X2. COPD acute exacerbation plan

X2.1 Initial assessment of severity

Assessment of severity of the exacerbation includes a medical history, examination, spirometry and, in severe cases (FEV₁ < 40% predicted), blood gas measurements, chest x-rays and electrocardiography. Patients should be provided with and bring a summary of their medical problems and treatment (eg, a personal health record). If available, results of previous stable lung function tests and arterial blood gas measurements are invaluable for comparison.

• Spirometry:
  Unless confused or comatose, even the sickest of patients can perform an FEV₁ manoeuvre. An FEV₁ less than 1.0 L (or < 40% predicted) is usually indicative of a severe exacerbation in patients with moderate COPD. For patients with stable levels below these values (ie, severe COPD), the most important signs of a severe exacerbation will be worsening hypoxaemia, acute respiratory acidosis (carbon dioxide retention), or both.

• Arterial blood gases:
  Arterial blood gas levels should be measured if the FEV₁ is less than 1.0 L or less than 40% predicted, or if there are signs of respiratory failure or cor pulmonale. Values obtained while breathing room air are the most useful for assessing ventilation–perfusion inequality. A PaO₂ less than 60 mmHg (8 kPa) indicates respiratory failure, while a PaCO₂ greater than 45 mmHg indicates ventilatory failure. A pH <7.20 indicates acute respiratory failure warranting consideration for assisted ventilation.

• Chest x-ray and electrocardiogram:
  These help to identify alternative diagnoses and complications, such as pulmonary oedema, pneumothorax, pneumonia, empyema, arrhythmias, myocardial ischaemia and others.

X2.2 Optimise treatment

An acute exacerbation of COPD may involve an increase in airflow limitation, excess sputum production, airway inflammation, infection, hypoxia, hypercarbia and acidosis. Treatment is directed at each of these problems.

• Bronchodilators:
  Inhaled beta-agonist (eg, salbutamol, 400–800 mcg; terbutaline, 500–100 mcg) and anticholinergic agent (ipratropium, 80 mcg) can be given by pressurised metered dose inhaler and spacer, or by jet nebulisation (salbutamol, 2.5–5 mg; terbutaline, 5 mg; ipratropium, 500 mcg). The dose interval is titrated to the response and can range from hourly to six-hourly.

• Glucocorticoids:
  Oral glucocorticoids hasten resolution and reduce the likelihood of relapse. Up to two weeks' therapy with prednisolone (40–50 mg daily) is adequate. Longer courses add no further benefit and have a higher risk of side effects.

• Antibiotics:
  Antibiotics are given for purulent sputum to cover for typical and atypical organisms.

• Controlled oxygen therapy:
  This is indicated in patients with hypoxia, with the aim of improving oxygen saturation to over 90% (PaO₂ > 50 mmHg, or 6.7 kPa). Use nasal prongs at 0.5–2.0 L/minute or a venturi mask at 24% or 28%. Minimise excessive oxygen administration, which can worsen hypercapnia.

• Ventilatory assistance:
  This is indicated for increasing hypercapnia and acidosis. Non-invasive positive pressure ventilation by means of a mask is the preferred method.

In exacerbations of COPD, the immediate bronchodilator effect is small, but may result in significant improvement in clinical symptoms in patients with severe obstruction.

Studies of acute airflow limitation in asthma indicate that beta-agonists are as effectively delivered by metered dose inhaler and spacer as by nebuliser. This may be applicable to patients with COPD, although no direct evidence exists.  An adequate dose should be used. The dose equivalent to 5 mg of salbutamol delivered by nebuliser is 8–10 puffs of 100 mcg salbutamol by metered dose inhaler and spacer. Airflow in the nebuliser should be 6 L per minute or higher to achieve an aerosol. Avoid using high-flow oxygen, which may worsen carbon dioxide retention. High doses of beta-agonists may induce hypokalaemia and predispose to cardiac arrhythmias.

Few studies have examined the use of ipratropium bromide in acute exacerbations of COPD.^245,246 One study which compared the effectiveness of ipratropium bromide with a beta-agonist showed that each drug produced a small but significant improvement in pulmonary function.²⁴⁵ Inhaled ipratropium bromide also produced a small but significant increase in PaO₂ (average, 6 mmHg, or 0.8 kPa) within 30 minutes of its delivery.

Hospital management of a severe exacerbation usually includes nebulised beta-agonist bronchodilator (eg, salbutamol, terbutaline), given continuously in extremely unwell patients and intermittently in others. This will usually be delivered by means of high flow air. An anticholinergic agent (ipratropium bromide) may be delivered together with the nebulised beta-agonist in patients with severe exacerbations (triage categories 1 and 2) or when response to beta-agonists alone is poor. However, a systematic review²⁴⁷ that included four randomised controlled trials did not demonstrate any additional benefit on FEV₁ of the combination of an anticholinergic compared with beta₂-agonist  alone. [evidence level I] Nebulised medications can also be administered through the assisted ventilation circuit if required.²⁴⁶

The mode of delivery should be changed to a metered dose inhaler with a spacer device or a dry powder inhaler within 24 hours of the initial dose of nebulised bronchodilator, unless the patient remains severely ill.^248,249

