Treating and preventing acute exacerbations of COPD

Antibiotics help, but exact strategy uncertain

Although antibiotic therapy is one of the three pillars of COPD exacerbation management, the optimal antimicrobial agent, duration of therapy, and which patients will benefit remain areas of controversy and research. Thus far, large trials have been unable to definitely show the superiority of one antibiotic over another.^33,34

A 1987 randomized controlled trial⁵ of antibiotic therapy in acute exacerbation of COPD found the greatest benefit to patients who had all three cardinal symptoms (ie, increased shortness of breath, sputum volume, and purulence), with less marked but still significant improvement in patients with two symptoms. In a 2012 multicenter trial³⁵ patients with mild to moderate COPD experiencing an exacerbation were treated with either combined amoxicillin and clavulanate or placebo if they had one of the three cardinal symptoms. The antibiotic group had a significantly higher clinical cure rate at days 9 to 11 (74.1% vs 59.9%) as well as a longer time until the next exacerbation (233 vs 160 days).

Recommendation. Optimal antibiotic management of COPD exacerbations may also depend on risk factors. For patients with at least two cardinal symptoms, we favor a scheme akin to one proposed for treating community-acquired pneumonia (Table 1).^16,36

INPATIENT MANAGEMENT

Corticosteroids improve outcomes

A Department of Veterans Affairs cooperative trial³⁷ randomized 271 patients hospitalized with COPD exacerbation to receive either corticosteroids (intravenous followed by oral) or placebo for either 2 weeks or 8 weeks. Corticosteroid recipients had lower rates of treatment failure at 30 and 90 days, defined as death from any cause, need for mechanical ventilation, readmission, or intensification of pharmacologic therapy. Corticosteroid therapy also reduced hospital length of stay and improved the rate of recovery. The longer corticosteroid course was associated with a higher rate of adverse effects.

Oral corticosteroids not inferior to intravenous

Using the same end point of treatment failure as the Veterans Affairs cooperative trial, deJong et al³⁸ demonstrated that prednisone 60 mg by mouth was not inferior to intravenous prednisone. Neither trial demonstrated a difference in mortality between corticosteroid use and placebo.

Short course of a corticosteroid not inferior to a long course

In 2013, the Reduction in the Use of Corticosteroids in Exacerbated COPD (REDUCE) trial³⁹ randomized 314 patients presenting with an acute COPD exacerbation (92% requiring hospital admission) to oral prednisone 40 mg daily for either 5 days or 14 days. They found that the short course was noninferior in preventing exacerbations over the ensuing 6 months in terms of death and the need for mechanical ventilation.

Recommendation. Our threshold for initiating systemic corticosteroid therapy is lower in hospitalized patients than in outpatients. We recommend the regimen of the REDUCE trial: prednisone 40 mg daily for 5 days.

Corticosteroids for patients on ventilatory support

Severe COPD exacerbations requiring admission to intensive care are a significant source of morbidity and mortality, and the strategy of corticosteroid treatment is still under investigation.

Intravenous corticosteroids are effective. A multicenter trial⁴⁰ in 354 patients requiring either invasive or noninvasive mechanical ventilation randomized them to treatment with either intravenous methylprednisolone (tapered) or placebo. Treatment was associated with fewer mechanical ventilation days and a lower rate of noninvasive ventilation failure.

Low-dose oral corticosteroids ineffective. In contrast, an open-label trial⁴¹ of patients requiring ventilatory support and randomized to either oral prednisone (1 mg/kg for up to 10 days) or usual care found no difference in intensive care length of stay or noninvasive ventilation failure. This study used the oral route and smaller doses, and its open-label design might have introduced bias.

Lower-dose steroids better than high-dose. A 2014 cohort study of 17,239 patients admitted to the ICU with acute exacerbations of COPD evaluated outcomes of treatment with high methylprednisolone dosages (> 240 mg per day) vs lower dosages, using propensity score matching.⁴² No mortality difference was found between the groups. The lower dosage group (median methylprednisolone dose 100 mg per day) had shorter hospital and intensive care unit stays, shorter duration of noninvasive positive pressure ventilation, less need for insulin therapy, and fewer fungal infections.

Antibiotics for hospitalized patients

Only scarce data are available on the use of antibiotics for patients hospitalized with COPD exacerbation. In a study of patients hospitalized with COPD exacerbations, adding doxycycline to corticosteroids led to better clinical success and cure rates at 10 days compared with placebo, but the primary end point of clinical success at 30 days was not different between the two groups.⁴³

BRONCHODILATORS: A MAINSTAY OF COPD TREATMENT

Bronchodilators are an important part of treatment of COPD exacerbations in inpatient and outpatient settings.

Nebulized beta-2 agonists are given every 1 to 4 hours. Albuterol at a 2.5-mg dose in each nebulization was found to be as effective as 5 mg for length of hospital stay and recovery of lung function in patients with an acute exacerbation of COPD.⁴⁴

Adding an anticholinergic may help. Nebulized anticholinergics can be given alone or combined with beta-2 agonists. Whether long-acting bronchodilators should be used to manage COPD patients hospitalized with an exacerbation requires further inquiry. In an observational study with historical controls, Drescher and colleagues⁴⁵ found cost savings and shorter hospital stays if tiotropium (a long-acting anticholinergic) was added to the respiratory care protocol, which also included formoterol (a long-acting beta-2 agonist).

