Abstract
Background
Most international guidelines currently recommend methylxanthines (e.g., theophylline, aminophylline) for severe exacerbations of chronic obstructive pulmonary disease (COPD), yet clinical trials underlying this recommendation have been small and underpowered.
Objectives
To determine the benefit of methylxanthines compared to placebo for COPD exacerbations.
Search methods
Randomised controlled trials (RCTs) were identified from the Cochrane Airways Review Group COPD Register, a compilation of systematic searches of CINAHL, EMBASE, MEDLINE and CENTRAL and hand searching of 20 respiratory journals. Primary authors and content experts were contacted to identify eligible studies. Bibliographies from included studies and reviews were searched. Searches are current to March 2005.
Selection criteria
Included studies were limited to RCTs of patients presenting with acute COPD exacerbations, treated with methylxanthines (oral or intravenous) or placebo plus standard care. Two reviewers independently selected articles for inclusion and assessed methodological quality.
Data collection and analysis
Two reviewers independently extracted data. Missing data were obtained from authors or calculated from other data presented in the paper. The data were analysed using the Cochrane Review Manager 4.1. Studies were pooled to yield weighted mean differences (WMD), standardised mean difference (SMD) or odds ratios (OR) and reported using 95% confidence intervals (95%CI).
Main results
From 29 identified references, 4 RCTs met inclusion criteria (169 patients). Mean change in forced expiratory volume in one second (FEV1) at 2 hours was similar in methylxanthine and placebo groups but transiently increased with methylxanthines at 3 days (WMD: 101 ml; 95% CI: 26 to 177). Data on clinical outcomes were sparse. Trends toward improvements in hospitalisation and length‐of‐stay were offset by a trend toward more relapses at one week. Changes in symptom scores were not significant. Methylxanthines caused more nausea and vomiting than placebo (OR: 4.6; 95% CI: 1.7 to 12.6) and trended toward more frequent tremor, palpitations, and arrhythmias.
Authors' conclusions
Given current evidence, methylxanthines should not be used for COPD exacerbations. Possible beneficial effects in lung function and clinical endpoints were modest and inconsistent, whereas adverse effects were significantly increased. More selective agents, tested in larger randomised trials, are necessary if methylxanthines are to have any role in the treatment of COPD exacerbations.
Plain language summary
Methylxanthines for exacerbations of chronic obstructive pulmonary disease
Methylxanthine drugs such as aminophylline and theophylline are recommended for use in patients who have acute exacerbations (episodes) of chronic obstructive pulmonary disease, particularly for patients unresponsive to standard therapies. This review identified four studies that compared these drugs with placebo. Over the first 2 hours of treatment there was no evidence that patients improved in terms of lung function, although a possible late benefit was detected. The studies do not give a clear indication of whether there was benefit in terms of reduced symptoms or hospital admissions, but side effects were found to be more common with methylxanthines. We conclude that, given current evidence, methylxanthines should not be used for acute exacerbations of chronic obstructive pulmonary disease.
Background
Methylxanthines produce a number of effects that may be beneficial to patients with stable COPD (Ram‐Rev 2002), including bronchodilation, immuno‐modulation, and broncho‐protection (Peleman 1998). They may also influence the course of COPD exacerbations via actions to decrease diaphragmatic muscle fatigue, increase mucociliary clearance, block centrally mediated hypoventilation, and decrease capillary leak (Weinberger 1996); however, the molecular mechanisms of action of methylxanthines are incompletely understood.
Some studies have suggested the clinical impact of methylxanthines to be larger than their modest bronchodilator effects (Wrenn 1991). Randomised controlled trials of methylxanthines for COPD exacerbations, however, have been small and have produced conflicting results. We therefore conducted a meta‐analysis of randomised controlled trials to determine the effect of methylxanthines on the course of COPD exacerbations.
Objectives
To determine the effect of adding methylxanthines to standard medical care on the course of COPD exacerbations.
Methods
Criteria for considering studies for this review
Types of studies
Randomised trials comparing the addition of methylxanthines, via any route, with the addition of placebo to standard medical care for COPD exacerbations. Standard medical care included beta2‐agonists, ipratropium, antibiotics and/or corticosteroids.
Types of participants
Adult patients with known COPD with an exacerbation requiring 1) presentation to the emergency department or other acute care setting, or 2) hospitalisation. Patients with a diagnosis of asthma, cystic fibrosis, bronchiectasis, or other lung diseases were excluded. Patients with partial reversibility on pulmonary function testing were included when available.
Types of interventions
Treatment with oral theophylline, intravenous aminophylline, or intravenous doxofylline administered 1) in the emergency department, or 2) immediately upon admission to a hospital floor.
Types of outcome measures
Pulmonary function testing outcomes were defined as:
Change in forced expiratory volume in 1 second (FEV1) at 2 hours and at 3 days
Clinical outcomes included:
Hospitalisation or relapses within 7 days in emergency department patients;
Length‐of‐stay in hospitalised patients;
Change in self‐rated symptom scores within hours and at 3 days;
Intubations and complications;
Adverse events included:
Nausea/vomiting, hypokalemia, hyperglycemia, headache, confusion, tremor, seizures, palpitations/arrhythmias, and death.
Search methods for identification of studies
Searches were current as of March 2005.
