilators, systemic corticosteroids, and/or antibiotics
- Level III is severe
  - Rapid deterioration in respiratory status that requires emergency department care or hospitalization
  - May result in acute respiratory failure and may be further classified by degree of respiratory failure:
    - No respiratory failure: characterized by respiratory rate of 20 to 30 breaths per minute, no use of accessory muscles, no change in mental status, hypoxemia improved with FIO₂ of 28% to 35%, and no increase in PaCO₂
    - Acute respiratory failure, not life-threatening: characterized by respiratory rate higher than 30 breaths per minute, accessory muscle use, hypoxemia improved with FIO₂ of 35% to 40%, PaCO₂ of 50 to 60 mm Hg or above baseline, and no change in mental status
    - Acute respiratory failure, life-threatening: characterized by respiratory rate higher than 30 breaths per minute, accessory muscle use, hypoxemia not improved by (or requiring more than) FIO₂ of 40%, PaCO₂ higher than 60 mm Hg or above baseline, or pH of 7.25 or less

Clinical Presentation

History

Periods of exacerbation are characterized by onset of or increase in dyspnea, cough, sputum production, and/or wheezing
Patients may complain of other symptoms suggestive of infection (eg, conjunctival irritation, rhinorrhea, sore throat, fever)
Fatigue and malaise are common but nonspecific symptoms
History of exposure to an environmental trigger may be elicited or self-evident (eg, poor outdoor air quality, heat wave)

Physical examination

Signs of exacerbation include:
- Anxiety, sometimes with diaphoresis
- New or worsening central cyanosis
- Tachypnea
- Labored breathing with nasal flare and use of accessory respiratory muscles
- Paradoxical chest wall movement with respiration
- Tachycardia may occur owing to anxiety, hypoxemia, and/or respiratory exertion
- Mental status deterioration (eg, confusion, somnolence) due to hypoxemia and/or hypercarbia
- Hemodynamic instability indicates impending respiratory arrest
- Limited respiratory effort indicates exhaustion of respiratory muscles and impending respiratory failure
Auscultation may find:
- Decreased breath sounds
- Prolonged expiratory phase with wheezing
- Diffuse or localized rales
- Rhonchi
- Loose secretions

Causes

Exacerbations may be triggered by bacterial or viral infections, environmental pollutants, left ventricular failure, pulmonary embolus, or ambient temperature and weather conditions ¹ ⁹
- Most common viral cause is rhinovirus (eg, common cold)
- Exacerbations associated with viral infections tend to be more severe and long-lasting than those caused by other triggers
- Chest trauma and oversedation also may trigger exacerbations secondary to sputum retention and hypoventilation ⁹

Risk factors and/or associations

Gender

Hospitalization rates, which may reflect occurrence of exacerbation, have been equal for males and females in recent years (ie, no statistically significant differences) ¹⁰

Other risk factors/associations

Greatest risk factor is the occurrence and number of previous exacerbations, particularly in the past year ¹
Increased risk for occurrence and severity of exacerbation is associated with the following: ¹
- Ratio of pulmonary artery diameter to aortic diameter is more than 1:1, as measured on CT scan, suggesting pulmonary hypertension
- Presence of chronic bronchitis
- Higher percentage of emphysema or thickness of airway walls shown by CT scan
- Decline in FEV₁
Other factors that increase risk of exacerbations include the following: ⁸
- Continued smoking or relapse for exsmokers
- Passive smoke
- Viral or bacterial infection
- Air pollution
- Lack of physical activity
- Certain seasons (winter and spring)

