Annals of Emergency Medicine
Volume 36, Issue 5 , Pages 477-480, November 2000

Inhaled corticosteroids for acute asthma after emergency department discharge☆☆☆

Division of Emergency Medicine University of Alberta and Capital Health Authority Edmonton, Alberta, Canada

Article Outline

Abstract 

[Rowe BH, Edmonds ML. Inhaled corticosteroids for acute asthma after emergency department discharge. Ann Emerg Med. November 2000;36:477-480.]

 

Back to Article Outline

Inhaled corticosteroids for acute asthma after emergency department discharge 

See related article, p. 417 .

The management of asthma has changed considerably in the past several decades. Inflammation is now recognized as the underlying pathophysiology in asthma,1 and anti-inflammatory agents are now considered the cornerstone of treatment. Oral and inhaled corticosteroids, mast cell stabilizers, and the newer leukotriene modifiers all address the inflammatory response and have been recommended in asthma. First-line treatment for patients with anything more than mild, episodic asthma is usually low- to moderate-dose inhaled corticosteroids.2, 3 A step-care approach has been recommended until symptom control and quality of life have returned to normal.

Despite these treatment advances, exacerbations of asthma remain a major problem. In the United States, more than 2 million visits to emergency departments annually are the direct result of acute asthma.4 In Canada, the costs associated with asthma care are more than $500 million5; in the United States, this cost is more than $5 billion.6 Approximately 25% of asthma care costs are related to the cost of acute management. In addition to this, many patients suffer prolonged impairment in their quality of life and experience further relapses after exacerbations.7

In the acute setting, considerable high-quality evidence suggests that inhaled albuterol combined with ipratropium bromide should be the first-line agents for most patients.8, 9 Evidence from systematic reviews suggests that metered-dose inhalers with holding chambers are as effective as nebulized treatment,10 despite the fact that most North American centers continue to nebulize these treatments. The early use of corticosteroids in the ED has also been shown to reduce admissions, especially in steroid-naive patients and those with more severe exacerbations.11 Finally, magnesium sulfate12 and inhaled corticosteroids13 may improve pulmonary functions and reduce admissions for patients with severe acute asthma.

Using these therapies, most asthmatic patients (90% of Canadian and 80% of US patients14) seen in the ED can be safely discharged to home. At discharge, the issue for emergency physicians is what treatment to provide to ensure continued improvement and return to normal function. Despite current knowledge, marked practice variation exists in the care provided to patients with asthma.15 Consequently, considerable efforts have gone into the development of guidelines for the treatment of both chronic and acute asthma.2, 3

In this issue of the Annals, Brenner et al16 report the results of a double-blind, placebo-controlled trial in which prednisone and flunisolide were compared with prednisone alone in the treatment of acute asthma in patients discharged from the ED. Patients were assigned randomly to receive either a fixed dose of oral corticosteroids for 5 days and inhaled flunisolide by metered-dose inhaler with aerochamber for 24 days, or a fixed dose of oral corticosteroids alone for 5 days. The primary outcome assessed was change in percent predicted peak expiratory flow rates (PEFR); other outcomes included relapse to ED return visit, symptom assessments, and β-agonist use. The authors were unable to demonstrate any significant benefit of inhaled corticosteroids on any of the outcomes assessed, and even found an increase in nocturnal wheeze and albuterol use.

Before concluding that inhaled corticosteroid agents are not beneficial in this setting, examination of all evidence is required. For example, these results conflict with those of a similar trial published previously,17 in which patients were randomly assigned to receive either 21 days of inhaled budesonide with 7 days of oral prednisone, or 7 days of oral prednisone alone. In this trial, the authors documented a 48% reduction in relapses, improved quality of life scores, lower symptom scores and less β-agonist use in those patients for whom an inhaled corticosteroid was prescribed. It is no wonder that understanding these differences and providing a balanced overview for this topic can be difficult.

Annals is to be commended for publishing this “negative trial” for a number of reasons. First, the bias whereby positive results are more favorably received and more commonly published has been widely discussed and can adversely influence decisionmaking.18 Second, the publication of negative trials provides a more balanced assessment of the effect of treatment, and assists trialists and systematic reviewers in preparing appropriate meta-analyses of therapeutic interventions. Finally, the publication of this trial in the face of a positive trial using similar methodology permits a more in-depth discussion of the reasons for variations in research results.

When 2 or more apparently similar trials have such marked disparity in results, what factors may be contributing to the observed differences? Differences between the populations included in the trials, the interventions under study, the measurement of outcomes, and the design of the trial may all account for the variation observed between trials. Finally, chance, or random variation, may also be responsible. In comparing these 2 studies, the studies appear to use similar designs (randomized, placebo controlled, double-blind studies), populations (acute asthma discharged from the ED), and outcomes (eg, relapse, functional outcomes, pulmonary functions). The main differences between the 2 studies appear to relate to the interventions.