Electronic searches
Trials were identified using the Cochrane Airways Group Specialised Register of trials which is derived from systematic searching of electronic databases including CENTRAL, MEDLINE, EMBASE and CINAHL, and hand‐searching of respiratory journals and meeting abstracts. All records in the Specialised Register coded as 'COPD' were searched using the following terms:
theo* or aminophyllin* or xanthin* or *methyl‐xanthin* or *methylxanthin* or doxofyllin* or caffeine* or *phyllin*
The search was not limited by language of publication.
Searching other resources
Reference lists of all primary studies and review articles were reviewed for additional references. Authors of identified trials were contacted and asked to identify other published and unpublished studies.
Data collection and analysis
Selection of studies
Two reviewers independently identified trials that appeared potentially relevant from title, abstract, and/or medical subject headings. Using the abstract or the full text of each study, as necessary, two reviewers independently selected trials for inclusion in the review.
Data extraction and management
Data extraction was performed independently by 2 reviewers (RGB, CAC). Authors of trials were contacted to provide missing data and intention‐to‐treat results, if not previously published. The data were checked and entered by one reviewer. In some cases, information regarding outcomes had to be estimated from graphs; two reviewers performed this independently.
All studies provided measures of standard deviation (SD) or standard error (SE) for FEV1 at different time points; however, the method of reporting differed between studies. SD was calculated from the SE by multiplying the SE by the square root of the number of subjects in each group. All studies provided the SD or SE of the pre‐treatment FEV1. Two (Rice 1987; Ram 2000) provided an estimate of the variance for the absolute change in FEV1, one (Seidenfield 1984) provided the SD for relative change in FEV1, and one (Wrenn 1991) provided the SD for post‐treatment FEV1. The two former studies were therefore directly comparable, whereas the latter two were not. For the latter two studies, individual study results are reported and estimates of the combined effect were made under various assumptions of the covariance. The variance was calculated pre‐ and post‐intervention from the standard deviation at each time‐point, and variances were combined using the formula:
Var1,2 = Var2 + Var1 ‐ 2(Covariance1,2)
Since the covariance between time‐points was not reported, analyses were performed with: 1) a conservative estimate of no covariance and, 2) with the covariance estimated as:
Covariance1,2 = r*sqrt( Var2 * Var1) where r is the correlation coefficient between Var2 and Var1 among all the included trials. The variance of the mean difference, Var1,2, was converted to the SD of the mean difference.
Assessment of risk of bias in included studies
Methodological quality assessment was performed using the Cochrane approach and the Jadad criteria (Jadad 1996). The Cochrane approach rates trials based on their description of allocation concealment whereas the Jadad criteria is a 0‐5 point scale based on randomisation, blinding, and reported losses to follow‐up. Two reviewers (RGB, CAC) independently extracted data. Authors of trials were contacted to provide missing data and intention‐to‐treat results, when necessary. In some cases, information regarding outcomes was estimated from graphs; in these instances, the two reviewers performed this independently.
Data synthesis
Trials were combined using the Review Manager and were analysed according to intention‐to‐treat. For continuous variables, mean difference and 95% confidence interval (95% CI) was calculated for each study. All similar studies were pooled using weighted mean difference (WMD) or standardised mean difference (SMD) and 95% CIs. For dichotomous variables, an odds ratio (OR) with 95% CI was calculated for individual studies and pooled results. Heterogeneity among pooled estimates was tested; p < 0.1 was considered statistically significant. Where there was no significant heterogeneity, results of the fixed effects model are reported; where there was significant heterogeneity, a random effects model was used.
Sensitivity analysis
Additional sensitivity analyses were performed using random effects vs. fixed effects modeling. The data were not evaluated for the presence of publication bias since published trials were predominantly negative, suggesting the absence of publication bias, and too few trials were available to perform a meaningful evaluation.
Results
Description of studies
Results of the search
A total of 1,299 articles were identified in the Cochrane Collaboration Airways COPD Registry. The review of titles and abstracts yielded 29 articles that possibly fulfilled inclusion criteria. Among these, four (Rice 1987; Seidenfield 1984; Wrenn 1991;Ram 2000) met criteria and were included in the analysis. Excluded studies and reason for exclusion are listed in Table 1. The study searches are considered updated to March 2005.
Included studies
Three studies included in the overview were published in the peer‐reviewed literature and the fourth has been published in abstract form. The characteristics of the studies are described in Table 2. The included trials yielded results for 169 patients. Two studies (Seidenfield 1984; Wrenn 1991) involved patients presenting to emergency departments and the other two studied hospitalised patients. All evaluated the incremental effectiveness of aminophylline added to standard therapy in COPD exacerbations. In general, standard therapy consisted of inhaled beta‐agonists and anti‐cholinergics, supplemental oxygen, steroids, and antibiotics.
Three of the four studies made substantial efforts to restrict asthmatic patients from the analysis. One study (Wrenn 1991) enrolled both asthma and COPD patients and then reported both combined and stratified results. In the case of this latter trial, data were extracted for patients with COPD only, whenever possible.
Risk of bias in included studies
Overall, the methodological quality of the studies was moderate. Concealment of allocation was unclear (Grade B) in all four. Using criteria of Jadad, two studies (Rice 1987; Ram 2000) scored 5/5, and two studies (Seidenfield 1984; Wrenn 1991) scored 4/5 for reporting of randomisation, blinding and follow‐up.
All four studies reported change in FEV1, and all but one (Seidenfield 1984) reported adverse events. All four reported some measure of symptoms score. Data on clinical outcomes, such as proportion hospitalised and length‐of‐stay, were sparse. The authors of two studies (Wrenn 1991; Ram 2000) kindly provided supplemental, unpublished data.
