Q J Med 2000; 93: 761-765
© 2000 Association of Physicians
Commentary papers |
Should aminophylline be abandoned in the treatment of acute asthma in adults?
From the Respiratory Medicine Unit, Western General Hospital, Edinburgh, UK
Summary
Intravenous aminophylline is widely used for the treatment of acute asthma and anecdotes about its apparent effectiveness abound. Early studies demonstrated that aminophylline is an inefficient bronchodilator compared with adrenergic agonists given by injection or inhalation. This paper presents the results of a review of randomized controlled trials examining the effect of adding aminophylline to standard modern therapy with a nebulized ß2 agonist and systemic corticosteroids in acute asthma in adults. Six of the seven trials, comprising 343 patients, failed to demonstrate any beneficial effect of aminophylline. Furthermore, minor toxicity was common. There is presently no evidence to support the use of aminophylline in addition to standard therapy for acute asthma in adults.
Introduction
One of the earliest reports of the efficacy of methylxanthines in asthma was published in the Edinburgh Medical Journal in 1859, where Henry Hyde Salter, himself an asthmatic, described his experience that ‘one of the commonest and best-reputed remedies of asthma... is strong coffee’.1,2 It was not until the 1920s that methylxanthines were found to relax bronchial smooth muscle in vitro.3 Theophylline and its water-soluble derivative aminophylline have since been widely used in the treatment of asthma. Of the methylxanthines, theophylline is the most potent bronchodilator, and it may also exhibit anti-inflammatory and immnuomodulatory actions,4 improve respiratory muscle function, hasten mucociliary clearance, and act centrally to stimulate respiration.5 In the 1960s and 1970s, theophylline monotherapy was a popular option for the treatment of chronic stable asthma, largely because of the disadvantages of alternative therapies.6 The potential toxic effects of theophylline were soon recognized, and with emphasis on stable serum levels serious toxicity became rare. In chronic asthma, there is evidence from several clinical studies that addition of regular oral theophylline confers benefit in patients who are already treated with inhaled corticosteroids.5 However, the efficacy of theophylline in chronic stable disease cannot be extrapolated to acute exacerbations of asthma. Indeed, the advent of selective ß2 agonists led to a decline in aminophylline use, since studies in acute asthma repeatedly showed that ß2 agonists, given by either injection or inhalation, were clearly superior to intravenous aminophylline.6 Despite the theoretical pharmacological benefits of aminophylline in acute asthma, there is a paucity of clinical evidence to support its use in patients who already receive standard modern therapy comprising an inhaled nebulized ß2 agonist and systemic corticosteroids. Disaffection with aminophylline use for acute exacerbations of asthma was compounded in 1988 with the publication of a meta-analysis of 13 controlled trials.7 Littenberg concluded from this study that ‘despite widespread practice, available trials do not provide adequate evidence to support or reject the use of aminophylline in the treatment of severe, acute asthma.’ However, it should be noted that ten of the 13 trials included in the meta-analysis compared the then standard therapy alone (often an injected adrenergic agonist) with aminophylline alone. Although aminophylline was found to be significantly inferior to standard therapy, these studies are not pertinent to the modern therapy of acute asthma where standard pharmacological therapy consists of an inhaled nebulized ß2 agonist and systemic corticosteroids.8 Only three of the 13 studies in Littenberg's meta-analysis actually compared the use of an inhaled ß2 agonist and/or systemic corticosteroids with or without intravenous aminophylline in adults, and no additional effect of aminophylline could be demonstrated. The aim of the present paper was to conduct a review of all subsequent randomized controlled trials of the effect of adding intravenous aminophylline to standard therapy in acute asthma in adults.
