A systematic survey of randomised trials that stopped early for reasons of futility.

BACKGROUND: Randomised trial protocols may incorporate interim analyses, with the potential to stop the study for futility if early data show insufficient promise of a treatment benefit. Previously, we have shown that this approach will theoretically lead to mis-estimation of the treatment effect. We now wished to ascertain the importance of this phenomenon in practice. METHODS: We reviewed the methods and results in a set of trials that had stopped for futility, identified through an extensive literature search. We recorded clinical areas, interventions, study design, outcomes, trial setting, sponsorship, planned and actual treatment effects, sample sizes; power; and if there was a data safety monitoring board, or a published protocol. We identified: if interim analyses were pre-specified, and how many analyses actually occurred; what pre-specified criteria might define futility; if a futility analysis formed the basis for stopping; who made the decision to stop; and the conditional power of each study, i.e. the probability of statistically significant results if the study were to continue to its complete sample size. RESULTS: We identified 52 eligible trials, covering many clinical areas. Most trials had multiple centres, tested drugs, and 40% were industry sponsored. There were 75% where at least one interim analysis was planned a priori; a majority had only one interim analysis, typically with about half the target total sample size. A majority of trials did not pre-define a stopping rule, and a variety of reasons were given for stopping. Few studies calculated and reported low conditional power to justify the early stop. When conditional power could be calculated, it was typically low, especially under the current trend hypothesis. However, under the original design hypothesis, a few studies had relatively high conditional power. Data collection often continued after the interim analysis. CONCLUSIONS: Although other factors will typically be involved, we conclude that, from the perspective of conditional power, stopping early for futility was probably reasonable in most cases, but documentation of the basis for stopping was often missing or vague. Interpretation of truncated trials would be enhanced by improved reporting of stopping protocols, and of their actual execution.

Reducing False Alarm Rates in Neonatal Intensive Care: A New Machine Learning Approach.

In neonatal intensive care units (NICUs), 87.5% of alarms by the monitoring system are false alarms, often caused by the movements of the neonates. Such false alarms are not only stressful for the neonates as well as for their parents and caregivers, but may also lead to longer response times in real critical situations. The aim of this project was to reduce the rates of false alarms by employing machine learning algorithms (MLA), which intelligently analyze data stemming from standard physiological monitoring in combination with cerebral oximetry data (in-house built, OxyPrem). MATERIALS & METHODS: Four popular MLAs were selected to categorize the alarms as false or real: (i) decision tree (DT), (ii) 5-nearest neighbors (5-NN), (iii) naïve Bayes (NB) and (iv) support vector machine (SVM). We acquired and processed monitoring data (median duration (SD): 54.6 (± 6.9) min) of 14 preterm infants (gestational age: 26 6/7 (± 2 5/7) weeks). A hybrid method of filter and wrapper feature selection generated the candidate subset for training these four MLAs. RESULTS: A high specificity of >99% was achieved by all four approaches. DT showed the highest sensitivity (87%). The cerebral oximetry data improved the classification accuracy. DISCUSSION & CONCLUSION: Despite a (as yet) low amount of data for training, the four MLAs achieved an excellent specificity and a promising sensitivity. Presently, the current sensitivity is insufficient since, in the NICU, it is crucial that no real alarms are missed. This will most likely be improved by including more subjects and data in the training of the MLAs, which makes pursuing this approach worthwhile.

Randomised trials with provision for early stopping for benefit (or harm): The impact on the estimated treatment effect.