Effects of interventions
Pulmonary Function Indices
Two trials reported baseline and change in FEV1 at 2 hours. One study (Seidenfield 1984) reported a small, non‐significant benefit with methylxanthines (relative change in FEV1: 27% [95% CI: 3 to 51%] for methylxanthines vs 22% [95% CI: 13 to 31%] for placebo), whereas the other (Wrenn 1991) showed a non‐significant worsening with methylxanthines (relative change in FEV1: 28% for methylxanthines vs 37% for placebo [95% CI, not estimatable from available data]). Due to variation in reporting, these trials could not be combined without additional assumptions. Estimates of the combined effect were made under various assumptions. All estimates of the combined effect showed a smaller improvement in FEV1 at 2 hours with methylxanthines than with placebo; in no cases was the difference statistically significant, although for some estimates the 95% CI excluded any clinically meaningful benefit (e.g, WMD: ‐36 ml; 95% CI: ‐134 to 63 ml, Analysis 1.1).
1.1. Analysis.
Comparison 1 Effect of methylxanthines on FEV1, Outcome 1 Change in FEV1 (ml) at 2 hours.
Two trials provided data on change in FEV1 at 3 days of hospitalisation. The pooled results of the trials for FEV1 were homogenous (P=0.36), and a fixed effects model showed a combined WMD of 101 ml (95% CI: 26 to 177ml, Analysis 1.2) in favour of methylxanthines. Only one (Ram 2000) of the two trials, however, showed a benefit of methylxanthines. In that trial, baseline FEV1 was considerably lower in intervention group than the placebo group (0.59L and 0.68L, respectively; a difference of 90 ml). The improvement in FEV1 in methylxanthine compared to placebo arms in that trial was only observed at days 3 and 4 over 7 days of follow‐up (Ram 2000). Severity of COPD, as measured by baseline FEV1, was similar in the two trials.
1.2. Analysis.
Comparison 1 Effect of methylxanthines on FEV1, Outcome 2 Change in FEV1 (ml) at 3 days.
Clinical Endpoints
Of the pre‐specified endpoints, data on admissions were available from only one trial (Wrenn 1991). This trial showed a statistically non‐significant reduction in hospital admissions with methylxanthine use (OR: 0.3; 95% CI: 0.1 to 1.8). Data on relapses within seven days requiring return to the emergency department were reported in two trials (Wrenn 1991; Seidenfield 1984). These revealed a statistically non‐significant increase in relapses in the methylxanthine group (OR: 1.5; 95% CI: 0.4 to 5.2). Among hospitalised patients, one trial (Ram 2000) demonstrated a statistically non‐significant reduction in length‐of‐stay in the methylxanthine group (absolute difference: ‐1.4 days; 95% CI: ‐2.9 to 0.1) in intention‐to‐treat analyses.
Symptom Scores
Data were extracted for improvement in any symptom‐based scale. One study (Wrenn 1991) reported changes in symptom scores over several hours as a dichotomised result. Seidenfield reported mean differences in 4 symptom scores over the same time interval; however, these were not interpretable as a dichotomous outcome.
The two studies that examined symptom scores in hospitalised patients over 3 days reported comparable, continuous outcomes which were comparable as improvement in a 100 point (overall) symptom score. Results at 3 days demonstrated heterogeneity (P<0.001), with one study reporting a trend toward benefit and the other reporting a statistically significant harm. The combined estimate suggested a small, non‐significant worsening of symptoms with methylxanthines (SMD: ‐1.4; 95% CI: ‐5.1 to 2.4). The extracted 3‐day symptom score for the intervention group in one trial (Rice 1987) was unrepresentative of the overall trend for symptom score in that trial. Re‐extraction of the closest, more representative score (at 2.5 days) and re‐analysis using this measure removed the heterogeneity in the analysis (P=0.69) and revealed an even smaller, non‐significant improvement with methylxanthines (SMD: 0.45; 95% CI: 0.0 to 0.9; P=0.05).
Adverse Effects
Three trials reported adverse effects of methylxanthines (Wrenn 1991; Rice 1987; Ram 2000). The trials were homogeneous for all adverse event outcomes, therefore the results of fixed effects models are reported. The odds of nausea or vomiting were significantly higher for patients receiving a methylxanthine (OR: 4.6; 95% CI: 1.7 to 12.6) than for patients receiving placebo. Trends toward more frequent tremor (OR: 1.8; 95% CI: 0.7 to 4.6) and palpitations and arrhythmias (OR: 4.1; 95% CI: 0.9 to 19.6) were observed. Other adverse effects were not reported frequently enough to allow combination. One definite myocardial infarction and one patient with acute T‐wave inversion and hyperglycemia suggestive of a myocardial infarction were reported among 97 patients receiving methylxanthines. One intubation was reported in both the methylxanthine and placebo groups, and no deaths were reported during treatment.
Discussion
This meta‐analysis examined the available randomised controlled trials on methylxanthines in COPD exacerbations and did not show a consistent benefit. Whereas a variety of potential benefits of methylxanthines on clinical outcomes were not confirmed at standard levels of statistical significance, nausea and vomiting were significantly elevated compared to placebo, and other adverse events were non‐significantly increased.
Methylxanthines had no consistent effect on FEV1 at 2 hours. At 3 days, the change in FEV1 was greater in the methylxanthine group, based heavily on the results from one study (Ram 2000). However, this finding may have been biased by an imbalance in baseline FEV1 in that study. The difference in baseline FEV1 between the theophylline and placebo groups was approximately as large as the difference in change in FEV1 between two groups, such that the FEV1 at the end of follow‐up 3 days was the same in treatment and placebo groups. In addition, in the original report (Ram 2000), the differential improvement observed in FEV1 at 3 days disappeared with follow‐up greater than 3 days.
