Methods of hysterectomy: systematic review and meta-analysis of randomised controlled trials

Objective To evaluate the most appropriate surgical method of hysterectomy (abdominal, vaginal, or laparoscopic) for women with benign disease.Design Systematic review and meta-analysis.Data sources Cochrane Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials, Medline, Embase, and Biological Abstracts.Selection of studies Only randomised controlled trials were selected; participants had to have benign gynaecological disease; interventions had to comprise at least one hysterectomy method compared with another; and trials had to report primary outcomes (time taken to return to normal activities, intraoperative visceral injury, and major long term complications) or secondary outcomes (operating time, other immediate complications of surgery, short term complications, and duration of hospital stay).Results 27 trials (total of 3643 participants) were included. Return to normal activities was quicker after vaginal than after abdominal hysterectomy (weighted mean difference 9.5 (95% confidence interval 6.4 to 12.6) days) and after laparoscopic than after abdominal hysterectomy (difference 13.6 (11.8 to 15.4) days), but was not significantly different for laparoscopic versus vaginal hysterectomy (difference -1.1 (-4.2 to 2.1) days). There were more urinary tract injuries with laparoscopic than with abdominal hysterectomy (odds ratio 2.61 (95% confidence interval 1.22 to 5.60)), but no other intraoperative visceral injuries showed a significant difference between surgical approaches. Data were notably absent for many important long term patient outcome measures, where the analyses were underpowered to detect important differences, or they were simply not reported in trials.Conclusions Significantly speedier return to normal activities and other improved secondary outcomes (shorter duration of hospital stay and fewer unspecified infections or febrile episodes) suggest that vaginal hysterectomy is preferable to abdominal hysterectomy where possible. Where vaginal hysterectomy is not possible, laparoscopic hysterectomy is preferable to abdominal hysterectomy, although it brings a higher chance of bladder or ureter injury.     

Role of multivitamins and mineral supplements in preventing infections in elderly people: systematic review and meta-analysis of randomised controlled trials

Objective To evaluate the effectiveness of multivitamins and mineral supplements in reducing infections in an elderly population.Design Systematic review and meta-analysis of randomised controlled trials.Data sources Medline and other databases. Reference lists of identified articles were inspected for further relevant articles.Selection of studies Trials were included if they evaluated the effect of multivitamins and mineral supplements on infections in an elderly population.Review methods Studies were assessed for the methodological quality by using the Jadad instrument. If the data required for the analyses were not available from the published articles we requested them from the original study authors. Meta-analysis was undertaken on three outcomes: the mean difference in number of days spent with infection, the odds ratio of at least one infection in the study period, and the incidence rate ratio for the difference in infection rates. Data on adverse events were also extracted.Results Eight trials met our inclusion criteria. Owing to inconsistency in the outcomes reported, only a proportion of the trials could be included in each meta-analysis. Multivitamins and mineral supplements were found to reduce the mean annual number of days spent with infection (three studies) by 17.5 (95% confidence interval 11 to 24, P < 0.001). The odds ratio for at least one infection in the study period (three studies) was 1.10 (0.81 to 1.50, P = 0.53). The infection rate ratio (four studies) was 0.89 (0.78 to 1.03, P = 0.11). Reporting of adverse events was poor.Conclusion The evidence for routine use of multivitamin and mineral supplements to reduce infections in elderly people is weak and conflicting. Study results are heterogeneous, and this is partially confounded by outcome measure.     

Drug-induced orthostatic hypotension: A systematic review and meta-analysis of randomised controlled trials