Stopping rules for clinical trials are primarily intended to control Type I error rates if interim analyses are planned, but less is known about the impact that potential stopping has on estimating treatment benefit. In this paper, we derive analytic expressions for (1) the over-estimation of benefit in studies that stop early, (2) the under-estimation of benefit in completed studies, and (3) the overall bias in studies with a stopping rule. We also examine the probability of stopping early and the situation in meta-analyses. Numerical evaluations show that the greatest concern is with over-estimation of benefit in stopped studies, especially if the probability of stopping early is small. The overall bias is usually less than 10% of the true benefit, and under-estimation in completed studies is also typically small. The probability of stopping depends on the true treatment effect and sample size. The magnitude of these effects depends on the particular rule adopted, but we show that the maximum overall bias is the same for all stopping rules. We also show that an essentially unbiased meta-analysis estimate of benefit can be recovered, even if some component studies have stopping rules. We illustrate these methods using data from three clinical trials. The results confirm our earlier empirical work on clinical trials. Investigators may consult our numerical results for guidance on potential mis-estimation and bias in the treatment effect if a stopping rule is adopted. Particular concern is warranted in studies that actually stop early, where interim results may be quite misleading.

Physiological and emotional effects of pentatonic live music played for preterm neonates and their mothers in the Newborn Intensive Care Unit: A randomized controlled trial.

OBJECTIVE: Despite attempts to increase calmness in the Newborn Intensive Care Unit (NICU), preterm neonates still experience stress. The question arises how to further promote the infants' wellbeing. Therefore, the immediate effects of pentatonic live music on preterm infants and their mothers were examined. DESIGN AND METHODS: In a two-centre randomized controlled trial with crossover design preterm infants were exposed sequentially to two conditions: live pentatonic harp music (LPHM) used in Anthroposophic Medicine or standard care. The order of the conditions was randomized within each subject. The primary outcome was change of the number of oxygen desaturations < 90%/h, whereas secondary outcomes were: heart rate, respiratory rate, oxygen saturation, heart rate variability (HRV), the perfusion index, pulse-transit-time and maternal anxiety and others not reported on in this article. RESULTS: 21 preterm infants were randomized (14 girls), mean gestational age at measurement 35 + 0 weeks (SD 1 week). The primary outcome parameter showed no significant changes. Regarding the secondary outcomes the comparison of the pre-post-differences between the conditions showed significant effects for the HRV parameters pNN50 (ΔpNN50 = 1.46%, z = -2.47, p = .001) and SDNN (ΔSDNN=-0.06 ms, z = -2.25, p = .002). The music intervention significantly increased the values of pNN50 (Mdn 1.2% vs. 2.6%, p = 0.04) and marginally those of SDNN (Mdn 31.7 ms vs. 36.4 ms, p = 0.05). No changes were found in the other parameters. CONCLUSIONS: While the use of music in the NICU had no effect on the number of oxygen desaturations, it increased two HRV parameters indicative of infants' parasympathetic tone.

Retrospective cohort study of all deaths among infants born between 22 and 27 completed weeks of gestation in Switzerland over a 3-year period.

OBJECTIVES: The aim of this research is to assess causes and circumstances of deaths in extremely low gestational age neonates (ELGANs) born in Switzerland over a 3-year period. DESIGN: Population-based, retrospective cohort study. SETTING: All nine level III perinatal centres (neonatal intensive care units (NICUs) and affiliated obstetrical services) in Switzerland. PATIENTS: ELGANs with a gestational age (GA) <28 weeks who died between 1 July 2012 and 30 June 2015. RESULTS: A total of 594 deaths were recorded with 280 (47%) stillbirths and 314 (53%) deaths after live birth. Of the latter, 185 (59%) occurred in the delivery room and 129 (41%) following admission to an NICU. Most liveborn infants dying in the delivery room had a GA ≤24 weeks and died following primary non-intervention. In contrast, NICU deaths occurred following unrestricted life support regardless of GA. End-of-life decision-making and redirection of care were based on medical futility and anticipated poor quality of life in 69% and 28% of patients, respectively. Most infants were extubated before death (87%). CONCLUSIONS: In Switzerland, most deaths among infants born at less than 24 weeks of gestation occurred in the delivery room. In contrast, most deaths of ELGANs with a GA ≥24 weeks were observed following unrestricted provisional intensive care, end-of-life decision-making and redirection of care in the NICU regardless of the degree of immaturity.

Perinatal health services organization for preterm births: a multinational comparison.

