Oral vs IV Corticosteroids for In-hospital Treatment of COPD Exacerbations

Oral vs IV Corticosteroids for In-hospital Treatment of COPD Exacerbations course of COPD is punctuated by T heacuteclinical exacerbations. These have been defined as “an event in the natural course of the disease characterized by a change in the patient’s baseline dyspnea, cough and/or sputum that is beyond normal day-to-day variation, is acute in onset and may warrant a change in regular medication . . .”1 The “worsening” symptoms are accompanied by variable decrements in lung function and worsening health status, with improvement in dyspnea and lung function generally within 1 to 2 weeks after initiation of treatment.2 However, the decline in health status may persist for months or even longer in cases of frequently recurring exacerbations,3 and frequent exacerbations may augment the accelerated rate of lung function decline that characterizes disease progression in COPD.4 While most patients with an acute exacerbation of COPD (AECOPD) are managed as outpatients, the treatment failure rate (requirement for intensification of therapy, unscheduled office or emergency department visits or hospitalization) is high, and epidemiologic studies5 indicate that 15 to 22% may require hospitalization. Hospital admissions for AECOPD have increased in recent years; in-hospital mortality rates of approximately 10% overall have been reported,6 while much higher rates (approximately 25%) have been observed in patients with acute ventilatory failure requiring admission to an ICU.7 Moreover, follow-up studies6 have revealed a mortality rate of 33% within a year of hospitalization for AECOPD. Besides its deleterious impact on the health and survival of individual patients, hospitalization for AECOPD is an important societal health issue, accounting for ⬎ 70% of the $18 billion in direct health-care costs for COPD in the United States.8 Because of the serious impact of acute exacerbations, a major goal of COPD management is their prevention and treatment. Maintenance therapy with inhaled bronchodilators with or without inhaled corticosteroids has been shown to be beneficial as preventive therapy for reducing the frequency of exacerbations.9 Regarding the management of AECOPD, current guidelines recommend an intensification of short-acting inhaled bronchodilator therapy, antibiotics (for patients with sputum purulence or those requiring mechanical ventilation), a 7- to 10-day course of oral corticosteroids (30 to 40 mg/d of prednisolone) for home management, and oral or IV corticosteroids for hospital 1728

treatment.1 The recommendation of systemic corticosteroid therapy is based on evidence from well-designed randomized controlled clinical trials that demonstrate such benefits as shortening of recovery time, earlier improvement in lung function, decrease in the risk of early relapse, and reduction in the length of hospital stay. For hospital management, both IV and oral corticosteroids have been found to be effective,10,11 with no evidence that prolonged extension of oral therapy (8 weeks vs 2 weeks) is more efficacious.10 What is still unclear, however, is whether any greater efficacy ensues from the IV vs oral route of administration, and from higher doses (eg, 125 mg of methylprednisolone q6h IV for the first 3 hospital days)10 than lower ones (eg, 30 mg of prednisone po qd),11 although higher doses have been shown to increase the risk of side effects (eg, hyperglycemia).10 In the current issue of CHEST (see page 1741), de Jong and colleagues12 address the first of these two questions. They hypothesized that oral prednisolone is not inferior to IV prednisolone when administered in bioequivalent doses (60 mg) over 5 days to patients hospitalized for management of a severe AECOPD, followed by a gradual tapering regimen of oral prednisolone beginning with a dose of 30 mg/d for a total 11-day course. The authors found that the oral and IV routes resulted in equivalent rates of treatment failure (the primary end point, defined as death, ICU admission, rehospitalization for COPD, or the need to intensify pharmacotherapy). Secondary outcomes were also equivalent, including improvement in FEV1 and quality of life from the day of hospital admission and length of hospital stay. A strength of the study is its carefully controlled, double-blind, double-dummy experimental design with stratified allocation to the treatment arms to achieve balance between the two groups on potentially influential baseline features, so that the results are unlikely to be confounded by differences in disease severity, preadmission therapy, or prior exacerbation history. Other strengths are the inclusion of patients who had failed outpatient treatment with oral corticosteroids, thereby making the results relevant to real-world clinical scenarios, and the completeness of the follow-up data for accurate capture of treatment failures following hospital discharge. A weakness of the study, however, is the exclusion of patients with very severe exacerbations manifested by acute ventilatory failure or with significant comorbidities, so that the results cannot be extrapolated to these not uncommon subsets of patients hospitalized with a COPD exacerbation. A surprising finding is the relatively Editorials