BackgroundDrug-induced orthostatic hypotension (OH) is common, and its resulting cerebral hypoperfusion is linked to adverse outcomes including falls, strokes, cognitive impairment, and increased mortality. The extent to which specific medications are associated with OH remains unclear.Methods and findingsWe conducted a systematic review and meta-analysis to evaluate the extent to which specific drug groups are associated with OH. EMBASE, MEDLINE, and Web of Science databases were searched from inception through 23 November 2020. Placebo-controlled randomised controlled trials (RCTs) on any drug reporting on OH as an adverse effect in adults (≥18 years) were eligible. Three authors extracted data on the drug, OH, dose, participant characteristics, and study setting. The revised Cochrane risk-of-bias tool for randomised trials (RoB 2) was used to appraise evidence. Summary odds ratios (ORs) were estimated for OH using fixed effects Mantel–Haenszel statistics. We conducted subgroup analysis on validity of OH measurement, drug dose, risk of bias, age, and comorbidity. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool was used to summarise the certainty of evidence. Of 36,940 citations, 69 eligible RCTs were included in the meta-analysis comprising 27,079 participants. Compared with placebo, beta-blockers and tricyclic antidepressants were associated with increased odds of OH (OR 7.76 [95% CI 2.51, 24.03]; OR 6.30 [95% CI 2.86, 13.91]). Alpha-blockers, antipsychotics, and SGLT-2 inhibitors were associated with up to 2-fold increased odds of OH, compared to placebo. There was no statistically significant difference in odds of OH with vasodilators (CCBs, ACE inhibitors/ARBs, SSRIs), compared to placebo. Limitations of this study are as follows: data limited to placebo-controlled studies, (excluding head-to-head trials), many RCTs excluded older participants; therefore results may be amplified in older patients in the clinical setting. The study protocol is publicly available on PROSPERO (CRD42020168697).ConclusionsMedications prescribed for common conditions (including depression, diabetes, and lower urinary tract symptoms) were associated with significantly increased odds of OH. Drugs causing sympathetic inhibition were associated with significantly increased odds of OH, while most vasodilators were associated with small nonsignificant differences in odds of OH, compared to placebo. Drugs targeting multiple parts of the orthostatic blood pressure (BP) reflex pathway (e.g. sympathetic inhibition, vasodilation, cardio-inhibitory effects) may carry cumulative risk, suggesting that individuals with polypharmacy could benefit from postural BP monitoring.

Cini Bhanu and colleagues evaluate the extent to which different drug groups are associated with orthostatic hypertension in this systematic review and meta-analysis.     

Zinc and glycemic control: A meta-analysis of randomised placebo controlled supplementation trials in humans

BackgroundImpaired zinc metabolism is prominent in chronic disorders including cardiovascular disease and diabetes. Zinc has the potential to affect glucose homeostasis in animals and humans and hence impact the risk of type 2 diabetes mellitus.MethodsA systematic review and meta-analysis of randomised placebo controlled trials was conducted to determine the effect of zinc supplementation on fasting blood glucose, HbA1c, serum insulin and serum zinc concentrations. Relevant studies for inclusion were identified from a literature search of electronic databases up to July 2011.ResultsFourteen reports (n = 3978 subjects) were included in the meta-analysis. In the overall analysis, a small but statistically significant reduction in fasting glucose concentrations was observed (?0.19 ± 0.08 mmol/L, P = 0.013) after zinc supplementation. HbA1c tended to decrease in zinc-supplemented individuals (?0.64 ± 0.36%, P = 0.072). No significant effect was observed for serum insulin concentrations. Plasma zinc concentrations increased significantly following supplementation (+4.03 ± 0.81 μmol/L, P = 0.001). In secondary analyses of participants with chronic metabolic disease (types 1 and 2 diabetes mellitus, metabolic syndrome and obesity), zinc supplementation produced a greater reduction in glucose concentrations (?0.49 ± 0.11 mmol/L, P = 0.001) compared to the effect that was observed in healthy participants.ConclusionThe significant albeit modest reduction in glucose concentrations and tendency for a decrease in HbA1c following zinc supplementation suggest that zinc may contribute to the management of hyperglycemia in individuals with chronic metabolic disease.     

Effectiveness of physiotherapy exercise after knee arthroplasty for osteoarthritis: systematic review and meta-analysis of randomised controlled trials