In the study by Brenner et al,16 the inhaled corticosteroid that was used was delivered by a metered-dose inhaler using a spacer device versus the budesonide dry powder (Pulmicort Turbuhaler; Astra, Mississauga, Ontario, Canada) delivery system in the Canadian study. The change to dry powder and newer delivery systems was in large part because of the desire to improve delivery of inhaled agents to their site of action in the lung19; however, the spacer device does promote drug delivery and reduces metered-dose inhaler side effects.10 Thus, the comparison of drug delivery techniques between the 2 studies represents a minor difference, as long as compliance with the spacer in Brenner et al’s sample was 100%. Although the drugs used in each study were different (flunisolide versus budesonide), there are now some generally accepted conversion doses for this class of agents.2, 3 Although Brenner et al downplay this issue, we believe one major difference between the 2 studies is the dose of inhaled corticosteroid; Brenner et al’s dose would be classified as “moderate” (2 mg/d), whereas the Canadian study used a “high” dose (1.6 mg/d). There is some preliminary evidence to suggest that the dose of inhaled corticosteroids may be an important component of acute response20 and for more severe chronic asthma,2 but clearly additional research needs to be conducted to better understand this relationship. Finally, the compliance with treatment was lower in the current study than the Canadian study (56% versus >92%) and follow-up rates were lower (72% versus 97%). These methodologic differences may further help to explain the variation in results, because noncompliance contributes to the ineffectiveness of efficacious treatment in the clinical setting. Unfortunately, these potential explanations are merely hypothesis-generating exercises at this point, since there are limited publications in this topic area to confirm or refute these theories.

One other option for resolving the differences among study results is the possible contribution of a systematic review. In fact, a systematic review has been published that incorporates the results of the 3 known studies dealing with this topic.21 All authors of the known primary studies contributed to the Cochrane Collaboration review, directed by members of the Airway Review Group. In this review, the 2 studies described here,16, 17 and a multicenter study published as an abstract,22 have been pooled. The results failed to demonstrate a clear benefit to adding inhaled corticosteroids at discharge on relapse rates (odds ratio 0.68; 95% confidence interval 0.46 to 1.02 at 20 to 24 days) or pulmonary functions (percent predicted PEFR at 20 to 24 days 2.3% lower in the inhaled corticosteroid group; 95% confidence interval –5 to 9).

Fortunately, the systematic review is part of the Cochrane Collaboration, and additions to the literature will be incorporated as they become available.23 Because this is an active area of research, it is likely that new data from other centers and investigators will soon be able to help us come to a more robust decision with respect to this question. In addition, with the publication of more research, important subgroup analyses will be possible and these may further assist in explaining the heterogeneity we are currently witnessing.24

Although the role of inhaled corticosteroids as first-line agents in the treatment of chronic stable asthma is well accepted, the role of adding inhaled corticosteroids for health care providers treating acute asthma remains unclear. Treatment with a short course (5 to 7 days) of oral corticosteroids remains the safest and most proven therapy for the outpatient management of asthma exacerbations.25, 26 Ultimately, improvements in our understanding of the issue of inhaled corticosteroid use and recommendation clarity will emerge only with continued publication of high-quality evidence. It is encouraging that groups of emergency physicians are leading this charge.

At this point, the best we can conclude is that more aggressive suppression of airway inflammation using inhaled corticosteroids may further reduce the rate of relapses and improve quality of life in some patients. For patients already taking an inhaled corticosteroid at the time of an exacerbation, the minimum approach should be to encourage inhaled corticosteroid compliance and use while adding a short course of an oral corticosteroid. For patients who are not taking an inhaled corticosteroid at the time of an exacerbation, adding inhaled corticosteroid therapy remains an individual physician decision. The option of adding inhaled corticosteroid therapy should be discussed with patients, especially those who have exhibited frequent asthma control problems. Because many patients with severe acute asthma already meet criteria for treatment with an inhaled corticosteroid by current guidelines,14, 15 adding the agent may be a wise “preventive” measure. In mild or moderate acute asthma where there is a low risk of relapse, questions such as the equivalence of oral and inhaled corticosteroids and whether adding inhaled corticosteroid treatment to oral corticosteroid therapy is immediately beneficial or cost-effective require further study.21