OBJECTIVE: To explore population characteristics, organization of health services and comparability of available information for very low birth weight or very preterm neonates born before 32 weeks' gestation in 11 high-income countries contributing data to the International Network for Evaluating Outcomes of Neonates (iNeo). STUDY DESIGN: We obtained population characteristics from public domain sources, conducted a survey of organization of maternal and neonatal health services and evaluated the comparability of data contributed to the iNeo collaboration from Australia, Canada, Finland, Israel, Italy, Japan, New Zealand, Spain, Sweden, Switzerland and UK. RESULTS: All countries have nationally funded maternal/neonatal health care with >90% of women receiving prenatal care. Preterm birth rate, maternal age, and neonatal and infant mortality rates were relatively similar across countries. Most (50 to >95%) between-hospital transports of neonates born at non-tertiary units were conducted by designated transport teams; 72% (8/11 countries) had designated transfer and 63% (7/11 countries) mandate the presence of a physician. The capacity of 'step-down' units varied between countries, with capacity for respiratory care available in <10% to >75% of units. Heterogeneity in data collection processes for benchmarking and quality improvement activities were identified. CONCLUSIONS: Comparability of healthcare outcomes for very preterm low birth weight neonates between countries requires an evaluation of differences in population coverage, healthcare services and meta-data.

Caffeine for apnea of prematurity: a neonatal success story.

Caffeine, a methylxanthine and nonspecific inhibitor of adenosine receptors, is an example of a drug that has been in use for more than 40 years. It is one of the most commonly prescribed drugs in neonatal medicine. However, until 2006, it had only a few relatively small and short-term studies supporting its use. It is thanks to the efforts of Barbara Schmidt and the Caffeine for Apnea of Prematurity (CAP) Trial Group that we now have high-quality and reliable data not only on short-term but also long-term outcomes of caffeine use for apnea of prematurity. CAP was an international, multicenter, placebo-controlled randomized trial designed to determine whether survival without neurodevelopmental disability at a corrected age of 18 months is improved if apnea of prematurity is managed without methylxanthines in infants at a high risk of apneic attacks. CAP was kept simple and pragmatic in order to allow for maximum generalizability and applicability. Infants with birth weights of 500-1,250 g were enrolled during the first 10 days of life if their clinicians considered them to be candidates for methylxanthine therapy. The most frequent indication for therapy reported in CAP was treatment of documented apnea, followed by the facilitation of the removal of an endotracheal tube. Only about 20% of the neonatologists in the trial started caffeine for the prevention of apnea and the findings of CAP cannot automatically be extrapolated to an exclusive prophylactic indication. However, recent data suggest that the administration of prophylactic methylxanthine by neonatologists is now common practice.

Survey of practices regarding utilization of inhaled steroids in 223 German neonatal units.

BACKGROUND: No survey has been published in recent years which primarily focuses on the prescription of inhaled corticosteroids in neonatal practice. Thus, the utilization rate of inhaled corticosteroids is unknown. OBJECTIVES: To elucidate the current utilization rate of inhaled corticosteroids in the prevention and therapy of bronchopulmonary dysplasia (BPD). METHODS: We developed an 18-item questionnaire that was distributed in March 2009, via electronic mail, to the pediatricians-in-chief of all the 343 German pediatric hospitals with a neonatal unit (all levels of neonatal care). We sent electronic reminders after 4 and 8 weeks. RESULTS: 223 hospitals (65%) returned the questionnaire. Of these, 102 (46%) administered inhaled corticosteroids to premature infants either as prophylaxis or treatment for BPD. Predominantly, treatment with inhaled steroids was seen as a 'rescue therapy' and used only if other therapeutic approaches had failed. Of the hospitals not administering inhaled steroids, the most frequently stated reason was 'insufficient robust evidence to support benefit of therapy' (57%). In the majority of hospitals (81%), the active substance of choice was budesonide. CONCLUSIONS: Of the responders, approximately 50% administer inhaled corticosteroids to premature infants either as a prophylaxis or treatment for BPD. Lack of beneficial evidence was the main reason for not administering inhaled steroids in about half of the units which took this approach. Future trials should address this discrepancy by aiming to establish a clear benefit-risk ratio of inhaled corticosteroids.