Objective To evaluate the effectiveness of physiotherapy exercise after elective primary total knee arthroplasty in patients with osteoarthritis.Design Systematic review.Data sources Database searches: AMED, CINAHL, Embase, King''s Fund, Medline, Cochrane library (Cochrane reviews, Cochrane central register of controlled trials, DARE), PEDro, Department of Health national research register. Hand searches: Physiotherapy, Physical Therapy, Journal of Bone and Joint Surgery (Britain) Conference Proceedings.Review methods Randomised controlled trials were reviewed if they included a physiotherapy exercise intervention compared with usual or standard physiotherapy care, or compared two types of exercise physiotherapy interventions meeting the review criteria, after discharge from hospital after elective primary total knee arthroplasty for osteoarthritis.Outcome measures Functional activities of daily living, walking, quality of life, muscle strength, and range of motion in the knee joint. Trial quality was extensively evaluated. Narrative synthesis plus meta-analyses with fixed effect models, weighted mean differences, standardised effect sizes, and tests for heterogeneity.Results Six trials were identified, five of which were suitable for inclusion in meta-analyses. There was a small to moderate standardised effect size (0.33, 95% confidence interval 0.07 to 0.58) in favour of functional exercise for function three to four months postoperatively. There were also small to moderate weighted mean differences of 2.9 (0.61 to 5.2) for range of joint motion and 1.66 (−1 to 4.3) for quality of life in favour of functional exercise three to four months postoperatively. Benefits of treatment were no longer evident at one year.Conclusions Interventions including physiotherapy functional exercises after discharge result in short term benefit after elective primary total knee arthroplasty. Effect sizes are small to moderate, with no long term benefit.     

Systematic review of randomised controlled trials of multiple risk factor interventions for preventing coronary heart disease.

OBJECTIVE: To assess the effectiveness of multiple risk factor intervention in reducing cardiovascular risk factors, total mortality, and mortality from coronary heart disease among adults. DESIGN: Systematic review and meta-analysis of randomised controlled trials in workforces and in primary care in which subjects were randomly allocated to more than one of six interventions (stopping smoking, exercise, dietary advice, weight control, antihypertensive drugs, and cholesterol lowering drugs) and followed up for at least six months. SUBJECTS: Adults aged 17-73 years, 903000 person years of observation were included in nine trials with clinical event outcomes and 303000 person years in five trials with risk factor outcomes alone. MAIN OUTCOME MEASURES: Changes in systolic and diastolic blood pressure, smoking rates, blood cholesterol concentrations, total mortality, and mortality from coronary heart disease. RESULTS: Net decreases in systolic and diastolic blood pressure, smoking prevalence, and blood cholesterol were 4.2 mm Hg (SE 0.19 mm Hg), 2.7 mm Hg (0.09 mm Hg), 4.2% (0.3%), and 0.14 mmol/l (0.01 mmol/l) respectively. In the nine trials with clinical event end points the pooled odds ratios for total and coronary heart disease mortality were 0.97 (95% confidence interval 0.92 to 1.02) and 0.96 (0.88 to 1.04) respectively. Statistical heterogeneity between the studies with respect to changes in mortality and risk factors was due to trials focusing on hypertensive participants and those using considerable amounts of drug treatment, with only these trials showing significant reductions in mortality. CONCLUSIONS: The pooled effects of multiple risk factor intervention on mortality were insignificant and a small, but potentially important, benefit of treatment (about a 10% reduction in mortality) may have been missed. Changes in risk factors were modest, were related to the amount of pharmacological treatment used, and in some cases may have been overestimated because of regression to the mean, lack of intention to treat analyses, habituation to blood pressure measurement, and use of self reports of smoking. Interventions using personal or family counselling and education with or without pharmacological treatments seem to be more effective at reducing risk factors and therefore mortality in high risk hypertensive populations. The evidence suggests that such interventions implemented through standard health education methods have limited use in the general population. Health protection through fiscal and legislative measure may be more effective.     

Corticosteroids in acute traumatic brain injury: systematic review of randomised controlled trials.

OBJECTIVE: To quantify the effectiveness and safety of corticosteroids in the treatment of acute traumatic brain injury. DESIGN: Systematic review of randomised controlled trials of corticosteroids in acute traumatic brain injury. Summary odds ratios were estimated as an inverse variance weighted average of the odds ratios for each study. SETTING: Randomised trials available by March 1996. SUBJECTS: The included trials with outcome data comprised 2073 randomised participants. RESULTS: The effect of corticosteroids on the risk of death was reported in 13 included trials. The pooled odds ratio for the 13 trials was 0.91 (95% confidence interval 0.74 to 1.12). Pooled absolute risk reduction was 1.8% (-2.5% to 5.7%). For the 10 trials that reported death or disability the pooled odds ratio was 0.90 (0.72 to 1.11). For infections of any type the pooled odds ratio was 0.92 (0.69 to 1.23) and for the seven trials reporting gastrointestinal bleeding it was 1.05 (0.44 to 2.52). With only those trials with the best quality of concealment of allocation, the pooled odds ratio estimates for death and death or disability became closer to unity. CONCLUSIONS: This systematic review of randomised controlled trials of corticosteroids in acute traumatic brain injury shows that there remains considerable uncertainty over their effects. Neither moderate benefits nor moderate harmful effects can be excluded. The widely practicable nature of the drugs and the importance of the health problem suggest that large simple trials are feasible and worth while to establish whether there are any benefits from use of corticosteroids in this setting.     

