Update on COPD Exacerbations: Part II—Management
By David J. Pierson, MD, Editor, Professor, Pulmonary and Critical Care Medicine, Harborview Medical Center, University of Washington, Seattle, is Editor for Critical Care Alert.
A recently published study using a large national administrative database found that only two-thirds of patients hospitalized with exacerbations of chronic obstructive pulmonary disease (COPD) received care that was consistent with current guidelines of the American College of Physicians and the American College of Chest Physicians.1 In addition, the investigators found that 45% of the 70,000 patients in the study received at least one form of therapy that was considered ineffective (that is, not supported by acceptable evidence) and thus was not recommended by the guidelines. With this kind of performance record, considering that each year some 750,000 patients are hospitalized because of COPD exacerbations in the United States, a review of currently recommended management seems like a good idea.
Part I of this Special Feature, published last month,2 discussed the definition and clinical importance of COPD exacerbations. It outlined an approach for diagnosing exacerbations, assessing clinical severity, and deciding which patients should be admitted to the hospital and to the ICU. This month's concluding segment is devoted to the different components of therapy: how best to use bronchodilators, corticosteroids, antibiotics, and other drugs; how to administer supplemental oxygen effectively and safely; when to use noninvasive positive-pressure ventilation (NPPV); and when intubation and invasive mechanical ventilation are most likely to be required. In summarizing these topics I will refer to the best available evidence, wherever possible from the Cochrane database (www.thecochranelibrary.com) or from other systematic reviews, as well as to the recommendations of the major clinical practice guidelines on managing COPD.3-5
Despite the fact that airflow obstruction in patients with COPD tends to be mostly irreversible, inhaled bronchodilator therapy remains a cornerstone of management during exacerbations. Increased airway inflammation may worsen obstruction acutely, and this may respond to bronchodilators. In addition, respiratory distress and the physiologic consequences of acute hyperinflation—as a phenomenon separate from airflow obstruction per se—may be amenable to more rapid resolution with aggressive bronchodilator therapy. Management of exacerbations mainly involves intensifying the use of the same drugs as used for chronic therapy, rather than adding new agents.
Most available evidence on the effectiveness and administration of bronchodilators comes from studies on acute asthma, and fewer investigations have been done in patients with COPD exacerbations. However, the available database in this area is large, and it permits the following conclusions to be drawn:
1) Albuterol and other short-acting beta agonists should be administered by inhalation, not parenterally. Aerosol delivery produces at least as much therapeutic effect, with considerably less tachycardia, tremor, and other adverse effects.
2) Beta agonists should be given at higher doses and greater frequency during an exacerbation—at least in initial management—than with long-term administration.
3) When this is done, there is no evidence that anticholinergics such as ipratropium provide greater benefit than beta agonists.6
4) Although both beta agonists and anticholinergics are commonly given together during exacerbations, meta-analysis of controlled trials comparing the combination to the effects of single-agent therapy shows no added benefit.6
5) Administration via metered-dose inhaler plus spacer is therapeutically equivalent to nebulization7 and costs less.
Studies comparing metered-dose inhalers to dry-powder inhalers for delivery of drugs to patients with COPD have shown these to be equivalent in stable patients, but similar studies in exacerbations have not been published. At present there is no way to deliver dry-powder aerosols effectively to intubated patients, and it is doubtful whether non-intubated patients who are too ill to use dry-powder inhalers according to the manufacturer's instructions can benefit from them.
Continuous nebulization is sometimes used for bronchodilator therapy in treating acute asthma in the emergency department. However, studies have failed to demonstrate that this is superior to conventional, intermittent therapy in terms of outcome, and the use of continuous nebulization for more than 2 or 3 hours should probably be avoided. Albuterol or another short-acting agent should be used for intensive beta-agonist therapy, and long-acting bronchodilators such as salmeterol and formoterol should not be used more frequently than recommended for long-term therapy.