Results
A Medline search of the published literature since Littenberg's meta-analysis revealed seven randomized placebo-controlled trials of intravenous aminophylline given in addition to standard therapy for acute asthma in adults (Table 1
). Six of the seven trials were double-blind. Similar treatment regimes were used in all of the studies. Standard therapy universally comprised supplemental oxygen, an inhaled ß2 agonist, and systemic corticosteroids. Repeated doses of salbutamol were delivered by a nebulizer, except in one trial where an aerosol inhaler and a large volume spacer were used. In one study nebulized ipratropium bromide was also administered. Steroids were given in the form of prednisolone tablets, or as intravenous hydrocortisone or methylprednisolone. Loading doses of aminophylline (or placebo) were administered intravenously, followed by infusions which were adjusted with the aid of frequent blood monitoring to achieve serum concentrations in the range 55–110 µmol/l (10–20 mg/l).
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Self and colleagues9 looked at 44 adults hospitalized with acute asthma (mean FEV1 approximately 40% predicted) who had failed to respond to standard therapy after 4 h in the emergency department. No difference in spirometric measurements between the two groups was observed during 32 h follow-up. FEV1 improved from 41.5±2.9% to 70.4±2.9% of predicted in the placebo group and from 34.7±2.3% to 63.7±2.8% of predicted in the aminophylline group. There were also no differences in subjective patient rating or duration of hospitalisation between the two groups. Subgroup analysis looking at 18 patients with more severe disease (FEV1<35% predicted) also failed to demonstrate any benefit of aminophylline. This study had 80% power to detect a 16% difference in FEV1 at the 5% significance level.9
In an emergency room setting, Wrenn and colleagues studied 133 adults with acute asthma or chronic obstructive pulmonary disease (COPD), of whom 77 were asthmatic. Patients who had received a theophylline preparation within the preceding 24 h were excluded. Follow-up was short, but at 2 h there was no difference in FEV1, patient satisfaction, or physician assessment between the placebo and aminophylline groups (mean serum level 54 µmol/l). Mean improvement in FEV1 was 0.5 l in the placebo group and 0.4 l in the aminophylline group. Surprisingly, only 6% of asthmatics in the aminophylline group were admitted to hospital compared with 19% of the placebo group.10 It should be noted however that pre-treatment lung function was better in the aminophylline group (FEV1 1.5 l compared with 1.0 l in the placebo group).
In a study of 59 patients (mean PEFR approximately 35% predicted) who were judged unfit for discharge home at 30 min following standard therapy along with nebulized ipratropium bromide, Coleridge and colleagues found no difference in PEFR or duration of hospital stay during a 12–48 h follow-up period.11 This study had 80% power to detect a 25% difference in PEFR.
Huang and colleagues examined the effect of adding intravenous aminophylline in 21 patients with acute asthma (mean FEV1 approximately 45% predicted) who had failed to respond to initial therapy with a nebulized ß2 agonist (three doses) and parenteral corticosteroids. The aminophylline-treated group exhibited an early improvement in FEV1 at three hours (29±23% vs. 10±10% improvement). The rate of increase of FEV1 remained constant thereafter during follow-up, resulting in sustained improvement in the aminophylline group at 48 h (FEV1 75.4±19.1% predicted vs. 57.9±14.5%). The aminophylline group also required significantly fewer nebulizations and a lower total dose of nebulized ß2 agonist (34±16 mg vs. 70±34 mg salbutamol). There were no differences in asthma scores, but the aminophylline group had a higher incidence of side effects.12
Murphy and colleagues also examined patients who failed to respond to initial therapy with a nebulized ß2 agonist and systemic corticosteroids (PEFR<40% predicted). Importantly, this study of 44 patients included only those subjects who had a low serum theophylline level on admission (<28 µmol/l). Despite mean serum theophylline levels of 74 µmol/l in the aminophylline group, follow-up to 6 h failed to identify any difference in PEFR between the two groups (
PEFR 233±82 l/min in the aminophylline group vs. 218±72 in the placebo group).13 The authors calculated that this study had 90% power to detect a 25% difference in PEFR.