OXYGEN: TITRATED APPROACH SAFER

Caution is needed to avoid hyperoxemic hypercapnia in patients on oxygen

Oxygen should be supplied during a COPD exacerbation to ensure adequate oxyhemoglobin saturation. Caution is needed to avoid hyperoxemic hypercapnia, particularly in patients with severe COPD and propensity to ventilatory failure. The routine administration of oxygen at high concentrations during a COPD exacerbation has been associated with a higher mortality rate than with a titrated oxygen approach.⁴⁶ Long-term oxygen treatment started at discharge or as outpatient therapy is associated with reduced hospital admissions and shorter hospital stays for acute exacerbations of COPD.⁴⁷

VENTILATION SUPPORT

Noninvasive positive-pressure ventilation is a useful adjunct to treatment of COPD exacerbations with evidence of ventilatory failure (ie, acute respiratory acidosis), helping to offset the work of breathing until respiratory system mechanics improve. Keenan et al⁴⁸ reviewed 15 randomized controlled trials, involving 636 patients, of noninvasive positive-pressure ventilation in the setting of COPD exacerbation. They concluded that noninvasive positive-pressure ventilation reduced the in-hospital mortality rate and length of stay compared with standard therapy. Noninvasive positive-pressure ventilation is most useful in patients with severe COPD exacerbations and acute respiratory acidosis (pH < 7.35).⁴⁹

Intubation and mechanical ventilation. Although no standards exist for determining which COPD exacerbations may be too severe for noninvasive positive-pressure ventilation, intubation is clearly indicated for impending respiratory failure or hemodynamic instability. Other factors to consider include the greater likelihood of noninvasive positive-pressure ventilation failure in patients with severe respiratory acidosis (pH < 7.25 is associated with a > 50% failure rate) and in those with no improvement in acidosis or respiratory rate during the first hour after initiation of noninvasive positive-pressure ventilation.⁵⁰

PREVENTING EXACERBATIONS

Recent data indicate that COPD exacerbations can often be prevented (Table 2).

Inhaled pharmacotherapy

Inhaled pharmacotherapeutic agents, singly or in combination, reduce the frequency of COPD exacerbations.

Combined long-acting beta-2 agonist and corticosteroid is better than single-agent therapy. In 2007, the Towards a Revolution in COPD Health (TORCH) trial⁵¹ evaluated outpatient therapy in more than 6,000 patients worldwide with either an inhaled long-acting beta-2 agonist (salmeterol), an inhaled corticosteroid (fluticasone), both drugs in combination, or placebo. Patients had baseline prebronchodilator FEV₁ of less than 60% and were followed for 3 years. No difference was found between the groups in the primary end point of deaths, but the annualized rate of moderate to severe exacerbations was reduced by 25% in the group that received combination therapy vs placebo. Combination therapy showed superior efficacy over individual drug therapy in preventing exacerbations. Treatment with the inhaled corticosteroid, whether alone or in combination with salmeterol, increased the risk of pneumonia.

A long-acting antimuscarinic agent is better than placebo. In 2008, the Understanding Potential Long-Term Impacts on Function With Tiotropium (UPLIFT) trial⁵² randomized nearly 6,000 patients with COPD and a postbronchodilator FEV₁ of less than 70% to placebo or tiotropium, a long-acting antimuscarinic agent. Tiotropium reduced the exacerbation rate by 14% compared with placebo and improved quality of life.

Antimuscarinics may be better than beta-2 agonists. Head-to-head comparisons suggest that long-acting antimuscarinic agents are preferable to long-acting beta-2 agonists for preventing COPD exacerbations.^53,54

Triple therapy: evidence is mixed. For patients with severe symptomatic COPD and frequent exacerbations, triple therapy with a combination of an inhaled long-acting antimuscarinic agent, an inhaled long-acting beta-2 agonist, and an inhaled corticosteroid has been suggested.

Data to support this practice are limited. In the Canadian Optimal Trial,⁵⁵ the rate of exacerbations was not different between tiotropium alone, tiotropium plus salmeterol, and triple therapy. However, the rate of hospitalization for severe exacerbation was lower with triple therapy than tiotropium alone. A large, retrospective cohort study also supported triple therapy by finding reduced mortality, hospitalizations, and need for oral corticosteroid bursts compared to combination therapy with an inhaled long-acting beta-2 agonist and an inhaled corticosteroid.⁵⁶

The drawback of triple therapy is an increased incidence of pneumonia associated with combined beta-2 agonist and corticosteroids, most likely due to the corticosteroid component.⁵¹ The risk appears to be higher for higher potency corticosteroids, eg, fluticasone.⁵⁷

In 2014, the Withdrawal of Inhaled Steroids During Optimised Bronchodilator Management (WISDOM) trial⁵⁸ randomized nearly 2,500 patients with a history of COPD exacerbation receiving triple therapy consisting of tiotropium, salmeterol, and inhaled fluticasone to either continue treatment or withdraw the corticosteroid for 3 months. The investigators defined an annualized exacerbation rate of 1.2 (ie, a 20% increase) as the upper limit of the confidence interval for an acceptable therapeutic margin of noninferiority. The study showed that the risk of moderate to severe exacerbations with combined tiotropium and salmeterol was noninferior to triple therapy.

Nevertheless, caution is advised when removing the corticosteroid component from triple therapy. The trial demonstrated a worsening in overall health status, some reduction in lung function, and a transient increase in severe exacerbations in the withdrawal group. Patients with increased symptom burden at baseline and a history of severe exacerbations may not be optimal candidates for this strategy.