Nurses' compliance with alarm limits for pulse oximetry: qualitative study.

OBJECTIVE: Monthly audits for the multicenter Canadian Oxygen Trial have shown that our neonatal team has consistently maintained study participants within the intended pulse oximetry alarm limits between 68 and 79% of the time during the first 3 days of life while infants were receiving supplemental oxygen. This good performance prompted us to explore our nurses' perceptions of what makes them compliant with alarm limits for pulse oximetry in preterm infants. STUDY DESIGN: The local neonatal research nurse interviewed all 41 staff nurses in the neonatal intensive care unit at the University Children's Hospital in Tuebingen, Germany, for this qualitative study. RESULT: Nurses identified education (22/41), prompt response to alarms (22/41), a favorable patient-to-staff ratio (18/41), root cause analysis at the bedside (15/41), and the high priority given to control of oxygen therapy in the department (14/41) as the five most important determinants of their good compliance. CONCLUSION: These findings may be useful for other neonatal teams who struggle to improve their compliance with alarm limits for pulse oximetry.

Early interventions involving parents to improve neurodevelopmental outcomes of premature infants: a meta-analysis.

OBJECTIVE: To determine in a systematic review, whether interventions for infant development that involve parents, improve neurodevelopment at 12 months corrected age or older. STUDY DESIGN: Randomized trials were identified where an infant intervention was aimed to improve development and involved parents of preterms; and long-term neurodevelopment using standardized tests at 12 months (or longer) was reported. RESULT: Identified studies (n=25) used a variety of interventions including parent education, infant stimulation, home visits or individualized developmental care. Meta-analysis at 12 months (N=2198 infants) found significantly higher mental (N=2198) and physical (N=1319) performance scores favoring the intervention group. At 24 months, the mental (N=1490) performance scores were improved, but physical (N=1025) performance scores were not statistically significant. The improvement in neurodevelopmental outcome was not sustained at 36 months (N=961) and 5 years (N=1017). CONCLUSION: Positive clinically meaningful effects (>5 points) are seen to an age of 36 months, but are no longer present at 5 years.

Probiotics for prevention of necrotizing enterocolitis in preterm infants.

BACKGROUND: Necrotizing enterocolitis (NEC) and nosocomial sepsis are associated with increased morbidity and mortality in preterm infants. Through prevention of bacterial migration across the mucosa, competitive exclusion of pathogenic bacteria, and enhancing the immune responses of the host, prophylactic enteral probiotics (live microbial supplements) may play a role in reducing NEC and associated morbidity. OBJECTIVES: To compare the efficacy and safety of prophylactic enteral probiotics administration versus placebo or no treatment in the prevention of severe NEC and/or sepsis in preterm infants. SEARCH STRATEGY: The standard search strategy for the Cochrane Neonatal Review Group was performed by two review authors. Searches were made of MEDLINE (1966 to December 2006), EMBASE (1980 to December 2006), Cochrane Library Controlled Trials Register (CENTRAL, The Cochrane Library Issue 3, 2006), and abstracts of annual meetings of the Society for Pediatric Research (1995 - 2006). The authors of published articles were contacted. SELECTION CRITERIA: Only randomized or quasi-randomized controlled trials that enrolled preterm infants < 37 weeks gestational age and/or < 2500 g birth weight were considered. Trials were included if they involved enteral administration of any live microbial supplement (probiotics) and measured at least one prespecified clinical outcome. DATA COLLECTION AND ANALYSIS: Standard methods of the Cochrane Collaboration and its Neonatal Group were used to assess the methodologic quality of the trials. Retrieved articles were assessed for eligibility and data abstracted independently by two review authors. Where data were incomplete, the primary investigator were contacted for further information and clarification. Where appropriate, data of individual trials were combined using meta-analytic techniques to provide a pooled estimate of effect assuming a fixed effect model. MAIN RESULTS: Nine eligible trials randomizing 1425 infants were included. Included trials were highly variable with regard to enrollment criteria (i.e. birth weight and gestational age), baseline risk of NEC in the control groups, timing, dose, formulation of the probiotics, and feeding regimens. Data regarding extremely low birth weight infants (ELBW) could not be extrapolated. In a meta-analysis of trial data, enteral probiotics supplementation significantly reduced the incidence of severe NEC (stage II or more) [typical RR 0.32 (95% CI 0.17, 0.60)] and mortality [typical RR 0.43 (95% CI 0.25, 0.75]. There was no evidence of significant reduction of nosocomial sepsis [typical RR 0.93 (95% CI 0.73, 1.19)] or days on total parenteral nutrition (TPN) [WMD -1.9 (95% CI -4.6, 0.77)]. The included trials reported no systemic infection with the probiotics supplemental organism. The statistical test of heterogeneity for NEC, mortality and sepsis was insignificant. AUTHORS' CONCLUSIONS: Enteral supplementation of probiotics reduced the risk of severe NEC and mortality in preterm infants. This analysis supports a change in practice in premature infants > 1000 g at birth. Data regarding outcome of ELBW infants could not be extracted from the available studies; therefore, a reliable estimate of the safety and efficacy of administration of probiotic supplements cannot be made in this high risk group. A large randomized controlled trial is required to investigate the potential benefits and safety profile of probiotics supplementation in ELBW infants.