While aggressive administration of inhaled bronchodilators may have a more immediate effect on airway function, the true mainstay of pharmacotherapy for COPD exacerbations is systemic corticosteroids. Although no randomized, controlled trials have been carried out exclusively in patients admitted to the ICU, strong support for the use of corticosteroids comes from numerous well-designed studies on hospitalized patients. A Cochrane review by Wood-Baker et al identified 10 such studies (951 patients) published through 2005 that met specified criteria.8 Based on high-quality evidence, the conclusions of this review are as follows with respect to the use of systemic corticosteroids vs placebo:
- Fewer treatment failures (odds ratio, 0.48; hazard ratio, 0.78; one treatment failure prevented for every 9 patients treated)
- More rapid improvement in FEV1 (weighted mean difference, 140 mL at 72 h)
- Significantly improved breathlessness and arterial blood gas values
- No difference in mortality
- Increased adverse effects (odds ratio, 2.29; one extra adverse reaction for every 6 people treated), primarily hyperglycemia
In addition, studies suggest that corticosteroid treatment prolongs the interval between exacerbations in patients who have them frequently.
Hospitalized patients have traditionally been treated with intravenous methylprednisolone, most often at a dose of 0.5 mg/kg every 6 hours. However, there is no compelling evidence that intravenous administration is more effective than oral, that it is beneficial to give the agent more often than once a day, or that the smaller doses recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD)3 and other guidelines (eg, 40 mg prednisone once daily for 10 to 14 days) are any less effective. Higher doses cause more adverse effects—especially hyperglycemia—and studies have shown no advantage of continuing therapy beyond 14 days. Guidelines recommend that patients receiving prolonged or frequent courses of systemic corticosteroids for exacerbations receive prophylaxis against osteoporosis.5
Maltais and associates9 carried out a multicenter, randomized, controlled trial of high-dose inhaled corticosteroid (budesonide) every 6 hours, as compared to oral prednisolone twice daily, and placebo, in 199 COPD patients with exacerbations. FEV1 improved more in 72 h in the 2 steroid groups than in patients treated with placebo; the improvement in FEV1 was somewhat less (but not significantly so) in the budesonide group. Because of the greater expense (for both drug and labor), and the fact that the patients in this trial had only relatively mild exacerbations (normal pH; minimal hypoxemia), treatment of ICU patients with inhaled corticosteroids cannot be recommended.
Meta-analyses of the considerable literature on antibiotics show that they are effective in severe exacerbations and conclude that they should be used.10,11 The most recent review, an evaluation of 10 trials (917 patients) by Ram et al,10 found that antibiotic therapy, regardless of which agent was used:
- Reduced mortality (relative risk, 0.23; number needed to treat = 8)
- Decreased treatment failure (relative risk 0.47; number needed to treat = 3)
- Reduced sputum purulence (relative risk 0.56; number needed to treat = 8)
In this meta-analysis, there was no significant effect of antibiotics on arterial blood gases or peak flow, but there was an increase in the incidence of diarrhea (relative risk, 2.86) among patients who received antibiotics.
The classic randomized trial by Anthonisen and colleagues during the 1980s12 showed benefit from antibiotic therapy only in patients who had at least 2 of the 3 cardinal symptoms of increased dyspnea, increased sputum volume, and increased sputum purulence. Thus, while those with mild exacerbations may not be helped by antibiotics, patients who are ill enough to be admitted to the hospital (and especially to the ICU) should receive them.
Which antibiotic should be used? Studies comparing one antibiotic to another are numerous in the literature, but much less robust than those using placebo controls and included in the meta-analyses just cited. The value of sputum Gram stains and cultures in patients with COPD exacerbations has been difficult to demonstrate, even knowing that such patients may have recently acquired new strains of bacterial pathogens. Because patients with COPD are commonly colonized with bacteria (most often S. pneumoniae, H. influenzae, and M. catarrhalis), finding these organisms in the sputum does not ensure that the exacerbation is bacterial in origin or that the recovered species are responsible.