Diagnostic Procedures

Primary diagnostic tools

Diagnosis is suggested by history and physical examination findings ¹
Laboratory tests and imaging serve to further assess severity of exacerbation, guide treatment, and provide baseline against which to measure response ⁸
- Pulse oximetry is first step in measuring oxygenation and determining need for direct blood gas measurements ²
- Direct blood gas measurements are recommended if peripheral oxygen saturation by pulse oximetry is less than 92%, if there is history of hypercapnia, if patient is confused or somnolent, or if respiratory failure appears imminent ¹ ²
  - Venous blood gas test is sufficient to detect hypercapnia; arterial blood gas test provides precise information on oxygenation
- Conduct a basic or comprehensive metabolic panel for patients with severe exacerbations and for those with major comorbidities ²
- CBC is recommended for patients who require hospitalization ²
- Testing for SARS-CoV-2 is indicated if COVID-19 infection is a possible cause of symptoms ¹¹
- Sputum culture and sensitivity test are not recommended routinely but are performed in patients with severe or frequent exacerbations and considered in patients with purulent sputum whose condition has not responded to empiric antibiotics ¹ ²
- Measure serum 25-hydroxyvitamin D in all patients who are hospitalized (recommended) ¹
- Provide chest radiograph for all patients requiring hospital admission (recommended) ¹ ²
- Other tests (eg, B-type natriuretic peptide level, ECG, serum troponin level, D-dimer level, chest CT) may be indicated when there are significant comorbidities or diagnostic uncertainty ²
- Use of biomarkers at point of care to guide selection of patients who will benefit from antibiotic therapy is being investigated ¹² ¹³
  - Procalcitonin, C-reactive protein, and interleukin-6 levels are elevated in patients with acute exacerbations of chronic obstructive pulmonary disease ¹⁴ ¹⁵
- Consider underlying pulmonary embolism in patients presenting with exacerbations of chronic obstructive pulmonary disease with chest pain or cardiac failure and absence of signs of respiratory infection ⁹ ¹⁶

Laboratory

Arterial blood gas levels
- Provide accurate measurement of oxygenation and PCO₂, as well as pH and bicarbonate levels ¹
  - Assessment of acid-base status is indicated if mechanical ventilation is necessary
- Significant hypoxia and hypercarbia, especially if they represent an acute change from baseline, may indicate impending respiratory failure: ¹
  - PaO₂ less than 8 kPa (60 mm Hg) on ambient air
  - PaCO₂ more than 6.7 kPa (50 mm Hg) on ambient air
Basic metabolic panel
- Hyperglycemia and electrolyte imbalances may be associated with exacerbations
CBC
- Polycythemia (hematocrit higher than 55%) may indicate chronic hypoxemia
- Neutrophilia or eosinophilia suggests an acute exacerbation ¹⁷
  - Eosinophilia also may predict efficacy of inhaled corticosteroids in preventing exacerbations ¹
B-type natriuretic peptide level
- When an exacerbation of heart failure (a common comorbid condition) might be contributing to dyspnea, this test may help to differentiate
- Probability of left ventricular heart failure is less than 10% if level is lower than 100 pg/mL ¹⁸
Sputum culture and sensitivity test
- Patients who may benefit from culture-guided therapy: ¹
  - Those whose condition has not responded to empiric antibiotics
  - Those who are at high risk for resistant organisms (eg, frequent or recent exacerbation treated with antibiotics) or poor outcome (eg, severe exacerbation)

Imaging

Chest radiography
- Recommended during moderate or severe exacerbation to exclude alternative diagnosis ²
- Features characteristic of chronic obstructive pulmonary disease include: ¹
  - Flattened diaphragm on lateral chest radiograph, owing to hyperinflation
  - Increased volume of retrosternal air space, owing to hyperinflation
  - Hyperlucency of lungs
  - Rapid tapering of vascular markings, owing to reduction or absence of vasculature

Functional testing

Oximetry
- Performed in all patients with chronic obstructive pulmonary disease who have exacerbation of respiratory symptoms (to assess oxygen saturation and guide supplemental oxygen therapy) ¹ ²
  - Arterial blood gas measurements are recommended if peripheral oxygen saturation is less than 92%
  - Compare with recent baseline value, if available; suggestive of acute exacerbation if level is 4% or more below those when stable ¹⁷

