|Home | About | Journals | Submit | Contact Us | Français|
The objective of this ‘umbrella’ review is to synthesize the evidence and provide clinicians a single report which summarizes the state of knowledge regarding the use of corticosteroids in adults with acute asthma. Systematic reviews in the Cochrane Library and additional clinical trials published in English from 1966 to 2007 in MEDLINE, EMBASE, CINAHL, and Cochrane CENTRAL and references from bibliographies of pertinent articles were reviewed. Results indicate that the evidence base is frequently limited to small, single-center studies. Findings suggest that therapy with systemic corticosteroids accelerates resolution of acute asthma and reduces the risk of relapse. There is no evidence that corticosteroid doses higher than standard doses (prednisone 50–100 mg equivalent) are beneficial. Oral and intravenous corticosteroids, as well as intramuscular and oral corticosteroid regimens appear to be similarly effective. A non-tapered 5–10 day course of corticosteroid therapy appears to be sufficient for most discharged patients. Combinations of oral and inhaled corticosteroids on emergency department/hospital discharge may minimize the risk of relapse.
Asthma is a common respiratory disorder characterized by chronic airway inflammation, airflow obstruction, and episodic symptoms such as wheeze, chest tightness, dyspnea and cough.1 Despite major advances in our understanding of the pathogenesis of asthma, episodes of acute asthma requiring emergency department visits and hospitalizations are common. In the United States alone, for example, there are about 2 million emergency department visits and 500,000 hospitalizations for acute asthma each year.2
Acute asthma is most often precipitated by respiratory viral infections and/or environmental exposures to irritants (e.g., air pollution) and/or allergens.3–7 These triggers dramatically augment airway inflammation, airflow obstruction, and respiratory symptoms. Over the past 50 years, there have been numerous randomized clinical trials that have established corticosteroids as the cornerstone of anti-inflammatory therapy in adults presenting to the emergency department or hospitalized for acute asthma.1,8 Corticosteroids reduce the amplification of the inflammatory cascade by altering transcriptional and post-transcriptional regulation, and may also have non-genomic actions.9
Data from randomized clinical trials have been examined in a number of high quality systematic reviews conducted by members of the Cochrane Airways Group (CAG) and published in the Cochrane Library. Such reviews, however, have each focused on specific aspects of corticosteroid use (e.g., dose).10–14 Treatment decisions by clinicians, however, include not only the corticosteroid dose, but other aspects of corticosteroid use, including the route of therapy (inhaled vs. oral vs. intramuscular vs. intravenous), duration of therapy, and use of fixed-dose vs. tapering regimens. Thus, clinicians would need to read multiple reviews to have sufficient information to provide evidence-based care in this population.
The objectives of the current “umbrella” review are to synthesize the findings from multiple reviews and additional randomized clinical trials that have been published since15–28 into a single document for easy use by clinicians. More specifically, this report will address the following clinically relevant questions in patients presenting to the emergency department or hospitalized for acute asthma:
For each question, we conducted a literature search for systematic reviews performed by CAG and searched for additional randomized clinical trials in the following electronic literature databases: MEDLINE, EMBASE, CINAHL, and Cochrane CENTRAL. Additional articles were identified by hand-searching 20 respiratory journals, references identified in the retrieved articles, and queries of content experts. A detailed description of the search methodology is provided elsewhere.29 We limited the search to English-language articles in adults published from 1966 to 2007. The level of evidence was graded based on the following criteria:30
|Level of evidence||Explanation|
|A||Well-designed randomized clinical trials in relevant populations|
|B||Randomized clinical trials with minor limitations or overwhelmingly consistent evidence from observational studies|
|C||Observational studies using case-control and cohort designs|
|D||Expert opinion, case reports, or reasoning (e.g., based on data from similar populations)|
|X||Exceptional situations where validating studies cannot be performed and there is a clear preponderance of benefit or harm|
Based on the level of evidence, we graded recommendations by consensus as follows:30
|Recommendation||Level of Evidence|
|Strong recommendation (S)||A, B, or X|
|Recommendation (R)||B, C, or X|
|Option (O)||A, B, C, or D|
|No recommendation (NR)||D|
A recommendation grade “S” means, that on the basis of the review, we believe that the benefits of the recommended approach clearly exceed the harms and that the quality of the evidence supporting this approach is either excellent or impossible to obtain. Clinicians should follow such guidance unless a compelling rationale for choosing an alternative approach is present. A recommendation grade “R” means that we believe that the benefits exceed the harms, but the quality of the evidence supporting this recommendation is not as strong. Clinicians should generally follow this guidance, but could adopt an alternate approach based on additional clinical information and patient preferences. A recommendation grade “O” means either that the quality of the evidence is inadequate or that well-designed studies have failed to demonstrate that one approach is superior to the alternate approach. Clinicians should adopt a flexible approach and choose the option that incorporates appropriate clinical factors, including patient preference and convenience. A recommendation grade “NR” is made when there is inadequate information about the balance between benefits and harms of various approaches. Clinician decision-making is not constrained based on evidence alone; patient preference should have a substantial role in the decision-making.