Our intention was to examine clinical outcomes and symptom scores, but this was constrained by sparse data and reporting vagaries. A trend toward fewer hospitalisations among emergency department patients in one study was offset by a trend toward a greater number of treatment relapses among patients sent home from the emergency department. Hospital length‐of‐stay was shorter among patients receiving theophylline than among those receiving placebo, although this result was not statistically significant. In the original study (Ram 2000), length‐of‐stay was significantly reduced; however, this was not an intention‐to‐treat analysis. Changes in symptom scores in the methylxanthine group did not differ significantly from changes in the placebo group. The magnitude of these changes was clinically unimportant, and the direction inconsistent depending on the analysis.
In contrast to findings for lung function and clinical endpoints, the higher risk of adverse events was statistically significant and consistent. The proportion of patients with nausea and vomiting was elevated in the methylxanthine group, such that more than a third of patients developing nausea or vomiting with methylxanthine use. Needless to say, nausea and vomiting may not be trivial side effects in patients in severe respiratory distress. Tremor and palpitations ‐ including non‐malignant arrhythmias ‐ also were elevated in the methylxanthine group, although not to statistically significant levels.
Most current international recommendations suggest the use of methylxanthines for severe COPD exacerbations or exacerbations that are not responding aerosol therapy (Pauwels 2001; Siafakas 1995; ATS 1995; Anonymous 1997). We had limited power to examine differences by subgroup of severity of exacerbations; however, no trends toward greater benefit were apparent for more severe exacerbations. In fact, all four studies evaluated the addition of a methylxanthine to aerosol therapy and enrolled patients with moderate‐to‐severe exacerbations (pre‐treatment FEV1 range 0.6‐0.8 L). Our results therefore apply to the target population of these recommendations. Our findings concur with the recommendations of the joint panel of the American College of Physicians‐American Society of Internal Medicine and the American College of Chest Physicians, which recommended against use of methylxanthines for COPD exacerbations (Snow 2001; Bach 2001).
The major limitation of this meta‐analysis was the paucity of randomised trial data. Whilst we could find no evidence of an early effect of methylxanthines on FEV1 at 2 hours, we could not reach firm conclusions about improvements in clinical endpoints and were unable to evaluate properly potential benefits in subgroups of patients such as patients with more severe disease. There is a possibility of publication and selection bias in any meta‐analysis; however, publication bias is unlikely to affect this analysis since the published trials were predominantly negative. To avoid selection bias, a systematic and comprehensive search was conducted and two reviewers independently evaluated trials for inclusion. In addition, we will continue to update the current review so it is unlikely that any trials in publication will be missed.
Authors' conclusions
Implications for practice.
The available data do not support the use of methylxanthines for the treatment of COPD exacerbations. Potential benefits of methylxanthines on lung function or symptoms were generally not confirmed at standard levels of significance, whereas adverse events of nausea and vomiting was significantly increased in patients receiving methylxanthines.
Implications for research.
The current meta‐analysis summarised data from a small number of trials involving relatively few patients. Based on its results, we anticipate that any potential clinical benefit found for methylxanthines in an adequately powered, large randomised trial would be offset by increased adverse effects. However, investigations of newer, more selective agents may have a better risk‐benefit profile. Until this evidence is available, methylxanthines should not be used for COPD exacerbations. Rather, physicians treating severe exacerbations of COPD should focus on applying treatments for which evidence of effectiveness exists, such as inhaled bronchodilators (McCrory 2002), systemic corticosteroids (Wood‐Baker 2002), antibiotics (Saint 1995), and non‐invasive ventilation (Peter 2002).
What's new
| Date | Event | Description |
|---|---|---|
| 7 August 2008 | Amended | Converted to new review format. |
History
Protocol first published: Issue 1, 1999 Review first published: Issue 2, 2001
| Date | Event | Description |
|---|---|---|
| 2 December 2002 | New citation required and conclusions have changed | Substantive amendment |
Acknowledgements
The authors wish to acknowledge the assistance of Stephen Milan, Karen Blackhall, Liz Arnold and Toby Lasserson of the Cochrane Airways Review Group. We are grateful to Gary M. Strauss MD for assistance with article selection and Keith Wrenn MD and Felix Ram for providing unpublished data. Finally, the assistance of Professor Paul Jones (Cochrane Airways Review Group Coordinating Editor) was greatly appreciated.
Data and analyses
Comparison 1. Effect of methylxanthines on FEV1.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Change in FEV1 (ml) at 2 hours | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2 Change in FEV1 (ml) at 3 days | 2 | 78 | Mean Difference (IV, Fixed, 95% CI) | 101.13 [25.61, 176.65] |
Comparison 2. Effect of methylxanthines on clinical endpoints.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Admissions among emergency department patients | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2 Emergency department returns within one week | 2 | 91 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.53 [0.45, 5.15] |
| 3 Difference in hospital length‐of‐stay (days) | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only |
2.1. Analysis.
Comparison 2 Effect of methylxanthines on clinical endpoints, Outcome 1 Admissions among emergency department patients.
2.2. Analysis.
Comparison 2 Effect of methylxanthines on clinical endpoints, Outcome 2 Emergency department returns within one week.