Evaluating the evidence for assessing BNP and NT-proBNP levels.

OBJECTIVES: To provide an overview of 5 systematic reviews in this issue of Clinical Biochemistry addressing the diagnostic and prognostic power of natriuretic peptides. DESIGN AND METHODS: Editorial. RESULTS: Limited quality of the primary studies and the large variability in their results limit the inferences that can be drawn from reviews in this series. CONCLUSIONS: The current data justify neither enthusiastic use, nor confident rejection, of BNP and NT-proBNP levels to inform the prognosis or diagnosis of heart failure.

Antithrombin for respiratory distress syndrome in preterm infants.

BACKGROUND: Acquired Antithrombin (AT) deficiency is a common and prognostically important finding in sick preterm infants with respiratory distress syndrome (RDS). It has been hypothesised that AT concentrate may improve clinical outcomes in preterm infants with RDS. OBJECTIVES: To determine whether the administration of AT concentrate decreases mortality in preterm infants with RDS compared with placebo or no treatment. SEARCH STRATEGY: An electronic literature search in the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE in August 2006 was performed. No language restriction was applied. References from identified studies were cross-checked for possible additional studies. Experts in the field and pharmaceutical companies were contacted for unpublished data. Abstracts of the American Society of Pediatric Research and European Society of Pediatric Research meetings (1983-2005) were searched and authors of relevant studies were contacted to obtain additional information. SELECTION CRITERIA: Randomized controlled trials comparing any dose and duration of AT therapy with placebo or no treatment in preterm infants with RDS. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data from included studies regarding mortality, intraventricular hemorrhage, mechanical ventilation, and other reported events in the clinical course of the patients. Data for similar outcomes were combined where appropriate, using a fixed-effects model in MetaView 4.2 (Update Software). MAIN RESULTS: Two trials consisting of 182 preterm infants, fulfilled the inclusion criteria. Mean gestational age of patients included was 28 weeks. In one trial, patients had to be intubated and ventilated for RDS to be eligible for the study. In the other trial, RDS was not mentioned as an inclusion criteria, however the vast majority of infants in the study received surfactant. No individual trial showed a significant difference in mortality. One of the trials was stopped early because of an increase in deaths in the AT group. The pooled analysis for mortality within the first week of life showed a typical relative risk of 2.67 (95% CI 0.72-9.83) in favour of the control group. Only the trial that was stopped early followed the infants long enough to report neonatal mortality. This trial reported 7 deaths (11.5%) in the AT group and two deaths (3.3%) in the placebo group within 28 days of life. Secondary outcomes included days of mechanical ventilation and supplemental oxygen which were only reported in 1 trial. Both outcomes were in favour of the control group and statistically significant (p < 0.05). AUTHORS' CONCLUSIONS: Preterm infants with RDS are unlikely to benefit from AT treatment and may be harmed.