Differential Diagnosis

Most common

Congestive heart failure
- Cardiac ventricular dysfunction resulting in insufficient perfusion to meet metabolic demands
- Right ventricular heart failure (cor pulmonale) may occur as a complication of advanced chronic obstructive pulmonary disease
- Dyspnea and fatigue are common to both exacerbation of chronic obstructive pulmonary disease and congestive heart failure
- Peripheral edema is a distinguishing feature of heart failure; a third heart sound and wet rales may be heard on auscultation
- Cardiomegaly, pulmonary venous congestion, and sometimes pleural effusions are chest radiograph findings typical of congestive heart failure; echocardiography with Doppler often finds reduced ejection fraction
Pneumonia
- Infection of lung parenchyma
- Like an exacerbation of chronic obstructive pulmonary disease, may be characterized by acute onset of dyspnea and cough
- Fever is more common in pneumonia than in exacerbation of chronic obstructive pulmonary disease, and the patient may have pleuritic pain
- Differentiation is made using chest imaging
Pulmonary embolism
- Sudden obstruction of a portion of the pulmonary arterial vasculature, usually by embolization of a lower extremity or pelvic thrombus
- Like an exacerbation of chronic obstructive pulmonary disease, characterized by acute onset of dyspnea and hypoxemia, which may be associated with tachypnea, tachycardia, and hypotension
- Onset is usually more abrupt than in exacerbation of chronic obstructive pulmonary disease; there may be associated chest pain
- Diagnosis is suggested by elevated serum levels of D-dimer and is confirmed by CT pulmonary angiography or ventilation-perfusion scintigraphy
Pneumothorax
- Air within pleural space from injury or spontaneous rupture of a pulmonary bleb
- Presents with sudden onset of dyspnea, often with pleuritic pain
- Onset is usually more abrupt than in exacerbation of chronic obstructive pulmonary disease
- Diagnosis usually can be confirmed by plain radiographs taken in upright position or by CT scan showing air in pleural space and sometimes collapse of underlying lung parenchyma

Treatment Goals

Relieve symptoms
Minimize duration and impact of the exacerbation
Prevent future exacerbations

Admission criteria

Patients with this disease may have an advance directive incorporating end-of-life wishes; failure to identify advance directives may lead to undesired emergency medical intervention and acute care admission during an acute exacerbation

Conditions and circumstances that may warrant hospital admission include: ¹

Severe symptoms (eg, sudden worsening of dyspnea, rapid respiratory rate, accessory muscle use, reduced oxygen saturation, confusion) ¹ ¹⁹
Onset of new physical signs (eg, peripheral edema, cyanosis) ¹
Acute respiratory failure ¹
Presence of serious comorbidities (eg, cardiac arrhythmia, heart failure) ¹
Exacerbation unresponsive to initial management ¹
Inability of patient to care for self or lack of support at home ¹
Symptoms that prevent adequate sleep or nutrition ¹⁸
Diagnostic uncertainty about cause of dyspnea, especially if clinical stability is marginal ¹⁸

Criteria for ICU admission

Conditions and circumstances that may warrant ICU admission include: ¹ ¹⁸
- Severe dyspnea unresponsive to initial treatment
- Change in mental status (eg, lethargy, confusion, coma)
- Severe or deteriorating hypoxemia despite supplemental oxygen and/or noninvasive ventilation
- Severe or deteriorating respiratory acidosis despite supplemental oxygen and/or noninvasive ventilation
- Need for invasive mechanical ventilation
- Hemodynamic instability with need for vasopressors ¹

Recommendations for specialist referral

Consult pulmonologist or critical care specialist for management of mechanical ventilation, if required
Consult pulmonologist to aid management of exacerbation and to guide subsequent outpatient therapy

Treatment Options

Initial therapy for exacerbations revolves around use of short-acting bronchodilators, which can be started de novo in previously untreated patients or added temporarily to an existing regimen of long-acting agents ¹ ²⁰