Back to Article Outline

References 

  1. O’Byrne P. Asthma pathogenesis and allergen-induced late responses. J Allergy Clin Immunol. 1998;102:S85–S89
  2. Boulet L-P, Becker A, Bérubé D, et al.  Canadian asthma consensus report. Can Med Assoc J. 1999;161(11 Suppl):S1–S62
  3. National Asthma Education Program . Expert Panel Report II: Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: : National Institutes of Health; 1997;
  4. Mannino DM, Homa DM, Pertowski CA, et al.  Surveillance for asthma—United States, 1960-1995. MMWR Morb Mortal Wkly Rep. 1998;47(No. SS-1):1–28
  5. Krahn MD, Berka C, Langlois P, et al.  Direct and indirect costs of asthma in Canada. Can Med Assoc J. 1996;154:821–831
  6. Weiss KB, Gergen PJ, Hodgson TA. An economic evaluation of asthma in the United States. N Engl J Med. 1992;326:862–866
  7. Rowe BH, Oxman AD. Performance of an asthma quality of life questionnaire in an outpatient setting. Am Rev Respir Dis. 1993;148:675–681
  8. Stoodley RG, Aaron SD, Dales RE. The role of ipratropium bromide in the emergency management of acute asthma exacerbation: a metaanalysis of randomized clinical trials. Ann Emerg Med. 1999;34:8–18
  9. Plotnick LH, Ducharme FM. Should inhaled anticholinergics be added to β-agonists for treating acute childhood and adolescent asthma?: A systematic review. BMJ. 1998;317:971–977
  10. Cates C, Rowe BH. Comparison of holding chambers and nebulisers for beta-agonists in acute asthma (Cochrane Review). In: The Cochrane Library. Oxford: : Update Software; 2000; (issue 3)
  11. Rowe BH, Spooner C, Ducharme FM, et al.  Early emergency department treatment of acute asthma with systemic corticosteroids (Cochrane Review). In: The Cochrane Library. Oxford: : Update Software; 2000; (issue 3)
  12. Rowe BH, Bretzlaff JA, Bourdon C, et al.  Intravenous magnesium sulfate treatment for acute asthma in the emergency department (Cochrane Review). In: The Cochrane Library. Oxford: : Update Software; 2000; (issue 3)
  13. Edmonds ML, Camargo CA, Pollack CV, et al.  Early use of inhaled corticosteroids in the emergency department treatment of acute asthma (Cochrane Review). In: The Cochrane Library. Oxford: : Update Software; 2000; (issue 3)
  14. Rowe BH, Bota GW, Pollack CV, et al.  Management of acute asthma among adults presenting to Canadian versus US emergency departments. [abstract] Ann Emerg Med. 1998;32:S2–S3
  15. Camargo CA, Woodruff PG. Management of acute asthma in US emergency departments: the Multicenter Asthma Research Collaboration. [abstract] Am J Respir Crit Care. 1998;157:A623
  16. Brenner BE, Chavda KK, Camargo CA. Randomized trial of inhaled flunisolide versus placebo among asthmatic patients discharged from the emergency department. Ann Emerg Med. 2000;36:417–426
  17. Rowe BH, Bota GW, Fabris L, et al.  Inhaled budesonide in addition to oral corticosteroids to prevent relapse following discharge from the emergency department: a randomized controlled trial. JAMA. 1999;281:2119–2126
  18. Misakian AL, Bero LA. Publication bias and research on passive smoking: comparison of published and unpublished studies. JAMA. 1998;280:250–253
  19. Simon RA. Update of inhaled corticosteroids: safety, compliance, and new delivery systems. Allergy Asthma Proc. 1999;20:161–165
  20. Rowe BH, Bota GW, Fabris L, et al.  Asthma quality of life following discharge from the emergency department: a double-blind, randomized trial of high vs low dose inhaled corticosteroids. [abstract] Acad Emerg Med. 1999;6:502
  21. Edmonds ML, Camargo CA, Brenner B, et al.  Inhaled steroids in acute asthma following emergency department discharge (Cochrane Review). In: The Cochrane Library. Oxford: : Update Software; 2000; (issue 3)
  22. Camargo CA, on behalf of the MARC-4 Investigators . Randomized trial of medium-dose fluticasone vs. placebo after an emergency department visit for acute asthma. [abstract] J Allergy Clin Immunol. 2000;105(1 Pt 2):S262
  23. Rowe BH, Alderson P. The Cochrane Collaboration: a resource for clinical problem solving in emergency medicine. Ann Emerg Med. 1999;34:86–90
  24. Oxman AD, Guyatt GH. A consumer’s guide to subgroup analyses. Ann Intern Med. 1992;116:78–84
  25. Rowe BH, Keller JL, Oxman AD. Steroid use in the emergency department treatment of asthma exacerbations: a meta-analysis. Am J Emerg Med. 1992;10:301–310
  26. Rowe BH, Spooner CH, Ducharme FM, et al.  Corticosteroids for preventing relapses following acute exacerbations of asthma (Cochrane Review). In: The Cochrane Library. Oxford: : Update Software; 2000; (issue 3)

☆ Reprints not available from the authors.

☆☆ Address for correspondence: Brian H. Rowe, MD, MSc, Division of Emergency Medicine, University of Alberta Faculty of Medicine and Dentistry, 1G1.63 Walter Mackenzie Centre, 8440-112th Street, Edmonton, Alberta, Canada T6G 2B7; 780-407-7047, fax 780-407-3314; E-mail brian.rowe@ualberta.ca .

PII: S0196-0644(00)06794-9

doi:10.1067/mem.2000.111426

Refers to article:

  • Randomized trial of inhaled flunisolide versus placebo among asthmatic patients discharged from the emergency department

    Barry E. Brenner, Kamal K. Chavda, Carlos A. Camargo
    Annals of Emergency Medicine November 2000 (Vol. 36, Issue 5, Pages 417-426)

Annals of Emergency Medicine
Volume 36, Issue 5 , Pages 477-480, November 2000

Article Tools