Two authors independently provided evidence-grading assessments on the seven clinical questions posed in this review. Disagreements were resolved by adjudication by a third author.
Nine placebo-controlled randomized trials enrolled a total of about 500 patients with acute asthma;15–17,31–36 481 were recruited in the emergency department, and 52 were recruited from the inpatient (hospitalized) setting. These studies largely focused on short-term outcomes (within 6 to 12 hours) after a single dose of systemic corticosteroids vs. placebo; a notable exception is one study that examined 14-day outcomes after a 10-day course of systemic corticosteroids vs. placebo.16 A systematic review of six of these trials31–33,34–36 reported a trend toward reduced hospital admission rates in adults presenting to the emergency department who were treated with systemic corticosteroids, usually within 90 minutes of emergency department arrival (OR: 0.58; 95% CI, 0.32 to 1.07).10 The effect of corticosteroids on pulmonary function was variable in the short-term, mainly due to insufficient reporting of results in the individual trials. Side effect profiles were similar between all corticosteroid treatment routes and placebo, suggesting that early treatment with corticosteroids is safe.
In addition, there have been 2 placebo-controlled randomized clinical trials that evaluated the benefit of systemic (oral16 and intravenous17) corticosteroids in a total of 52 adults hospitalized for acute asthma. Despite the small number of participants, results indicate that systemic corticosteroids significantly accelerated the resolution of acute asthma (symptoms, examination, and lung function) in this population. For example, there is a significantly greater improvement in airflow obstruction (forced expired volume in 1 second (FEV1)) with corticosteroid therapy compared to placebo (0.43L vs. 0.0L, p<0.02).17
Taken together, these studies in emergency department and hospitalized patients provide Level B evidence that systemic corticosteroids provide clinically meaningful benefits in patients presenting with acute asthma. The vast majority of studies, however, were of small size (n=38–98 patients per study), and only two were multi-center studies.15,16
Direct comparisons of different doses of systemic corticosteroids were not identified in emergency department patients. In a systematic review of hospitalized patients, corticosteroid dose regimens were classified as very high dose (> 450 mg/day prednisone equivalent), high dose (101 to 450 mg/day prednisone equivalent) or standard dose (≤ 100 mg/day prednisone equivalent) using standard conversions.11 Of nine randomized clinical trials in adults presenting to the emergency department and subsequently admitted to the hospital, six randomized clinical trials (total N = 272)18,37–41 provided sufficient data to contribute to the pooled analysis. Overall, there were no clinically or statistically significant differences in FEV1 % predicted between the 3 groups after 24, 48 or 72 hours, despite the approximate 55-fold range of corticosteroid doses used. At 48 hours, the weighted mean difference (WMD) in FEV1 was −3.3% predicted (95% CI, −12.4 to 5.8%) for the standard vs. high dose comparison, −1.9% predicted (95% CI, −8.1 to 4.3%) for the high vs. very high dose comparison and +0.5% predicted (95% CI, −7.8 to 8.8%) for the standard vs. very high dose comparison. Also there were no clinically or statistically significant differences in FEV1 at 24 hours in patients treated with 50 mg/d prednisone equivalent vs. very high dose; the pooled WMD in FEV1 was +7.2% predicted (95% CI, −2.3 to +16.7%), favoring patients treated with the standard dose.37,38
While patients with respiratory failure requiring mechanical ventilation were excluded from these randomized clinical trials, analyses restricted to patients with severe episodes (an initial post-bronchodilator FEV1<50% predicted) also failed to identify significant benefits of very high doses compared to standard doses in this subset (WMD in FEV1 at 48 hours low vs. high +2.3% predicted (95% CI, −6.6 to 11.2%)).11 In addition, there were no significant differences in side effects or rates of respiratory failure among the varying doses of corticosteroids. While these studies were not designed to ‘prove’ equivalence (i.e., not equivalency trials), this body of evidence (Hospital, Level B; Emergency department, Level D, extrapolating from studies in hospitalized patients) in patients without respiratory failure does not favor using higher than standard doses of corticosteroids.