A short-acting β₂-agonist is recommended as the initial agent
Increase dose and/or frequency for patients who use these drugs regularly
Add a short-acting muscarinic antagonist if needed
May be given by metered dose inhaler with spacer or by nebulizer (methods are equally effective)

Systemic corticosteroids (oral or parenteral) are recommended for both ambulatory ⁵ and inpatient ¹ treatment of exacerbations ²⁰ ²¹ ²²

Result in earlier improvement, shorter hospital stays, and reduced relapse rates; more effective in patients who are not critically ill ³ ²³
Oral formulations are preferred for patients who can take them ⁵
Short courses of treatment are preferred; typically 7 to 14 days of treatment have been recommended, but evidence suggests that 5 days are likely to be sufficient ⁸ ²⁴ ²⁵

Antibiotic treatment is controversial and there is no universal consensus on empiric use: beneficial in patients in ICU but small or inconsistent effects in others ²⁶

GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines recommend antibiotics in the following circumstances: ¹
- Combination of 3 cardinal symptoms: increased dyspnea, increased sputum production, and purulent sputum
- Presence of 2 of the 3 cardinal symptoms if 1 of them is purulent sputum
- Mechanical ventilation is required
European Respiratory Society/American Thoracic Society joint guidelines recommend empiric antibiotics, selected based on local antimicrobial susceptibility patterns, for ambulatory patients with an exacerbation; the guidelines note that patients with purulent sputum are more likely to benefit ⁵
Australasian guidelines recommend antibiotics for patients with clinical evidence of infection (increased sputum volume, change in color of sputum, and/or fever) ⁹
The American Academy of Family Physicians recommends prescribing a 7-day course of systemic antibiotics for adults with acute exacerbation of chronic obstructive pulmonary disease with antibiotic selected based on local resistance patterns, cost, and patient’s history and preferences ²¹
Several biomarkers have potential to aid identification of patients with acute exacerbation of chronic obstructive pulmonary disease who are most likely to benefit from antibiotics
- C-reactive protein level may be measured at point of care and incorporated into clinical decision-making for outpatients ¹² ²⁷ ²⁸
  - One strategy studied involved prescribing antibiotics when C-reactive protein levels were higher than 40 mg/L and withholding antibiotics when levels were lower than 20 mg/L; levels between 20 and 40 mg/L were considered a gray area ¹³
    - Resulted in lower antibiotic use with similar clinical outcomes
- Procalcitonin-guided antibiotic therapy may reduce antibiotic prescribing without impacting clinical cure, mortality, and readmission rates

Give all patients respiratory support with oxygen and, if necessary, ventilatory support with noninvasive or invasive mechanical ventilation to achieve target oxygen saturation of 88% to 92% ²⁹

Noninvasive ventilation is recommended for hospitalized patients with hypercapnic respiratory failure due to an exacerbation of chronic obstructive pulmonary disease; it may obviate intubation and improve outcomes ⁵
Controlled oxygen delivery of 0.5 to 2 L/min ⁹ is recommended over high flow oxygen (rates up to 60 L/min ¹); titrated oxygen to achieve oxygen saturation of 88% to 92% is associated with reduced mortality when compared with high flow oxygen ²² ³⁰

Pulmonary rehabilitation is recommended for patients who have been hospitalized for an exacerbation ⁵ ⁶

Once stable, encourage all current smokers to quit, and prescribe a smoking cessation program for patients who are willing to attempt ¹ ⁷

Optimize maintenance therapy and measures to prevent subsequent exacerbations once patient is stable before discharge ¹