Efficacy of topical non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis: meta-analysis of randomised controlled trials

Objective To assess the efficacy of topical non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of osteoarthritis.Data sources Medline, Embase, Scientific Citation Index, CINAHL, Cochrane Library, and abstracts from conferences.Review methods Inclusion criterion was randomised controlled trials comparing topical NSAIDs with placebo or oral NSAIDs in osteoarthritis. Effect size was calculated for pain, function, and stiffness. Rate ratio was calculated for dichotomous data such as clinical response rate and adverse event rate. Number needed to treat to obtain the clinical response was estimated. Quality of trial was assessed, and sensitivity analyses were undertaken.Results Topical NSAIDs were superior to placebo in relieving pain due to osteoarthritis only in the first two weeks of treatment. Effect sizes for weeks 1 and 2 were 0.41 (95% confidence interval, 0.16 to 0.66) and 0.40 (0.15 to 0.65), respectively. No benefit was observed over placebo in weeks 3 and 4. A similar pattern was observed for function, stiffness, and clinical response rate ratio and number needed to treat. Topical NSAIDs were inferior to oral NSAIDs in the first week of treatment and associated with more local side effects such as rash, itch, or burning (rate ratio 5.29, 1.14 to 24.51).Conclusion Randomised controlled trials of short duration only (less than four weeks) have assessed the efficacy of topical NSAIDs in osteoarthritis. After two weeks there was no evidence of efficacy superior to placebo. No trial data support the long term use of topical NSAIDs in osteoarthritis.     

Efficacy of short-term high-dose statin in preventing contrast-induced nephropathy: a meta-analysis of seven randomized controlled trials

Background

A few studies focused on statin therapy as specific prophylactic measures of contrast-induced nephropathy have been published with conflicting results. In this meta-analysis of randomized controlled trials, we aimed to assess the effectiveness of shor-term high-dose statin treatment for the prevention of CIN and clinical outcomes and re-evaluate of the potential benefits of statin therapy.

Methods

We searched PubMed, OVID, EMBASE, Web of science and the Cochrane Central Register of Controlled Trials databases for randomized controlled trials comparing short-term high-dose statin treatment versus low-dose statin treatment or placebo for preventing CIN. Our outcome measures were the risk of CIN within 2–5 days after contrast administration and need for dialysis.

Results

Seven randomized controlled trials with a total of 1,399 patients were identified and analyzed. The overall results based on fixed-effect model showed that the use of short-term high-dose statin treatment was associated with a significant reduction in risk of CIN (RR = 0.51, 95% CI 0.34–0.76, p = 0.001; I² = 0%). The incidence of acute renal failure requiring dialysis was not significant different after the use of statin (RR = 0.33, 95% CI 0.05–2.10, p = 0.24; I² = 0%). The use of statin was not associated with a significant decrease in the plasma C-reactive protein level (SMD −0.64, 95% CI: −1.57 to 0.29, P = 0.18, I² = 97%).

Conclusions

Although this meta-analysis supports the use of statin to reduce the incidence of CIN, it must be considered in the context of variable patient demographics. Only a limited recommendation can be made in favour of the use of statin based on current data. Considering the limitations of included studies, a large, well designed trial that incorporates the evaluation of clinically relevant outcomes in participants with different underlying risks of CIN is required to more adequately assess the role for statin in CIN prevention.     

Pharmacological treatment of painful HIV-associated sensory neuropathy: a systematic review and meta-analysis of randomised controlled trials

Background

Significant pain from HIV-associated sensory neuropathy (HIV-SN) affects ∼40% of HIV infected individuals treated with antiretroviral therapy (ART). The prevalence of HIV-SN has increased despite the more widespread use of ART. With the global HIV prevalence estimated at 33 million, and with infected individuals gaining increased access to ART, painful HIV-SN represents a large and expanding world health problem. There is an urgent need to develop effective pain management strategies for this condition.