Direct comparisons of IV and oral corticosteroid agents were not identified in emergency department patients. In a randomized clinical trial of 70 adults hospitalized for acute asthma,18 investigators failed to identify clinically meaningful or statistically significant differences in FEV1 or length of hospital stay between patients treated with oral corticosteroids (200 mg/day or 400 mg/day prednisone equivalent) or IV corticosteroids (625 mg/day or 1,250 mg/day prednisone equivalent) regimens, despite substantially higher (1.5 to 6-fold higher) daily corticosteroid doses in the IV corticosteroid groups. There were also no significant differences in the rate of side effects. Thus, the available evidence (Level B in hospitalized patients; Level D in emergency department patients) does not support the superiority of IV over oral corticosteroid therapy.
No emergency department-based studies exist comparing different durations of corticosteroid therapy following discharge in adults were identified. Two small randomized clinical trials examined the benefit of different total durations of systemic corticosteroid therapy in 64 adults hospitalized for acute asthma (including therapy received during hospitalization: 5 vs. 10 days,19 and 10 vs. 17 days).20 These studies used 40 mg/day19 or 0.5 mg/kg/day20 prednisone equivalent doses after hospital discharge and all patients were discharged on daily inhaled corticosteroid therapy. Patients on chronic oral corticosteroids or requiring mechanical ventilation for near-fatal asthma were excluded from both studies. Lung function (PEFR) and relapse rates were similar in the treatment groups; the studies failed to identify any benefit of extending systemic corticosteroid therapy beyond a total of 5 to 10 days. Once again, while these findings cannot be interpreted as proving equivalence, the weight of evidence (Level B in hospitalized patients; Level D in emergency department patients) does not favor any particular duration beyond 5 days in adults.
Tapering regimens of corticosteroids, in which the dose of corticosteroids is gradually reduced, offer the theoretical advantage of minimizing the risks of worsening airway inflammation, suppressed hypothalamic-pituitary-adrenal axis, and relapse when corticosteroids are discontinued compared to shorter fixed-dose regimens. However, slowly tapering regimens tend to be longer and more complicated for patients than fixed-dose regimens, which may increase the risk of corticosteroid-related adverse effects and non-adherence to therapy, respectively.42
Two randomized clinical trials compared an eight-day fixed-dose course of oral corticosteroids (40 mg/d prednisone equivalent) to an eight-day taper of oral corticosteroids in patients discharged home from the emergency department.21,22 The two trials were small (total N = 41 participants) and excluded patients using inhaled or systemic corticosteroids within the previous two weeks. There were no significant differences between groups in FEV1% predicted, rates of relapse at day 12 or 21 after discharge, or suppression of the hypothalamic-pituitary-adrenal axis.