2.3. Analysis.
Comparison 2 Effect of methylxanthines on clinical endpoints, Outcome 3 Difference in hospital length‐of‐stay (days).
Comparison 3. Effect of methylxanthines on symptom scores.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Proportion with improvement in symptom score within hours | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2 Change in symptoms score at 3 days | 2 | 78 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.36 [‐5.11, 2.40] |
3.1. Analysis.
Comparison 3 Effect of methylxanthines on symptom scores, Outcome 1 Proportion with improvement in symptom score within hours.
3.2. Analysis.
Comparison 3 Effect of methylxanthines on symptom scores, Outcome 2 Change in symptoms score at 3 days.
Comparison 4. Adverse effects.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Effect of methyl‐xanthines on nausea/vomiting | 3 | 117 | Odds Ratio (M‐H, Fixed, 95% CI) | 4.62 [1.70, 12.56] |
| 2 Effect of methylxanthines on tremor | 3 | 117 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.83 [0.73, 4.56] |
| 3 Effect of methylxanthines on palpitations/arrhythmias | 2 | 89 | Odds Ratio (M‐H, Fixed, 95% CI) | 4.14 [0.87, 19.61] |
4.1. Analysis.
Comparison 4 Adverse effects, Outcome 1 Effect of methyl‐xanthines on nausea/vomiting.
4.2. Analysis.
Comparison 4 Adverse effects, Outcome 2 Effect of methylxanthines on tremor.
4.3. Analysis.
Comparison 4 Adverse effects, Outcome 3 Effect of methylxanthines on palpitations/arrhythmias.
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Ram 2000.
| Methods | Type: Parallel group. Duration: 7 days or duration of hospitalisation (lesser of). Randomization: blocks of 4, computer generated. Outcome blinding: Double‐blind. Co‐interventions: salbutamol 5mg QID, ipratropium 0.5mg QID, prednisone 40mg one time a day, oral antibiotic (if purulent sputum). Confounders: none noted. Assessment score: 5 | |
| Participants | Setting: Medical ward. Inclusion criteria: Admission for acute COPD exacerbation, age >= 50 years, smoked >= 20 packyears, FEV1 on admission <= 1.5L. Exclusion criteria: Use of theophylline in prior week or need for IV aminophylline, dx of pneumonia or congestive heart failure, prior dx of asthma, bronchiectasis, carcinoma, interstitial lung disease, paroxysmal atrial fibrillation or intolerance to theophylline. Number recruited: 50 Mean age: 71 years Gender: 46% male Baseline FEV1: 0.6 L | |
| Interventions | Experimental: longacting oral theophylline (Neulin‐24, 3M) 200mg or greater titrated to serum theo level of 10‐20 mg/L Control: Placebo. | |
| Outcomes | Analysed: Change in FEV1 at 3 days, length‐of‐stay, change in symptom scores, adverse effects. Reported: Change in FVC, Sa02 Mortality: None Morbidity: Experimental group; myocardial infarction (1), non‐malignant tachycardia (2); Control group; none. | |
| Notes | Likelihood of COPD: Stringent spirometry criteria | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Unclear risk | Information not available |
Rice 1987.
| Methods | Type: Parallel group. Duration: 72 hrs. Randomization: block. Outcome blinding: Double‐blinded, with the exception of one investigator who adjusted theophylline and placebo infusion rates. Co‐interventions: 0.3mL of 5% Metaproterenol sulfate/2.5mL of normal saline q4hrs; methylprednisolone 0.5mg/kg q6hrs, Ampicillin 500mg q6hrs, O2 prn. Confounders: None identified. Assessment score: 5 | |
| Participants | Setting: ED/medical walk‐in. Inclusion criteria: Prior diagnosis of COPD, prior spirometry of FEV1 < 2 SD below predicted and FEV1/FVC <60%, current diagnosis of COPD exacerbation requiring hospitalization. Exclusion criteria: Prior diagnosis of asthma, readily reversible exacerbations, prior bronchodilator response of >30% change in FEV1, left heart failure, pneumonia, intubated. Number recruited: 30 Mean age: 65 years Gender: 96% male Baseline FEV1: 0.6 L | |
| Interventions | Experimental: IV aminophylline 0‐6mg/kg load (based on prior theo use), 0.5mg/kg maintenance infusion for level of 72‐94 umol/L (abstract lists 72‐83 umol/L). Control: Placebo solution. | |
| Outcomes | Analysed: Change in FEV1, dyspnea index, adverse effects. Reported: Change in FVC, pO2 and pCO2. Others: None Mortality: None Morbidity: Experimental group; intubation (1), Control group; intubation (1). | |
| Notes | Likelihood of COPD: Stringent spirometry criteria | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Unclear risk | Information not available |
Seidenfield 1984.
| Methods | Type: Parallel group. Duration: 2 hours. Randomization: random number generator. Outcome blinding: Double‐blinded. Co‐interventions: 0.3 ml metaproterenol sulfate/2.5 ml saline nebulizer, 28% O2. Confounders: Treating physician could break randomization code if necessary. Assessment score: 4 | |
| Participants | Setting: ED. Inclusion criteria: ATS definition of chronic bronchitis (1962). Exclusion criteria: Febrile (>37.5 C), direct admission, arrhythmia, pneumonia, congestive heart failure. Number recruited: 52 Mean age: 63 years Gender: 100% male Baseline FEV1: 0.8 L | |
| Interventions | Experimental: IV aminophylline 2.8‐5.6mg/kg over 1 hour (based on prior theophylline exposure). Control: D5W. | |
| Outcomes | Analysed: Change in FEV1 at 2 hours, returns to ED in one week. Reported: 17 patients hospitalised within 1 week, but not reported by treatment group 6‐month mortality: Experimental (3), Control (5) Morbidity: "No significant side effects observed" | |
| Notes | Likelihood of COPD: Clinical diagnosis of chronic bronchitis, baseline FEV1 0.8 L. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Unclear risk | Information not available |
Wrenn 1991.