high treatment failure rate in both treatment groups at 90 days (61.7% and 56.3%), which is higher than the failure rate at a comparable time period in the study of Nieweoehner et al (37%).10 A subanalysis suggests that differences between the two studies in entry criteria (the latter study excluded patients who had used systemic corticosteroids within the preceding 30 days) probably do not explain this discrepancy. However, the lower treatment failure rate in the study by Niewoehner et al10 might be attributable to the much higher 3-day initial and 15-day cumulative doses of prednisolone administered in that study (total of 1,680 mg) compared to the doses used in the current study over 11 days (405 mg). Future carefully designed trials will need to address the impact of different dosing regimens of systemic corticosteroids on outcomes in patients hospitalized with an AECOPD. Nonetheless, since doses were equivalent between the two treatment arms in the study of de Jong et al,12 their observations of similar efficacy in a head-to-head equivalence trial of oral vs IV corticosteroids provide convincing support for the more convenient and less costly oral route in the inpatient management of AECOPD whenever oral intake is feasible. Donald P. Tashkin, MD, FCCP Los Angeles, CA Dr. Taskin is Professor of Medicine, David Geffen School of Medicine at UCLA. The author has no conflict of interest to disclose. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Donald P. Tashkin, MD, FCCP, Professor of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095-1690; e-mail: dtashkin@ mednet.ucla.edu DOI: 10.1378/chest.07-1622

References 1 Global initiative for chronic obstructive pulmonary disease. Global strategy for the diagnosis, management and prevention of COPD 2006. Available at: www.goldcopd.org/ Guideline item. Accessed January 22, 2007 2 Parker CM, Voduc N, Aaron SC, et al. Physiological changes during symptom recovery from moderate exacerbations of COPD. Eur Respir J 2005; 26:376 –378 3 Spencer S, Jones PW, GLOBE Study Group. Time course of recovery of health status following an infective exacerbation of chronic bronchitis. Thorax 2003; 58:589 –593 4 Donaldson GC, Seemungal TA, Bhowmik A, et al. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax 2002; 57:847– 852 5 Celli BR, Barnes PJ. Exacerbations of chronic obstructive pulmonary disease. Eur Respir J 2007; 29:1224 –1238 6 Gunen H, Hacievliyagil SS, Kosar F, et al. Factors affecting survival of hospitalized patients with COPD. Eur Respir J 2005; 26:234 –241 www.chestjournal.org

7 Ai-Ping C, Lee K-H, Lim T-K. In-hospital and 5-year mortality of patients treated in the ICU for acute exacerbation of COPD: a retrospective study. Chest 2005; 128:518 –524 8 Wouters EF. Economic analysis of the Confronting COPD survey: an overview of results. Respir Med 2003; 97(Suppl C):S3–S14 9 Sin DD, McAlister FA, Man SFP, et al. Contemporary management of chronic obstructive pulmonary disease: scientific review. JAMA 2003; 290:2301–2312 10 Niewoehner DE, Erbland MC, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. N Engl J Med 1999; 340: 1941–1947 11 Davies L, Angus RM, Calverley PMA. Oral corticosteroids in patients admitted to hospital with exacerbations of chronic obstructive pulmonary disease: a prospective randomized controlled trial. Lancet 1999; 354:456 – 460 12 de Jong YP, Uil SM, Grotjohan HP, et al. Oral or intravenous prednisolone in the treatment of COPD exacerbations: a randomized controlled, double-blind study. Chest 2007; 132: 1741–1747

Hypercapnic Obstructive Sleep Apnea An Underappreciated Marker of Severity during wakefulness is a marker of H ypercapnia disease severity in patients with sleep apnea.

These patients are often very obese, have long apnea events with marked oxygen desaturation, evidence of pulmonary hypertension, and right-heart failure. Without appropriate treatment, such patients require frequent hospital admission1 and have alarming mortality rates.2 Fortunately, following the successful application of continuous positive airway pressure (CPAP) or bilevel ventilation, daytime hypercapnia often improves3 and recurrent hospital admission rates decrease.1 Unfortunately, clinicians may underestimate the severity of illness of these patients and often miss an opportunity to intervene. Presenting symptoms are nonspecific and include fatigue, sleepiness, subtle changes in mental status, and headaches. Since there is often no increase in respiratory rate or use of accessory muscles to breathe, their tenuous status is not fully appreciated. Even the underlying obstructive sleep apnea (OSA) as well as the hypoventilation in these patients is often missed. When oxyhemoglobin desaturation and right-heart failure are detected, supplemental oxygen is often provided without the knowledge of arterial blood gas abnormalities. Therefore, these hypercapnic patients often go unrecognized and undertreated with high risk for recurrent hospitalization and even early death.2 CHEST / 132 / 6 / DECEMBER, 2007

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