Intravenous aminophylline for acute severe asthma in children over two years receiving inhaled bronchodilators.

BACKGROUND: Since the advent of inhaled beta2-agonists, anticholinergic agents and glucocorticoids, the role of aminophylline in paediatric acute asthma has become less clear. There remains some consensus that it is beneficial in children with acute severe asthma, receiving maximised therapy (oxygen, inhaled bronchodilators, and glucocorticoids). OBJECTIVES: To determine if the addition of intravenous aminophylline produces a beneficial effect in children with acute severe asthma receiving conventional therapy. SEARCH STRATEGY: The Cochrane Airways Group register of trials was used to identify relevant studies. The latest search was carried out in December 2004 SELECTION CRITERIA: Randomised-controlled trials comparing intravenous aminophylline with placebo in addition to usual care in children met the inclusion criteria. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed studies and extracted data. Disagreement in the selection of trials was resolved by consensus. Attempts were made to contact authors to verify accuracy of data. MAIN RESULTS: Seven trials met the inclusion criteria (380 participants). Methodological quality was high. All studies recruited children with acute severe asthma and requiring hospital admission. Six studies sought participants who were unresponsive to nebulised short-acting beta-agonist and administered systemic steroids to study participants. In two studies where some children were able to perform spirometry, baseline FEV1 was between 35 and 45% predicted. The addition of aminophylline to steroids and beta2-agonist significantly improved FEV1% predicted over placebo at 6-8 hours, 12-18 hours and 24 hours. Aminophylline led to a greater improvement in PEF% predicted over placebo at 12-18 hours. There was no significant difference in length of hospital stay, symptoms, frequency of nebulsations and mechanical ventilation rates. There were insufficient data to permit aggregation for oxygenation and duration of supplemental oxygen therapy. Aminophylline led to a three-fold increase in the risk of vomiting. There was no significant difference between treatment groups with regard to hypokalaemia, headaches, tremour, seizures, arrhythmias and deaths. AUTHORS' CONCLUSIONS: In children with a severe asthma exacerbation, the addition of intravenous aminophylline to beta2-agonists and glucocorticoids (with or without anticholinergics) improves lung function within 6 hours of treatment. However there is no apparent reduction in symptoms, number of nebulised treatment and length of hospital stay. There is insufficient evidence to assess the impact on oxygenation, PICU admission and mechanical ventilation. Aminophylline is associated with a significant increased risk of vomiting.

[The German guideline clearing-project on bronchial asthma - part 2: recommendations and key topics for a national guideline on bronchial asthma]. / Das Leitlinien-Clearingverfahren Asthma bronchiale - 2. Empfehlungen zu Eckpunkten für eine nationale Leitlinie Asthma bronchiale.

BACKGROUND: In order to promote the quality of asthma management in Germany, a national asthma guidelines clearing project was initiated in 2000 by the German Guidelines Clearinghouse (Sponsors: German Medical Association (GMA), National Association of the Statutory Health Insurance Physicians (NASHIP), German Hospital Federation, Federal Association of the Statutory Sickness Funds. This Part shows the key topics which should be dealt with in a German guideline on bronchial asthma. SUMMARY POINTS: For quality promotion of bronchial asthma management in Germany, the development of a national evidence-based guideline, using the internationally accepted quality criteria for clinical practice guidelines, was recommended by an expert group of the German Guideline Clearinghouse. The experts identified and peer-reviewed 16 out of 54 guidelines, which might be useful as benchmarks and examples for a German asthma guideline. From the peer review results, the expert group identified 18 key topics for a national asthma guideline.

Ketotifen alone or as additional medication for long-term control of asthma and wheeze in children.