Three randomized clinical trials in 113 hospitalized adults evaluated the benefit of adding an oral corticosteroid taper after completing a six to fourteen day course of systemic corticosteroids.23–25 All patients were discharged home on inhaled corticosteroids and patients requiring mechanical ventilation were excluded from two23,24 of the three studies. Follow-up four weeks24,24 and 12 weeks25 after discharge failed to detect differences in lung function, relapse rates, symptoms, or rates of adrenal suppression. Thus, the evidence from emergency department and hospitalized populations does not demonstrate a benefit from using oral corticosteroid tapers compared to a fixed-dose regimen.
Non-adherence to corticosteroid therapy (inhaled or systemic) is surprisingly common (about 50%) in patients discharged from the emergency department or hospital following initial therapy for acute asthma, and is one of the main factors associated with relapse.43–45 Intramuscular formulations can ensure that patients continue to receive corticosteroids following discharge from the emergency department or hospital. Five randomized clinical trials in adults have examined the relative benefits of intramuscular corticosteroids compared to oral corticosteroids for the outpatient treatment of acute asthma following discharge from the emergency department.13,26 These randomized clinical trials (575 adults) compared oral vs. intramuscular corticosteroids after emergency department discharge in patients with acute asthma.26–28,46,47 No similar studies have been conducted in patients discharged after a hospital stay.
A single intramuscular corticosteroid dose was compared to fixed-dose corticosteroid regimens in two studies27,28 and to an oral corticosteroid regimen with gradually decreasing doses (taper) in three studies.26,46,47 Overall, there were no significant differences in relapse rates between intramuscular and oral corticosteroids at 10 days (RR = 0.73; 95% CI, 0.49 to 1.09) or at 21 days (RR = 1.03; 95% CI, 0.73 to 1.44).26 Some studies, however, reported a higher rate of complications at the injection site (e.g., pain, bruising) in patients who received intramuscular corticosteroids. For example, in the study by Lahn et al.,26 the mean pain at injection site (on a scale of 10 (higher scores indicate more pain): 3.3 vs. 1.9, p<0.05) and rates of bruising at the injection site (8% vs. 0%, p<0.05) were significantly higher in the intramuscular compared to the oral corticosteroid group. Thus, Level B evidence in emergency department patients (and Level D evidence from hospitalized patients) does not support the superiority of depot intramuscular corticosteroids over a multi-dose oral corticosteroid regimen; however, there is evidence of more injection-site adverse effects in patients receiving intramuscular corticosteroids.
Adding daily inhaled corticosteroids to a short course of systemic corticosteroids offers patients the potential benefit of further suppressing airway inflammation after completing a course of systemic corticosteroids, during the resolution phase of acute asthma. It also provides a ‘teachable moment’ in which appropriate inhaler technique and adherence to treatment for chronic asthma (e.g., inhaled corticosteroids) to prevent future episodes of acute asthma can be reviewed and reinforced. Three randomized clinical trials have evaluated the utility of combining inhaled and oral corticosteroids compared to oral corticosteroids alone following emergency department discharge; 48–50 two have been published as full-length manuscripts.48,49 No randomized clinical trials in hospitalized adults were identified.
Pooled results from these emergency department-based studies, representing a total N = 909 adults in the three trials, indicate a non-significant trend towards fewer relapses after discharge in the group treated with combination corticosteroid therapy (OR: 0.68; 95% CI, 0.46 to 1.02)14 with side effects of hoarseness and sore throat being significantly higher in the inhaled corticosteroid group. Of note, observational studies using administrative data of ED51 and hospitalized52 patients suggest that inhaled corticosteroid therapy significantly reduces the risk of relapse after discharge. Moreover, patients with acute asthma are more symptomatic than patients with moderate or severe forms of chronic asthma, two groups for which national guidelines already recommend inhaled corticosteroid therapy.1 Thus, Level B evidence (emergency department patients) and Level C evidence (hospitalized patients), favors the use of combination of inhaled and oral corticosteroids.