| Methods | Type: Parallel group. Duration: Until discharge from ED. Randomization: yes. Outcome blinding: Double‐blind. Co‐interventions: 0.3 ml metaproterenol sulfate/2.5 ml saline nebuliser q30 min prn, methylprednisolone 80mg IV once, 28% O2. Confounders: Randomization not stratified by type of obstructive airways disease. Assessment score: 4 | |
| Participants | Setting: ED. Inclusion criteria: asthma exacerbation or wheeze, age >45 years, smoking history of 20 pack‐years, duration of disease >20 years OR disease onset after age 45 years. Exclusion criteria: Theophylline use in prior 24 hrs, adverse reaction to theophylline, corticosteroids, or beta‐agonists, type 1 diabetes mellitus, possible myocardial infarction, pulmonary edema. Number recruited: 39 Mean age: 62 years Gender: 64% male Baseline FEV1: 0.7 L | |
| Interventions | Experimental: intravenous aminophylline 5.6mg/kg over 20 minutes, then 0.9mg/kg constant infusion. Control: Placebo. | |
| Outcomes | Analysed: Change in FEV1, PEFR, hospitalizations, return to ED in 3 days, adverse effects Reported: Change in FVC. Approximate costs, emergency department LOS Mortality: None reported Morbidity: Experimental group; new T‐wave inversions on EKG + hyperglycemia (1), Control group; none. | |
| Notes | Likelihood of COPD: No prior PFT data; likely some misclassification with asthma since asthma/COPD subgroups established post hoc. Hospitalization decision made by non‐investigator with prespecified criteria. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Unclear risk | Information not available |
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Bone 1980 | Not randomised |
| Brantingham 1970 | Stable COPD |
| Chiappini 1990 | Relevant endpoints not reported |
| Chin 1983 | Not randomised |
| Dolcetti 1988 | Crossover design not appropriate for assessment of treatment of exacerbations |
| Donner 1980 | Stable COPD |
| Dorow 1978 | Stable COPD |
| Furukawa 1988 | Asthma |
| Holford 1993 | No placebo group |
| Holford 1993a | No placebo group |
| Jenkins 1982 | Stable COPD |
| Jonsson 1988 | Asthma |
| Light 1983 | Not randomised |
| Lloberes 1988 | Unclear if randomised; stabilised exacerbation |
| Morandini 1989 | Stable COPD |
| Musil 1988 | Not randomised |
| Perret 1980 | Stable COPD |
| Reinecke 1986 | No intervention |
| Sahay 1984 | Stable COPD |
| Sahay 1986 | Stable COPD |
| Schmidt 1988 | Stable COPD |
| Seeto 2004 | Stable COPD |
| Tanser 1982 | Stable COPD |
| Tedders 1976 | Stable COPD |
| Thomas 1992 | Stable COPD |
| Vozeh 1982 | No placebo group |
Contributions of authors
RG Barr: protocol development, article selection, data extraction, analysis, manuscript preparation. BH Rowe: protocol development, analysis, manuscript preparation. CA Camargo Jr: protocol development, article selection, data extraction, analysis, manuscript preparation.
Sources of support
Internal sources
No sources of support supplied
External sources
PE‐1101, HL‐07427, NRSA; Robert Wood Johnson Generalist Physician Faculty Scholar Award (RG Barr), USA.
HL‐63841, NIH (CA Camargo Jr), USA.
NHS Research and Development, UK.
Canadian Institute of Health Research (BH Rowe), Canada.
Declarations of interest
The authors who have been involved in this review have done so without any known conflicts of interest. Dr. Rowe has received research grants from Boehringer‐Ingelheim, GlaxoSmithKline and AstraZeneca; Dr. Camargo has received research grants from these and other pharmaceutical manufacturers. None of the authors were involved with the primary studies.