Knowledge of local antibiotic resistance patterns is important, although the choice of antimicrobial agent remains largely empirical.13,14 Traditional recommendations have been for inexpensive agents—trimethoprim-sulfamethoxazole, amoxicillin, or a tetracycline, for example—that cost far less than whatever heavily marketed oral agent has most recently been approved for this indication, especially for less severe exacerbations. I still use these old standbys for outpatient treatment. Fluoroquinolones and macrolides are increasingly used when patients are admitted to the hospital, and a good case can be made for this. When patients have evidence for pneumonia, Pseudomonas infection, or sepsis, or have already been taking antibiotics when admitted, more extensive bacteriologic investigation and broader antimicrobial coverage are probably indicated.
Methylxanthines. A generation ago, intravenous aminophylline was a therapeutic mainstay in managing COPD exacerbations. However, although its use was supported by several hypothetical benefits—bronchodilation, an inotropic effect on the diaphragm, stimulation of ventilatory drive, diuresis—when subjected to current standards for therapeutic evidence, aminophylline and other methylxanthines have been found wanting. A recent Cochrane review of clinical trials comparing aminophylline to placebo in COPD exacerbations found no clinically important differences in lung function either immediately or after 3 days, no symptomatic benefit, an increase in nausea and vomiting, and a greater likelihood of relapse at 1 week.15 These drugs have a narrow therapeutic window, and unlike the inhaled bronchodilators they have the substantial potential for serious or even fatal adverse effects (eg, arrhythmias, seizures) during acute administration. Current guidelines either advise against their use in exacerbations,1 or caution that serum levels be monitored closely because of the danger of side effects.3
Sedatives. Although patients with COPD exacerbations are often restless and anxious, the use of benzodiazepines, opioids, and other agents with sedating effects in managing them is difficult and dangerous. Respiratory distress is the result of an increase in the work of breathing, and treatment aims to ameliorate the former by reducing the latter. Blunting the patient's perception or manifestation of distress without improving the mechanical situation runs the risk of worsening hypercapnia and academia, and thus of precipitating the need for intubation. Although small doses of lorazepam or other benzodiazepine may sometimes succeed in calming an agitated patient without overtly depressing ventilation, such therapy must be used with extreme caution, given that intubation is associated with increased mortality, more complications, and increased lengths of stay in the ICU and the hospital. The skillful use of noninvasive positive-pressure ventilation (NPPV), as discussed below, allows a reduction in the patient's work of breathing that is usually manifested by reduced distress and less potential need for sedation.
Mucolytics and respiratory stimulants have traditionally been used more often in Europe and some other regions than in the United States. Neither category of drug is recommended by the current international guidelines for use in exacerbations.3-5
Hypoxia is the greatest immediate threat to life in patients with severe COPD exacerbations, yet generations of clinicians have been hesitant to treat it aggressively for fear of acutely worsening hypercapnia. As a result, patients are sometimes allowed to remain dangerously hypoxemic, even after admission to the hospital. The traditional teaching is that such patients may be "running entirely on their hypoxic drive," and that blunting the latter with too much oxygen will precipitate CO2 narcosis and frank ventilatory failure. Several studies over the last 25 years have shown that this fear is unnecessarily exaggerated, but also that the mechanism of hypercapnia is more complicated than originally believed.
Robinson et al studied 22 patients with severe COPD (baseline FEV1 30% of predicted) who were admitted to the hospital with exacerbations.16 They measured arterial blood gases, cardiac output, and ventilation-perfusion distribution using the multiple-inert-gas elimination technique, while the patients breathed ambient air and again after 20 minutes breathing 100% oxygen. None of the patients went into frank ventilatory failure, although arterial PCO2 rose by more than 3 mm Hg in 12 of them. Compared to the other 10 patients, these 12 "retainers" had lower overall minute ventilation, but also had greater perturbation of ventilation-perfusion matching and an increase in physiological dead space. Thus, administering too much oxygen to patients with COPD exacerbations can indeed cause acute hypercapnia, but the mechanism is more complex than simply depressing their ventilatory drive.