Commence long-acting bronchodilators if not already using

Drug therapy

Short-acting β₂-agonists
- If delivered via nebulizer, air-driven nebulization is preferred over oxygen-driven ¹
- Albuterol
  - Albuterol Sulfate Nebulizer solution; Adults: 2.5 mg via nebulizer every 6 to 8 hours as needed. Optimal dose during acute COPD exacerbation not established; adjust dosing to patient response and tolerance. A nebulized albuterol dose of 5 mg every 4 hours has been used, as well as 2.5 mg given every 20 minutes for 2 hours.
- Levalbuterol
  - Levalbuterol Hydrochloride Nebulizer solution; Adults: 0.63 mg via nebulizer 3 times daily, given every 6 to 8 hours. If response not adequate, may increase to 1.25 mg via nebulizer 3 times daily. During acute COPD exacerbation, adjust dosing to patient response and tolerance.
Short-acting muscarinic antagonist
- Ipratropium
  - Ipratropium Bromide Nebulizer solution; Adults: 500 mcg (1 vial) via nebulizer 3 or 4 times per day. Doses should be spaced 6 to 8 hours apart. (Ipratropium may be mixed with albuterol in the nebulizer if used within 1 hour of mixing). Max: 2,000 mcg/day via nebulizer.
Systemic corticosteroids
- Short course is indicated to treat significant exacerbations to reduce inflammation and thus to improve lung function and shorten recovery time; avoid longer courses ¹ ¹⁹
- Regular (long-term) use of systemic corticosteroids beyond the setting of exacerbation is not recommended owing to increased risk of adverse events ³¹
- Prednisone
  - Prednisone Oral tablet; Adults: 40 mg PO once daily for 5 days is the most commonly recommended regimen. The use of systemic steroids for no more than 5 to 7 days is recommended by GOLD guidelines.
- Methylprednisolone
  - Recommended only if patient is unable to take medication orally
    - Methylprednisolone Sodium Succinate Solution for injection; Adults: Initially, 10 to 40 mg IV or IM. Subsequent IV/IM doses are determined by response and condition.
Antibiotics
- Choice of antibiotic is based on severity of exacerbation, treatment setting of exacerbation (inpatient versus outpatient), recent use of antibiotics, patient living situation (community versus health care facility), and local resistance patterns ¹
  - First line empiric antibiotics include amoxicillin, doxycycline, and clarithromycin ³² ³³
    - Switch to alternative if no improvement with initial choice after 2 to 3 days
  - Alternatives for patients at high risk for treatment failure (eg, previous repeated courses of antibiotics, resistant bacteria on current or previous sputum culture) include amoxicillin-clavulanate or levofloxacin ³²
- Repeated courses of antibiotics for exacerbations may increase the risk of antibiotic-resistant bacterial strains, making treatment of future exacerbations more difficult ¹
- Some recommended agents for empiric administration include the following:
  - β-lactam antibiotics
    - Amoxicillin with or without clavulanate
      - Amoxicillin Trihydrate Oral tablet; Adults: 1 g PO every 8 hours for at least 5 days.
      - Amoxicillin Trihydrate, Clavulanate Potassium Oral tablet; Adults: 875 mg amoxicillin with 125 mg clavulanate PO every 12 hours or 500 mg amoxicillin with 125 mg clavulanate PO every 8 hours for at least 5 days.
    - Ampicillin
      - Ampicillin Sodium Oral capsule; Adults: 250 mg PO 4 times daily.
    - Cephalosporins
      - Cefpodoxime
        Cefpodoxime Proxetil Oral tablet; Adults: 200 mg PO every 12 hours for at least 5 days.
      - Cefprozil
        Cefprozil Oral tablet; Adults: 500 mg PO every 12 hours for 5 to 7 days.
      - Cefuroxime
        Cefuroxime Axetil Oral tablet; Adults: 500 mg PO every 12 hours for at least 5 days.
  - Macrolides
    - Azithromycin
      - Azithromycin Oral tablet; Adults: 500 mg PO once daily for 3 days, or 500 mg PO once daily for 1 day followed by 250 mg PO once daily for 4 days.
    - Clarithromycin
      - Clarithromycin Oral tablet; Adults: 500 mg PO every 12 hours for at least 5 days.
  - Tetracyclines
    - Doxycycline
      - Doxycycline Hyclate Oral capsule; Adults: 100 mg PO every 12 hours for at least 5 days.
  - Fluoroquinolones
    - Levofloxacin
      - Levofloxacin Oral tablet; Adults: 750 mg PO every 24 hours for at least 5 days.
    - Moxifloxacin
      - Moxifloxacin Hydrochloride Oral tablet; Adults: 400 mg PO once daily for 5 days. Due to the risk for serious and potentially permanent side effects, only use in cases where alternative treatment options cannot be used.