Edited (no change to conclusions)
References
References to studies included in this review
Ram 2000 {published and unpublished data}
- Ram FSF, Poole PJ, Bagg W, Stewart J, Black PN. Randomised, controlled trial of theophylline for the treatment of exacerbations of chronic obstructive pulmonary disease [abstract]. American Journal of Respiratory and Critical Care Medicine 2000;161(Suppl):A489. [Google Scholar]
Rice 1987 {published data only}
- Rice KL, Leatherman JW, Duane PG, Snyder LS, Harmon KR, Abel J, et al. Aminophylline for acute exacerbations of chronic obstructive pulmonary disease. A controlled trial. Annals of Internal Medicine 1987;107(3):305‐9. [DOI] [PubMed] [Google Scholar]
Seidenfield 1984 {published data only}
- Seidenfeld JJ, Jones WN, Moss RE, Tremper J. Intravenous aminophylline in the treatment of acute bronchospastic exacerbations of chronic obstructive pulmonary disease. Annals of Emergency Medicine 1984;13:248‐52. [DOI] [PubMed] [Google Scholar]
Wrenn 1991 {published and unpublished data}
- Wrenn K, Slovis C, Murphy F, Greenberg R. Aminophylline therapy for acute bronchospastic disease in the emergency room. Annals of Internal Medicine 1991;115:241‐47. [DOI] [PubMed] [Google Scholar]
References to studies excluded from this review
Bone 1980 {published data only}
- Bone RC. Treatment of respiratory failure due to advanced chronic obstructive pulmonary disease. Archives of Internal Medicine 1980;140:1018‐21. [PubMed] [Google Scholar]
Brantingham 1970 {published data only}
- Brantingham P. Clinical trial of theograd. British Journal of Clinical Practice 1970;24:165‐70. [PubMed] [Google Scholar]
Chiappini 1990 {published data only}
- Chiappini F, Bevignani G, Fresu R. Effects of theophylline on the course of hypercapnic respiratory insufficiency. Clinica Terapeutica 1990;135:121‐7. [PubMed] [Google Scholar]
Chin 1983 {published data only}
- Chin R, Pescoe R. Practical aspects in management of respiratory failure in chronic obstructive pulmonary disease. Critical Care Quarterly 1983;6:1‐21. [Google Scholar]
Dolcetti 1988 {published data only}
- Dolcetti A, Osella D, DeFilippis G, Carnuccio C, Grossi E. Comparison of intravenously administered doxofylline and placebo for the treatment of severe acute airways obstruction. The Journal of International Medical Research 1988;16:264‐69. [DOI] [PubMed] [Google Scholar]
Donner 1980 {published data only}
- Donner C, Fracchia C, Ioli F. Bronchospasm management by means of ipratropium, beclomethasone, and their combination. Giornale Italiano Delle Malattie Del Torace 1980;34:307‐10. [Google Scholar]
Dorow 1978 {published data only}
- Dorow P. The effect of oral aminophylline compound with protracted activity on respiratory resistance and blood gases in obstructive respiratory diseases. Arzneimittel‐Forschung 1978;28:853‐6. [PubMed] [Google Scholar]
Furukawa 1988 {published data only}
- Furukawa CT. Comparative trials including a ß2 adrenergic agonist, a methylxanthine, and a mast cell stabilizer. Annals of Allergy 1988;60:472‐6. [PubMed] [Google Scholar]
Holford 1993 {published data only}
- Holford N, Black P, Couch R, Kennedy J, Briant R. Theophylline target concentration in severe airways obstruction ‐‐ 10 or 20 mg/L? A randomised concentration‐controlled trial. Clinical Pharmacokinetics 1993;25(6):495‐505. [DOI] [PubMed] [Google Scholar]
Holford 1993a {published data only}
- Holford N, Hashimoto Y, Sheiner LB. Time and theophylline concentration help explain the recovery of peak flow following acute airways obstruction. Population analysis of a randomised concentration controlled trial. Clinical Pharmacokinetics 1993;25(6):506‐15. [DOI] [PubMed] [Google Scholar]
Jenkins 1982 {published data only}
- Jenkins PF, White JP, Jariwalla AJ, Anderson G, Campbell IA. A controlled study of slow‐release theophylline and aminophylline in patients with chronic bronchitis. British Journal of Diseases of the Chest 1982;76:57‐60. [PubMed] [Google Scholar]
Jonsson 1988 {published data only}
- Jonsson S, Kjartansson G, Gislason D, Helgason H. Comparison of the oral and intravenous routes for treating asthma with methylprednisone and theophylline. Chest 1988;94:723‐6. [DOI] [PubMed] [Google Scholar]
Light 1983 {published data only}
- Light RW. Conservative treatment of hypercapnic acute respiratory failure. Respiratory Care 1983;28:561‐6. [Google Scholar]
Lloberes 1988 {published data only}
- Lloberes P, Ramis L, Montserrat J, et al. Effect of three different bronchodilators during an exacerbation of chronic obstructive pulmonary disease. European Respiratory Journal 1988;1:536‐9. [PubMed] [Google Scholar]
Morandini 1989 {published data only}
- Morandini G. Treatment of chronic bronchitis: combined therapy with sustained‐release theophylline and a mucoactive drug sobrerol. Clinical Trials Journal 1989;26:163‐74. [Google Scholar]
Musil 1988 {published data only}
- Musil J, Hirsch V, Votroubkova O. The role of theophylline in threatment of exacerbations of chronic obstructive pulmonary disease. Pracovni Lekarstvi 1998;78:319‐20. [Google Scholar]
Perret 1980 {published data only}
- Perret L, Laitinen LA. Aspects of chronic bronchitis and emphysema. Finska Lakaresallskapets Handlingar 1980;124:101‐3. [Google Scholar]
Reinecke 1986 {published data only}
- Reinecke T, Seger D, Wears R. Rapid assay of serum theophylline levels. Annals of Emergency Medicine 1986;15:147‐51. [DOI] [PubMed] [Google Scholar]
Sahay 1984 {published data only}
- Sahay JN, Bell R, Chatterjee SS, Jayaswal R. Comparative study of the effects of intravenous aminophylline, salbutamol and terbutaline in patients suffering from reversible airways obstruction. Current Medical Research and Opinion 1984;9:1‐6. [DOI] [PubMed] [Google Scholar]
Sahay 1986 {published data only}
- Sahay JN, Chatterjee SS, Summerfield PJ. A comparative trial of ipratropium bromide, controlled release theophylline, and a combination of these in patients with reversible airflow obstruction. British Journal of Clinical Practice 1986;40:198‐202. [PubMed] [Google Scholar]
Schmidt 1988 {published data only}
- Schmidt EW, Ulmer WT. Increase of arterial oxygen pressure in therapy with theophylline in patients with obstructive ventilation disorder and partial respiratory insufficiency [Ansteif des arteriellen sauerstoffdruckes unter therapie mit theophyllin bei patienten mit obstruktiver ventilationsstorung und respiratorischer partialinsuffizienz]. Prax Klin Pneumol 1988;42(7):600‐2. [PubMed] [Google Scholar]
Seeto 2004 {published data only}
- Seeto LJ, Ito K, Hamid Q, Plowman L, Adcock I, Lim S. Effect of low dose oral theophylline in patients with chronic obstructive pulmonary disease (COPD) [Abstract]. American Thoracic Society 100th International Conference May 21‐26. 2004:C22, Poster 515.