The use of methylxanthines (oral theophylline and IV aminophylline) in the management of acute exacerbations of COPD has diminished because of their potential for toxicity^250-254. Methylxanthines can also provoke a number of arrhythmias including multifocal atrial tachycardia.³³ A systematic review of four Randomised Controlled Trials found a transient increase of 101ml in FEV₁ after three days and a 4-6 fold increased risk of nausea and vomiting²⁵⁵[evidence level I]. The routine use of aminophylline is not recommended for for non-acidotic acute exacerbations [evidence level II].²⁵⁶

Bacterial infection may have either a primary or secondary role in about 50% of exacerbations of COPD.^{230,233,238,258} Haemophilus influenzae, Streptococcous pneumoniae and Moraxella catarrhalis are most commonly involved.^230,232,237 Mycoplasma pneumoniae and Chlamydia pneumoniae are seen relatively frequently.^230,236 As lung function deteriorates (FEV₁ < 35%), Pseudomonas aeruginosa and Staphylococcus aureus are often encountered.^230,232,238

Two systematic reviews have found similar benefits for antibiotic treatment over placebo in severe acute exacerbations requiring hospitalisation, despite including different studies. Ram et al²⁶⁰, including mostly hospital-based studies, found a significant decrease in mortality (RR 0.23, 95% CI 0.10 to 0.52) with a NNT of 8 (95% CI 6 to 17). Puhan et al²⁶¹ also found a decrease in mortality of their sub-group analysis of severe exacerbations requiring hospitalisation (OR 0.20, 95% CI 0.06 to 0.62) with a NNT of 14 (95% CI 12 to 30). Both systematic reviews also found a significant decrease in treatment failure. Although Puhan did not combine the results of adverse drug effects due to heterogeneity, Ram found antibiotic treatment increased adverse events, most notably diarrhoea (RR 2.86, 95% CI 1.06 to 7.76) with a NNH of 20 (95% CI 10 to 100). The effect of antibiotics in the general practice setting is unclear. Puhan found no significant benefit for treatment failure in mild and moderate exacerbations treated outside the hospital setting (OR 1.09, 95% CI 0.75 to 1.59).

A systematic review of RCTs has confirmed the overall benefit of antibiotics given for at least five days in acute exacerbations (although most of the data is from the hospital setting).²⁶⁰ Antibiotics for increased cough and sputum purulence decreased mortality, treatment failure and end of treatment sputum purulence at a cost of an increased risk of diarrhoea. A significant decrease in mortality (RR 0.23; 95% CI 0.10 to 0.52) was found, meaning 8 (95% CI 6 to 17) people needed antibiotic treatment to prevent one death. Treatment increased adverse events, most notably diarrhoea (RR 2.86; 95% CI 1.06 to 7.76), meaning antibiotic treatment in 20 (95% CI 10 to 100) people would result in one additional episode of diarrhoea. Unfortunately, these data are limited by participant numbers and setting, the majority of studies being performed in the hospital setting. Generalisability, especially to the primary care setting where most exacerbations are seen, is unclear.

Therapeutic guidelines: antibiotic²⁶² recommend the use of oral agents such as doxycycline or amoxycillin (alternatively, erythromycin or roxithromycin). If patients do not respond, or if resistant organisms are suspected, amoxycillin–clavulanate should be prescribed. If pneumonia, pseudomonas or staphylococci is suspected, appropriate antibiotics should be used.

Typically, a course of treatment should be over seven to 10 days. A response is usually seen within three to five days, and a change of antibiotic should be considered if the response is unsatisfactory. If parenteral administration was commenced, oral treatment should be substituted within 72 hours.

Radiologically proven pneumonia in patients with COPD, especially in those who have been frequently hospitalised, may not be restricted to the above organisms. Gram-negative organisms, Legionella spp. and even anaerobic organisms may be responsible. Initial empiric antibiotic therapy should be tailored according to clinical and radiographic criteria.

A randomised controlled trial of systemic glucocorticoids for acute exacerbations of COPD showed a moderate improvement in clinical outcomes.²⁶⁴ Maximum improvement was gained within two weeks of therapy, and prolonging the course of treatment thereafter did not result in further benefit. An important side effect was hyperglycaemia, often sufficiently severe to warrant treatment. Blood glucose levels should be monitored. Oral or parenteral glucocorticoids are recommended for treating acute exacerbations of COPD [evidence level I]. The optimal dose has not been established, but 30–50 mg prednisolone daily is sufficient for most patients. If intravenous therapy was commenced, this should be changed to oral therapy within 48 hours.  An updated systematic review of systemic corticosteroids for acute exacerbations showed that it would have been necessary to treat nine patients (95% CI 6 to 14) with systemic corticosteroids to avoid one treatment failure in this time period. Overall, one extra adverse effect occurred for every six people treated (95% CI 4 to 10).

The continued use of inhaled corticosteroids and the administration technique should be reviewed. At discharge, therapy with oral prednisolone (25–37.5 mg daily) may be continued but the optimal duration is unknown. Tapering of glucocorticoid therapy is not necessary after short-term administration. However, patients who have taken glucocorticoids for more than three consecutive weeks may have adrenal suppression,^264,265and their glucocorticoid therapy should not be ceased abruptly.

Patients on long-term oral steroid therapy (≥ 7.5 mg prednisolone daily for more than 6 months) are at risk of developing osteoporosis. Prevention and treatment of steroid-induced osteoporosis should be considered.