Nondrug and supportive care

Supplemental oxygen
- Indicated for hospitalized patients with an acute exacerbation
- Controlled oxygen delivery of 0.5 to 2 L/min is recommended over high flow oxygen (rates up to 60 L/min)
- Titrate to target oxygen saturation of 88% to 92% ¹ ⁹
- Venturi masks provide oxygen at an accurate and controlled rate but are poorly tolerated by patients; alternatively, nasal cannula may be used
- Take care not to overoxygenate, which reduces the drive to breathe and results in CO₂ retention
  - Measure arterial blood gas levels 30 to 60 minutes after starting or changing supplemental oxygen, and measure if somnolence is increasing ¹
Ventilatory support ¹
- Noninvasive ventilation
  - First line ventilatory support in hospitalized patients experiencing an acute exacerbation with any of the following:
    - Respiratory acidosis (PaCO₂ of 45 mm Hg or more plus arterial pH of 7.35 or less)
    - Severe dyspnea with clinical signs of increased work of breathing and respiratory muscle fatigue
    - Persistent hypoxemia despite supplemental oxygen
  - May be administered as BPAP or CPAP with pressure support ventilation ³⁴
    - Reduces need for invasive mechanical ventilation
    - Decreased mortality rate compared with invasive mechanical ventilation
- High-flow nasal therapy ¹
  - Alternative to standard noninvasive ventilation or oxygen therapy in patients with acute hypoxemic respiratory failure
  - May improve oxygenation and reduce hypercarbia in patients with chronic obstructive pulmonary disease
- Invasive mechanical ventilation
  - Indicated for patients with an acute exacerbation requiring ventilatory support in the following situations:
    - Unable to tolerate noninvasive ventilation
    - Hypoxemia refractory to noninvasive ventilation
    - Post–respiratory arrest or post–cardiac arrest status
    - Significant aspiration
    - Persistent vomiting ¹
    - Inability to clear secretions
    - Decreased level of consciousness or psychomotor agitation refractory to sedation
    - Hemodynamic instability refractory to fluids and vasoactive medications
    - Severe ventricular or supraventricular arrhythmias
  - Complications include:
    - Ventilator-associated pneumonia
    - Failure to wean
      - Weaning may be facilitated with noninvasive ventilation
    - Barotrauma
Pulmonary rehabilitation ¹
- Multidisciplinary program, individualized for patient, with the following components:
  - Interventions such as chest physiotherapy using vibration, percussion, or massage, breathing techniques, and/or resistance training ³⁰
  - Exercise training, education, nutrition counseling, and psychosocial support
- Improves quality of life and exercise capacity after an exacerbation; however, impact on subsequent hospital admissions for exacerbation is unclear ⁴
  - One metaanalysis showed pulmonary rehabilitation reduced early mortality and readmission rates when initiated during or within 4 weeks after hospitalization for an acute exacerbation
- Recommended to start during recovery phase of exacerbation or within 3 to 4 weeks after acute exacerbation
Vitamin D supplementation
- Recommended for patients with severe deficiency identified at admission
- Supplementation reduces acute exacerbations and hospitalizations in patients with 25-hydroxyvitamin D levels below 25 nmol/L