How often hyperoxia-induced hypercapnia is a clinically important problem when over-oxygenation is avoided was evaluated by Moloney et al, who studied 24 consecutive patients presenting to the emergency department with COPD exacerbations.17 The patients had very severe underlying COPD, and initial mean arterial PO2 and PCO2 values breathing room air were 46 and 56 mm Hg, respectively. These authors carefully titrated the administration of supplemental oxygen, raising SpO2 above 90% but keeping it always below 92%, and re-checked arterial blood gases after 2 hours. Using this approach, only 3 of the 24 patients experienced a rise in PCO2 of more than 7.5 mm Hg, and arterial pH fell below 7.25 in only 1 of them. No patient required intubation, and none experienced a worsening of PCO2 or pH beyond 2 hours. In keeping with the findings of other studies, patients with the highest initial PCO2 values tended to have greater increases with supplemental oxygen.
The bottom line, consistent with the recommendations of all current guidelines,3-5 is that SpO2 should be raised above 90% (corresponding to a PO2 > 60 mm Hg) in all patients, and that clinically important CO2 retention is unlikely if SpO2 is kept in the low 90s. Patients with more severe initial hypercapnia should be monitored closely during initial oxygen administration.
Should oxygen be given by nasal cannulae or by Venturi mask? The delivered oxygen concentration is known and constant with the latter—but actually only in the mask itself, since there is always some entrainment of room air when the patient inspires. Nasal prongs are more likely to remain on the patient, and do not have to be removed when talking, expectorating, taking medications, or eating. The theoretical risk that the inspired oxygen concentration may increase if the patient hypoventilates while the nasal oxygen flow remains constant can be mitigated by continuous SpO2 monitoring and titration of the liter flow to maintain the target value of 90-92%. Either administration technique can be used effectively, but I prefer the nasal cannula.
The most important advance in the management of COPD exacerbations during the last 15 years has been the emergence and validation of NPPV as the standard of care for patients with acute-on-chronic ventilatory insufficiency. Several previous Critical Care Alert special features have dealt with the practical application of NPPV in this and other settings, and I will not discuss the technical aspects of this therapy here. However, a brief review of the evidence supporting NPPV is warranted.
The database on the efficacy of NPPV in COPD exacerbations is extensive. It includes 14 randomized controlled trials (758 patients) meeting criteria for a recent systematic review by Ram et al.18 These authors drew the following conclusions from their analysis:
- NPPV reduces mortality (relative risk, 0.52; number needed to treat = 10)
- It decreases the need for intubation (relative risk, 0.41; number needed to treat = 4)
- It reduces treatment failure (relative risk, 0.48; number needed to treat = 5)
- Tachypnea, arterial pH, and PCO2 improve more rapidly with NPPV
- It decreases treatment-associated complications (relative risk, 0.38)
- It shortens hospital length-of-stay (weighted mean difference, 3.24 fewer days)
Simply stated, the use of NPPV in 10 patients with COPD exacerbations can be expected to save 1 life, compared with not using NPPV, all other aspects of management being the same. At least 2 of those 10 patients will avoid intubation who would otherwise require invasive mechanical ventilation. The risk of complications associated with their care would be reduced by 62%. And, based on the available literature, if managed with NPPV those 10 patients would have an aggregate hospital stay of more than a month less than they would otherwise.
Not all patients are appropriate for NPPV. Based on currently available evidence, as well as on the recommendations of leading guidelines, Tables 1 and 2 list the indications and contraindications for NPPV in patients with COPD exacerbations.
Confalonieri and associates19 have recently developed and validated a chart for predicting NPPV failure in patients with COPD exacerbations. They used a series of 1,033 consecutive patients, 797 of whom were successfully managed with NPPV, in developing the chart, which uses the APACHE II score and the Glasgow Coma Scale score as well as the patient's respiratory rate and arterial pH initially and after 2 hours of therapy, to predict the likelihood of NPPV failure. They then validated the chart prospectively in an additional 145 patients. To identify patients in whom NPPV was more likely to fail than to succeed, the chart had sensitivities and specificities of 33% and 97% on admission and of 53% and 94% after 2 hours of NPPV, respectively. Whether use of this chart will prove to be beneficial beyond the circumstances of this study remains to be established.