The current evidence is based largely on a small number of relatively under-powered, single-center randomized clinical trials which excluded patients with respiratory failure requiring mechanical ventilation (Level B–D Evidence). Until more definitive evidence from larger-scale, multi-center randomized clinical trials is available, we make the following recommendations:
Large-scale, multi-center trials of corticosteroid use are needed to provide a more definitive evidence base for the management of acute asthma; studies in patients with respiratory failure (e.g., those who undergo mechanical ventilation) are urgently needed. In addition, there is emerging evidence that leukotriene modifiers (e.g., montelukast, zafirlukast), when initiated in the emergency department during acute asthma, may rapidly improve lung function and reduce the risk of relapse after emergency department discharge.53,54 A recent randomized clinical trial failed to show a benefit for improving relapse rates when LABAs were added to inhaled and systemic corticosteroids (vs. inhaled and systemic corticosteroids alone) at the time of discharge from the emergency department (10.1% vs. 14.7%, p=0.42).55 Thus, further large, multi-center clinical trials are needed to clarify the incremental benefit (and risk) of combining corticosteroids with other agents (e.g., inhaled/oral corticosteroids with long-acting bronchodilators, inhaled/oral corticosteroids with leukotriene modifiers) during acute asthma.
Limited evidence exists in chronic asthma that treatment strategies that incorporate decisions to suppress eosinophilic airway inflammation (measured directly by induced sputum eosinophils, or indirectly by exhaled nitric oxide) provide better control of asthma and fewer episodes of acute asthma compared to treatment decisions based on assessment of symptoms and lung function alone.56, 57 While potentially appealing, given the cost and availability of these tests, further research is needed to evaluate the clinical benefit of incorporating biomarkers of eosinophilic airway inflammation in the acute care setting.58,59
There is increasing recognition that neutrophils, which are resistant to the effects of corticosteroids, also contribute to the pathogenesis of airway inflammation in both chronic asthma and during acute asthma, particularly following respiratory viral infections.60–63 The presence of mixed eosinophil-neutrophil or neutrophil-predominant airway inflammation may help explain why some patients with acute asthma develop complications (i.e., respiratory failure or relapse) despite aggressive anti-inflammatory therapy with corticosteroids or the results of a recent study which suggested that macrolides (which may reduce neutrophilic airway inflammation) may improve respiratory symptom control in patients with acute asthma.64,65 Further research is needed to develop practical approaches to identify phenotypes of airway inflammation in the acute setting, as well as to develop and evaluate the safety and efficacy of novel therapies (e.g., anti-virals)66 directed at suppressing the neutrophilic component of airway inflammation.
A randomized clinical trial conducted in adults hospitalized for acute asthma indicates that an inpatient asthma education program (compared to usual care) reduces the risk of relapse and lowers costs.66 Additional, larger, studies are needed to confirm these findings to evaluate the effectiveness and cost-effectiveness of non-pharmacological components of optimizing asthma care in the acute setting, such as strategies to improve asthma self-management and patient-physician communication, and avoidance of environmental triggers.
Despite the existence of many international and national asthma guidelines, relapse after emergency department and hospital discharge occur regularly. A greater emphasis on an evidence-based approach to the management of acute asthma and strategies to implement this knowledge are clearly needed. The cornerstone of acute and chronic asthma therapy is the use of corticosteroids to suppress airway inflammation. In this umbrella review, we have summarized the substantial body of evidence supporting the use of systemic and inhaled corticosteroids during acute asthma in emergency department and hospitalized adults. Physician attention to the use of these agents in appropriate patients, in addition to bronchodilators, and other aspects of guideline consistent care (regular follow-up with a primary care provider, avoidance of environmental triggers, use of an action plan)1, will permit patients to more rapidly regain asthma control and return to their regular activities. Additional research to improve the evidence base and to identify novel therapies to improve outcomes of this patient population is also needed.
Funding sources: Parker B. Francis Fellowship Award and the National Institutes of Health (HL67850); NHMRC Australia and an NHMRC Practitioner Fellowship award (PG); 21st Century Research Chair Program from the Government of Canada (BHR).
Conflict of interest: Dr. Rowe has received research support and speakers fees from GlaxoSmithKline (once: $1000) and AstraZeneca (multiple: ~$3000/year) in the past 3 years; he is not a paid consultant or employee of either.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.