In a study of 94 acute asthmatic attacks in adults (mean FEV1 27% predicted) Rodrigo and colleagues found that intravenous aminophylline conferred no improvement in FEV1 (FEV1 0.68±0.45 l in the aminophylline group vs. 0.75±0.41 l in the placebo group). In this study, salbutamol was delivered by an aerosol inhaler and a large volume spacer device. There were no differences in ß2 agonist requirement or hospital admission rate from the emergency department. Subgroup analysis was performed to look at those patients with severe disease (FEV1<30% predicted), but also failed to show any effect of aminophylline.14
An unblinded Malaysian study of 25 adults with acute asthma again found no demonstrable effect of intravenous aminophylline over a 48 h follow-up period, with almost identical improvements in PEFR in the two treatment groups.15
Discussion
A significant benefit of aminophylline therapy was found in only one of the seven studies, and this was also the smallest, comprising only 21 of the total of 364 patients. Huang et al. found an early sustained increase in spirometric measurements following intravenous infusion of aminophylline in patients who had initially failed to respond to standard therapy.12 However, this study was very small, and the result was not confirmed by three larger studies which also examined patients who had initially failed to respond to standard therapy.9,11,13 Six studies, comprising 343 patients, failed to demonstrate any beneficial effect of intravenous aminophylline.
There are several possible explanations for the apparent lack of efficacy of aminophylline in this series of controlled trials. Some of the studies described here were performed in an emergency room setting, and as a result follow-up was performed over a relatively short period. Two hours may be insufficient time to reveal a positive effect of intravenous aminophylline. An apparent effect of aminophylline may be masked because some patients who were subsequently randomized to the placebo groups were already taking an oral theophylline preparation with a therapeutic blood level on admission. One uncontrolled study found that the change in PEFR following aminophylline infusion was negatively correlated with the plasma theophylline level before treatment in adult patients who were already taking an oral theophylline preparation.16 However, there was still no demonstrable effect of aminophylline in the study of 44 patients who had a low serum theophylline level on admission.13
All of the studies were small and of insufficient power to detect a small but possibly clinically important improvement in outcome. The three papers which included power calculations suggested that a 16–25% improvement in spirometric measurements could be detected with 80–90% power at a significance level of 0.05.9,11,13 However, the six negative trials reported almost identical improvements in spirometry in the placebo and treatment groups, with no evidence of any trend in favour of aminophylline.
Despite these considerations, one interpretation of the published data is that aminophylline is ineffective in acute asthma in adults when added to standard therapy. Moreover, toxicity in the form of gastrointestinal symptoms is common and contributes to significant morbidity in these patients. Overall, nausea was reported by 22% of patients who received aminophylline compared with 6% who received placebo in those studies that recorded toxicity.
Aminophylline is also widely used for the treatment of acute exacerbations of chronic obstructive pulmonary disease (COPD) despite a lack of evidence to support this practice. For example, in a recent multicentre randomized trial of nasal ventilation for acute respiratory failure in COPD, 50 of the 85 patients (59%) received intravenous aminophylline.17 In addition to the trial by Wrenn and colleagues in which 56 of the 133 patients had COPD (Table 1
),10 there has been published only a single small randomized controlled trial of 20 patients with COPD, in whom addition of intravenous aminophylline to nebulized ß2 agonists and systemic corticosteroids had no significant effect on any outcome measure.18
The conclusion from this review of published randomized controlled trials is no different from that of Littenberg following his meta-analysis over 10 years ago. There is no evidence to support the use of intravenous aminophylline in acute severe asthma in adults. It remains possible that aminophylline confers a small but clinically significant benefit when added to standard therapy, but minor toxicity is common and the benefit-risk ratio is unknown. Large well-conducted clinical trials are required to establish once and for all whether aminophylline has any role to play in the treatment of acute asthma in adults.
Notes
Address correspondence to Dr S.P. Hart, Respiratory Medicine Unit, Ward 30, Edinburgh Royal Infirmary, Lauriston Place, Edinburgh. whart{at}globalnet.co.uk 
References
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