Patients with COPD exacerbations who do not meet the criteria listed in Table 1 may be less likely to benefit from NPPV. Keenan et al recently published an evaluation of NPPV vs usual care in a cohort of 25 patients with milder exacerbations than included in most series.20 They found that only about half of the patients tolerated the therapy, and that there were no significant differences in length of stay or other outcomes in the NPPV and usual-care groups.
Invasive Mechanical Ventilation
Even when patient assessment is performed appropriately, and NPPV is applied when and as it should be, some patients require intubation and invasive mechanical ventilation. Table 3 lists the findings and circumstances in which intubation is indicated.
How to ventilate patients once they are intubated is beyond the scope of this article. However, the goals of mechanical ventilation are to unload the respiratory muscles so that they can recover from the overload that led to ventilatory failure; to provide adequate oxygenation; to improve acid-base status without disrupting any underlying compensation and causing alkalemia; to avoid dynamic hyperinflation and auto-PEEP; and to make the period of intubation as short as possible. Realizing these goals is not easy, and the frequency and severity of complications of invasive mechanical ventilation in patients with severe COPD underscore the importance of making every effort to avoid it. The guidelines summarized in this article may assist in this effort.
- Lindenauer PK, et al. Quality of care for patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease. Ann Intern Med. 2006;144:894-903.
- Pierson DJ. Update on COPD exacerbations, part I: Overview and patient assessment. Critical Care Alert. 2006;14:36-40.
- Global Initiative for Chronic Obstructive Lung Disease (GOLD). www.goldcopd.com.
- American Thoracic Society/European Respiratory Society Task Force. Standards for the Diagnosis and Management of Patients with COPD. www.thoracic.org/copd/.
- National Collaborating Centre for Chronic Conditions. Chronic obstructive pulmonary disease. National clinical guideline on management of chronic obstructive pulmonary disease in adults in primary and secondary care. Thorax. 2004;59(Suppl 1):1-232. www.thorax.bmjjournals.com/content/vol59/suppl_1/
- McCrory DC, Brown CD. Anti-cholinergic bronchodilators versus beta2-sympathomimetic agents for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2002;(4):CD003900.
- Cates CJ, et al. Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma. Cochrane Database Syst Rev. 2006(2):CD000052.
- Wood-Baker RR, et al. Systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2005;(1):CD001288.
- Maltais F, et al. Comparison of nebulized budesonide and oral prednisolone with placebo in the treatment of acute exacerbations of chronic obstructive pulmonary disease: a randomized controlled trial. Am J Respir Crit Care Med. 2002;165:698-703.
- Ram FS, et al. Antibiotics for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2006;(2):CD004403.
- Saint S, et al. Antibiotics in chronic obstructive pulmonary disease exacerbation. A meta-analysis. JAMA. 1995;273:957-960.
- Anthonisen NR, et al. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med. 1987;106:196-204.
- Sharma S, Anthonisen N. Role of antimicrobial agents in the management of exacerbations of COPD. Treat Respir Med. 2005;4:153-167.
- Sethi S. Pathogenesis and treatment of acute exacerbations of chronic obstructive pulmonary disease. Semin Respir Crit Care Med. 2005;26:192-203.
- Barr RG, et al. Methylxanthines for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2003(2):CD002168.
- Robinson TD, et al. The role of hypoventilation and ventilation-perfusion redistribution in oxygen-induced hypercapnia during acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;161:1524-1529.
- Moloney ED, et al. Controlled oxygen therapy and carbon dioxide retention during exacerbations of chronic obstructive pulmonary disease. Lancet. 2001;357:526-528.
- Ram FS, et al. Non-invasive positive pressure ventilation for treatment of respiratory failure due to exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2004;(3):CD004104.
- Confalonieri M, et al. A chart of failure risk for noninvasive ventilation in patients with COPD exacerbation. Eur Respir J. 2005;25:348-355.
- Keenan SP, et al. Noninvasive positive-pressure ventilation in patients with milder chronic obstructive pulmonary disease exacerbations: a randomized controlled trial. Respir Care. 2005;50:610-616.