Tanser 1982 {published data only}
- Tanser RA. Maintenance of bronchodilation in chronic reversible airways obstruction. Comparison between choline theophylline and salbutamol. Practitioner 1982;226(1365):569‐71. [PubMed] [Google Scholar]
Tedders 1976 {published data only}
- Tedders JG, Thomas AK, Edwards G. A double‐blind comparison of a microcrystalline theophylline tablet and salbutamol in reversible airways obstruction. British Journal of Clinical Practice 1976;30:212‐6. [PubMed] [Google Scholar]
Thomas 1992 {published data only}
- Thomas P, Pugsley JA, Stewart JH. Theophylline and salbutamol improve pulmonary function in patients with irreversible chronic obstructive pulmonary disease. Chest 1992;101:160‐65. [DOI] [PubMed] [Google Scholar]
Vozeh 1982 {published data only}
- Vozeh S, Kewitz G, Perruchuchoud A, et al. Theophylline serum concentration and therapeutic effect in severe bronchial obstruction: the optimal use of intravenously administered aminophylline. American Review of Respiratory Disease 1982;125:181‐84. [DOI] [PubMed] [Google Scholar]
Additional references
Anonymous 1997
- Anonymous. BTS guidelines for the management of chronic obstructive pulmonary disease. The COPD Guidelines Group of the Standards of Care Committee of the BTS. Thorax 1997;52(Suppl 5):S1‐S28. [PMC free article] [PubMed] [Google Scholar]
ATS 1995
- American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 1995;152(Suppl):S77‐S121. [PubMed] [Google Scholar]
Bach 2001
- Bach PB, Brown C, Gelfand SE, McCrory DC. Management of exacerbations of chronic obstructive pulmonary disease: a summary and appraisal of the published evidence. Annals of Internal Medicine 2001;134:600‐20. [DOI] [PubMed] [Google Scholar]
Jadad 1996
- Jadad AR, Moore RA, Carroll D, Jenkinson C, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Controlled Clinical Trials 1996;17:1‐12. [DOI] [PubMed] [Google Scholar]
McCrory 2002
- McCrory DC, Brown CD. Anti‐cholinergic bronchodilators versus beta2‐sympathomimetic agents for acute exacerbations of chronic obstructive pulmonary disease. The Cochrane Database of Systematic Reviews 2002, Issue 4. [DOI] [PMC free article] [PubMed] [Google Scholar]
Pauwels 2001
- Pauwels RA, Buist AS, Calverley PMA, Jenkins CR, Hurd SS, GOLD Scientific Committee. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop Summary. American Journal of Respiratory and Critical Care Medicine 2001;163(2):1256‐76. [DOI] [PubMed] [Google Scholar]
Peleman 1998
- Peleman RA, Kips JC, Pauwels RA. Therapeutic activities of theophylline in chronic obstructive pulmonary disease. Clinical and Experimental Allergy 1998;28(Suppl 3):53‐6. [PubMed] [Google Scholar]
Peter 2002
- Peter JV, Moran JL, Phillips‐Hughes J, Warn D. Noninvasive ventilation in acute respiratory failure‐‐a meta‐analysis update. Critical Care Medicine 2002;30:555‐62. [DOI] [PubMed] [Google Scholar]
Ram‐Rev 2002
- Ram FSF, Jones PW, Castro AA, Brito Jardim JR, Atallah AN, Lacasse Y, et al. The Cochrane Database of Systematic Reviews 2002, Issue 4. [DOI] [PMC free article] [PubMed] [Google Scholar]
Saint 1995
- Saint S, Bent S, Vittinghoff E, Grady D. Antibiotics in chronic obstructive pulmonary disease. JAMA 1995;273:957‐60. [PubMed] [Google Scholar]
Siafakas 1995
- Siafakas NM, Vermeire P, Pride NB, et al. [Optimal assessment and management of chronic obstructive pulmonary disease (COPD)]. European Respiratory Journal 1995;8:1398‐420. [DOI] [PubMed] [Google Scholar]
Snow 2001
- Snow V, Lascher S, Mottur‐Pilson C, Joint Expert Panel on COPD of the American College of Chest Physicians and the American College of Physicians ‐ American Society of Internal Medicine. Evidence base for management of acute exacerbations of chronic obstructive pulmonary disease. Annals of Internal Medicine 2001;134(7):595‐599. [DOI] [PubMed] [Google Scholar]
Weinberger 1996
- Weinberger M, Hendeles L. Theophylline in asthma. New England Journal of Medicine 1996;334:1380‐88. [DOI] [PubMed] [Google Scholar]
Wood‐Baker 2002
- Wood‐Baker R, Walters EH, Gibson P. Oral corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. The Cochrane Database of Systematic Reviews 2002, Issue 3. [DOI] [PubMed] [Google Scholar]