Comorbidities

Cardiovascular disease
- Ischemic heart disease
  - Patients with this disease have increased risk of myocardial damage during exacerbations of chronic obstructive pulmonary disease
  - Treat this disease according to standard recommendations, regardless of presence of chronic obstructive pulmonary disease
- Heart failure
  - A very common comorbidity, occurring in 20% to 70% of patients with chronic obstructive pulmonary disease
  - Decompensation of heart failure may accompany or be mistaken for an exacerbation of chronic obstructive pulmonary disease
  - Use selective β₁-blockers to treat heart failure in patients with chronic obstructive pulmonary disease (recommended)
  - There is no evidence that using selective β₁-blockers to treat heart failure is harmful to patients with chronic obstructive pulmonary disease, and they improve survival in patients with heart failure
- Atrial fibrillation
  - Common condition that occurs concomitant with exacerbation of chronic obstructive pulmonary disease; may trigger an exacerbation or may result from one
  - Long-acting β₂-agonists are not thought to increase the risk of precipitating atrial fibrillation; caution is advised with short-acting β₂-agonists
- Hypertension
  - Both conditions may be treated according to standard recommendations; there is no evidence to support adjusting recommended regimens
Osteoporosis
- If possible, avoid repeated use of systemic corticosteroids to treat exacerbations because these medications may worsen osteoporosis
Gastroesophageal reflux
- An independent risk factor for exacerbations
- Proton pump inhibitors may reduce risk of exacerbation
Bronchiectasis
- Associated with increased duration of exacerbations and increased mortality
- When antibiotics are required to treat exacerbations, longer, more aggressive antibiotic therapy may be warranted
Respiratory infections
- Many exacerbations are triggered by viral or bacterial respiratory infections
COVID-19
- Increased risk of developing severe acute respiratory syndrome requiring ICU admission or mechanical ventilation and death in patients with chronic obstructive pulmonary disease who become infected with SARS-CoV-2
- Continue regular maintenance medications to treat chronic obstructive pulmonary disease during the pandemic, and start systemic corticosteroids, if indicated, to treat exacerbations
- Avoid using nebulized medications in patients with COVID-19 owing to risk of aerosolizing the virus
- GOLD offers a COVID-19 guidance webpage
- Elsevier Novel Coronavirus Information Center offers evolving COVID-19 content

Monitoring

During acute exacerbation, use pulse oximetry to monitor response to treatment. Blood gas levels are recommended for patients who are hypercapnic and/or acidotic, until stable
For patients who have been discharged after an exacerbation, follow-up is recommended within a month for clinical evaluation and oximetry
Further follow-up is recommended at 3 to 4 months for clinical evaluation, oximetry and/or blood gas levels, and spirometry
Some patients who present to the emergency department with an exacerbation may be managed with close follow-up at home (hospital-at-home program) until stabilized
- Patients must meet certain criteria (eg, absence of acute cardiac conditions, normal level of consciousness, no indications for mechanical ventilation)
- These protocols include frequent home visits by a physician or nurse with specialty training
- In patients who meet selection criteria, readmissions are reduced and there is a trend toward reduced mortality

Complications

Rib fractures due to coughing
- Restricted breathing due to pain may lead to atelectasis and pneumonia
Pneumothorax
- Coughing or mechanical ventilation may result in rupture of an emphysematous bleb
Permanent loss of lung function (ie, failure to return to baseline) may necessitate long-term oxygen use

Prognosis

Most exacerbations subside within 7 to 10 days
Exacerbations are associated with subsequent loss of exercise capacity (eg, 6-minute walking distance) and overall performance
Exacerbations may be followed by a progressive decline in lung function
- In a large randomized controlled trial, patients who had up to 1 moderate to severe exacerbation per year experienced a 37% faster decline in lung function over 3 years, compared with patients who did not experience exacerbations; those with more frequent exacerbations experienced a 65% faster decline
22% to 25% of patients hospitalized for an acute exacerbation are readmitted within 30 days
5-year mortality after an exacerbation is approximately 50%
- Severity of exacerbation and history of previous hospitalization for an exacerbation increase the risk
- Other factors associated with higher risk of mortality after exacerbation are older age, lower BMI, presence of comorbidities, and clinical evidence of advanced lung disease (eg, poor exercise capacity, poor quality of life, and poor lung function demonstrated by spirometry)
- Exacerbations requiring hospitalization are associated with higher mortality