Method and Findings

Objective: To evaluate the clinical effectiveness of analgesics in treating painful HIV-SN. Design: Systematic review and meta-analysis. Data sources: Medline, Cochrane central register of controlled trials, www.clinicaltrials.gov, www.controlled-trials.com and the reference lists of retrieved articles. Selection criteria: Prospective, double-blinded, randomised controlled trials (RCTs) investigating the pharmacological treatment of painful HIV-SN with sufficient quality assessed using a modified Jadad scoring method. Review methods: Four authors assessed the eligibility of articles for inclusion. Agreement of inclusion was reached by consensus and arbitration. Two authors conducted data extraction and analysis. Dichotomous outcome measures (≥30% and ≥50% pain reduction) were sought from RCTs reporting interventions with statistically significant efficacies greater than placebo. These data were used to calculate RR and NNT values.

Results

Of 44 studies identified, 19 were RCTs. Of these, 14 fulfilled the inclusion criteria. Interventions demonstrating greater efficacy than placebo were smoked cannabis NNT 3.38 95%CI(1.38 to 4.10), topical capsaicin 8%, and recombinant human nerve growth factor (rhNGF). No superiority over placebo was reported in RCTs that examined amitriptyline (100mg/day), gabapentin (2.4g/day), pregabalin (1200mg/day), prosaptide (16mg/day), peptide-T (6mg/day), acetyl-L-carnitine (1g/day), mexilitine (600mg/day), lamotrigine (600mg/day) and topical capsaicin (0.075% q.d.s.).

Conclusions

Evidence of efficacy exists only for capsaicin 8%, smoked cannabis and rhNGF. However,rhNGF is clinically unavailable and smoked cannabis cannot be recommended as routine therapy. Evaluation of novel management strategies for painful HIV-SN is urgently needed.     

Effects of statins in patients with chronic kidney disease: meta-analysis and meta-regression of randomised controlled trials

Objective To analyse the benefits and harms of statins in patients with chronic kidney disease (pre-dialysis, dialysis, and transplant populations).Design Meta-analysis.Data sources Cochrane Central Register of Controlled Trials, Medline, Embase, and Renal Health Library (July 2006).Study selection Randomised and quasi-randomised controlled trials of statins compared with placebo or other statins in chronic kidney disease.Data extraction and analysis Two reviewers independently assessed trials for inclusion, extracted data, and assessed trial quality. Differences were resolved by consensus. Treatment effects were summarised as relative risks or weighted mean differences with 95% confidence intervals by using a random effects model.Results Fifty trials (30 144 patients) were included. Compared with placebo, statins significantly reduced total cholesterol (42 studies, 6390 patients; weighted mean difference −42.28 mg/dl (1.10 mmol/l), 95% confidence interval −47.25 to −37.32), low density lipoprotein cholesterol (39 studies, 6216 patients; −43.12 mg/dl (1.12 mmol/l), −47.85 to −38.40), and proteinuria (g/24 hours) (6 trials, 311 patients; −0.73 g/24 hour, −0.95 to −0.52) but did not improve glomerular filtration rate (11 studies, 548 patients; 1.48 ml/min (0.02 ml/s), −2.32 to 5.28). Fatal cardiovascular events (43 studies, 23 266 patients; relative risk 0.81, 0.73 to 0.90) and non-fatal cardiovascular events (8 studies, 22 863 patients; 0.78, 0.73 to 0.84) were reduced with statins, but statins had no significant effect on all cause mortality (44 studies, 23 665 patients; 0.92, 0.82 to 1.03). Meta-regression analysis showed that treatment effects did not vary significantly with stage of chronic kidney disease. The side effect profile of statins was similar to that of placebo. Most of the available studies were small and of suboptimal quality; mortality data were provided by a few large trials only.Conclusion Statins significantly reduce lipid concentrations and cardiovascular end points in patients with chronic kidney disease, irrespective of stage of disease, but no benefit on all cause mortality or the role of statins in primary prevention has been established. Reno-protective effects of statins are uncertain because of relatively sparse data and possible outcomes reporting bias.     

Strategies for increasing recruitment to randomised controlled trials: systematic review

Background

Recruitment of participants into randomised controlled trials (RCTs) is critical for successful trial conduct. Although there have been two previous systematic reviews on related topics, the results (which identified specific interventions) were inconclusive and not generalizable. The aim of our study was to evaluate the relative effectiveness of recruitment strategies for participation in RCTs.

Methods and Findings

A systematic review, using the PRISMA guideline for reporting of systematic reviews, that compared methods of recruiting individual study participants into an actual or mock RCT were included. We searched MEDLINE, Embase, The Cochrane Library, and reference lists of relevant studies. From over 16,000 titles or abstracts reviewed, 396 papers were retrieved and 37 studies were included, in which 18,812 of at least 59,354 people approached agreed to participate in a clinical RCT. Recruitment strategies were broadly divided into four groups: novel trial designs (eight studies), recruiter differences (eight studies), incentives (two studies), and provision of trial information (19 studies). Strategies that increased people''s awareness of the health problem being studied (e.g., an interactive computer program [relative risk (RR) 1.48, 95% confidence interval (CI) 1.00–2.18], attendance at an education session [RR 1.14, 95% CI 1.01–1.28], addition of a health questionnaire [RR 1.37, 95% CI 1.14–1.66]), or a video about the health condition (RR 1.75, 95% CI 1.11–2.74), and also monetary incentives (RR1.39, 95% CI 1.13–1.64 to RR 1.53, 95% CI 1.28–1.84) improved recruitment. Increasing patients'' understanding of the trial process, recruiter differences, and various methods of randomisation and consent design did not show a difference in recruitment. Consent rates were also higher for nonblinded trial design, but differential loss to follow up between groups may jeopardise the study findings. The study''s main limitation was the necessity of modifying the search strategy with subsequent search updates because of changes in MEDLINE definitions. The abstracts of previous versions of this systematic review were published in 2002 and 2007.

Conclusion

Recruitment strategies that focus on increasing potential participants'' awareness of the health problem being studied, its potential impact on their health, and their engagement in the learning process appeared to increase recruitment to clinical studies. Further trials of recruitment strategies that target engaging participants to increase their awareness of the health problems being studied and the potential impact on their health may confirm this hypothesis. Please see later in the article for the Editors'' Summary     

Commentary: educational initiatives deserve randomised controlled trials.

The media have been full of reports of crisis in the NHS. Although national analyses suggest that the NHS should be able to cope within the increases in spending it has been given, local pressures can leave parts of the service struggling. Firstly, the change to allocation of funds on the basis of population needs has meant that some authorities and trusts have had effective cuts in their budgets, requiring them to trim services. Secondly, the government''s insistence on an annual 3% increase in efficiency may have resulted in authorities taking short term measures that actually decrease efficiency in the long term. Thirdly, health authorities have had to bear the costs of national targets such as reducing waiting lists and junior doctors'' hours as well as local problems such as higher numbers of mentally disordered offenders. However, all these factors can be controlled by national or local management and so their impact is not inevitable.     

Methylxanthines for exacerbations of chronic obstructive pulmonary disease: meta-analysis of randomised trials

Objective To evaluate the addition of methylxanthines to standard treatments in patients presenting with acute exacerbations of chronic obstructive pulmonary disease (COPD).Design Meta-analysis of randomised controlled trials.Data source The Cochrane airways review group''s COPD register. Two reviewers independently selected articles for inclusion, assessed methodological quality, and extracted data.Selection of studies Four trials met the inclusion criteria, with 169 patients.Main outcome measures Mean change in spirometry, clinical end points, symptom scores, and adverse events.Results Mean change in forced expiratory volume at one second at two hours was similar in methylxanthine and placebo groups but transiently increased with methylxanthines at three days. Non-significant reductions in admissions to hospital and length of stay were offset by a non-significant increase in relapses at one week. Changes in symptom scores did not reach significance. Methylxanthines caused more nausea and vomiting than placebo (odds ratio 4.6, 95% confidence interval 1.7 to 12.6), and non-significant increases in tremor, palpitations, and arrhythmias were also observed.Conclusions The available data do not support the use of methylxanthines for the treatment of exacerbations of chronic obstructive pulmonary disease. Potential benefits of methylxanthines for lung function and symptoms were generally not confirmed at standard levels of significance, whereas the potentially important adverse events of nausea and vomiting were significantly increased in patients receiving methylxanthines.