Prevention

Regular use of an optimal regimen of inhaled maintenance therapy is recommended to prevent exacerbations
- Both long-acting muscarinic antagonists and long-acting β₂-agonists are recommended; muscarinic antagonists are favored over β₂-agonists for preventing exacerbations
- Dual bronchodilator therapy (eg, a long-acting muscarinic antagonist plus a long-acting β₂-agonist) as indicated for therapy of stable chronic obstructive pulmonary disease is effective for preventing exacerbations
- Regimens containing inhaled corticosteroids in combination with a long-acting β₂-agonist or muscarinic antagonist are effective for preventing exacerbations; monotherapy with inhaled steroids is not recommended
In patients with moderate to severe chronic obstructive pulmonary disease who have had 1 or more moderate to severe exacerbations within the past year despite optimal maintenance inhaler use, long-term macrolide therapy is suggested to prevent exacerbations
- Appropriate for patients who have normal QT interval on ECG and no colonization or acute infection with atypical mycobacterium
- Reduces exacerbation but may be associated with adverse effects (eg, hearing loss, tinnitus, long QT interval, antibiotic resistance)
For an acute exacerbation, administration of systemic steroids within first 30 days may prevent subsequent severe exacerbations
For patients with moderate to severe chronic obstructive pulmonary disease with bronchitis and 1 or more exacerbations within the past year, roflumilast (a phosphodiesterase 4 inhibitor) is suggested to prevent further exacerbations
- Use for patients most likely to benefit as inhaled maintenance therapy may have adverse effects, including gastrointestinal symptoms, headache, backache, and insomnia
When added to standard therapy, mucolytics reduce the number of exacerbations for patients with frequent exacerbations who are not receiving inhaled corticosteroids
- Erdosteine is the most effective; reduces risk and duration of acute exacerbations and risk of hospitalization
- Oral N-acetylcysteine or carbocysteine are alternatives
Pneumococcal, COVID-19, and annual influenza vaccinations are recommended as a means to prevent exacerbations
- Annual influenza vaccination as soon as it becomes available for the upcoming season
  - Moderate-quality evidence shows reduced risk of acute exacerbation
- Pneumococcal pneumonia vaccine (ie, PCV13 and/or PPSV23)
  - Shown to reduce incidence of community-acquired pneumonia and exacerbations of chronic obstructive pulmonary disease
- Vaccination against COVID-19 (SARS-CoV-2) is recommended
Smoking cessation is recommended to prevent exacerbations
- Evidence-based strategies include nicotine replacement products, pharmacotherapy (eg, bupropion, varenicline), and counseling
  - High-quality evidence indicates that a combination of pharmacotherapy and high-intensity behavioral treatment is more effective than high-intensity behavioral treatment alone
  - Moderate evidence indicates that nicotine replacement therapy combined with psychosocial support increases abstinence from smoking and reduces mortality
  - Some evidence indicates that high-intensity behavioral treatment is more effective than low-intensity or usual care
- Refer to available evidence-based guidelines for initiating pharmacologic therapy
Pulmonary rehabilitation is recommended in patients with moderate or severe chronic obstructive pulmonary disease who have had an exacerbation within the preceding 4 weeks; it is a means of preventing further exacerbations
Education, a written action plan, and active case management in combination are recommended to prevent exacerbations
Regular follow-up as an outpatient (3 or more times per year) is associated with lower rates of acute exacerbation requiring hospitalization
- Likely due to more regular assessment of disease status and adjustment of treatment accordingly and improved adherence with treatment

Sources

Global Initiative for Chronic Obstructive Lung Disease: Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: 2021 Report. GOLD website. Published 2021. Accessed September 21, 2021. https://goldcopd.org/wp-content/uploads/2020/11/GOLD-REPORT-2021-v1.1-25Nov20_WMV.pdf

Exacerbations of COPD