BACKGROUND: Ketotifen is an antihistamine which may be used to treat asthma. Since administering inhaled therapy to younger children can be difficult, an oral agent such as ketotifen offers potential advantages. OBJECTIVES: The objective of this review is to determine, whether ketotifen alone or in combination with other co-interventions results in better control of asthma in children with asthma and/or wheezing and examine its safety profile. SEARCH STRATEGY: We searched the Cochrane Airways Group register of trials (based on MEDLINE, EMBASE, CINAHL and handsearched respiratory journals) and reference lists of articles. The latest search was carried out in October 2002. SELECTION CRITERIA: Clinical studies had to be randomised-controlled and double-blinded, comparing oral ketotifen with placebo in children with asthma and/or wheeze for at least eight weeks at a dose not less than one mg daily. DATA COLLECTION AND ANALYSIS: Two reviewers independently performed selection of trials, quality assessment and data extraction; a third reviewer was included in the consensus process if necessary. MAIN RESULTS: A total of 26 relevant studies involving 1826 participants were included in this review. Children's age ranged from 4 months to 18 years and ketotifen was given between 10 and 32 weeks. The proportion of children able to reduce or stop their bronchodilator use within 12 to 16 weeks of treatment was significantly higher in the ketotifen group (relative risk 2.39, 95% CI 1.64 to 3.48) based on four trials; this result was statistically significant in a subgroup of two trials with well described and adequate method of blinding. Statistically significant beneficial effects of ketotifen were also observed in the following secondary outcomes: efficacy evaluated by physician (10 trials) and parents/patients (7 trials), asthma symptom score (4 trials), asthma exacerbations (2 trials), and reduction in use of oral steroids (4 trials). However, sub-group analyses of trials with well described and adequate method of blinding was only significant for the outcome asthma symptom score and non-significant for the remaining secondary outcomes. Reported side effects were more frequent in the ketotifen group (sedation: 21%, weight gain: 27%) than in the placebo group (sedation: 12%, weight gain: 17%). REVIEWER'S CONCLUSIONS: Evidence from randomised controlled trials indicates that ketotifen alone or in combination with other co-interventions improves control of asthma and wheezing in children with mild and moderate asthma. However due to the high proportion of children with atopy in some trials the results cannot necessarily be generalised to all asthmatic children. The benefit is obtained at the cost of minor side effects, namely sedation and weight gain. The validity of this conclusion is limited by the low reported, methodological quality of included trials.

[The German guideline clearing-project on bronchial asthma-part 1: Methodology and results of formal appraisal]. / Das Leitlinien-Clearingverfahren Asthma bronchiale--1. Methodik und Ergebnisse der formalen Bewertung.

BACKGROUND: In order to promote quality of asthma management in Germany, a national asthma guidelines clearing project was initiated in 2000 by the German Guidelines Clearinghouse (Sponsors: German Medical Association (GMA), National Association of the Statutory Health Insurance Physicians (NASHIP), German Hospital Federation, Federal Association of the Statutory Sickness Funds. Part 1 of this article shows the methodology and the results of the appraisal, part 2 (to be published) shows the key topics which should be dealt with in a german guideline on bronchial asthma. OBJECTIVES: To identify and compare evidence-based, high-quality German- and English language asthma guidelines as benchmarks for ongoing guideline development and implementation programmes. To disseminate information about asthma guidelines developed in accordance with current methodological know-how. To identify and consent key topics for a national evidence-based guideline for Germany. METHODS: Search procedure, formal appraisal: Systematic search using literature databases (XMED, incl. Medline and Embase) and English-/German-language guideline databases (via www. leitlinien.de), published between January 1990 and March 2000. Abstract screening of the search results according to the inclusion criteria (n = 54 of a total of 502 hits). Methodological guideline evaluation of 16 guidelines using the German checklist for methodological guideline appraisal. Appraisal of guidelines' contents: Peer review of guidelines with the following inclusion criteria: Bronchial Asthma-general, German and English language, based in references published later than 1994, new guideline or actual update. Peer review was performed by a multidisciplinary focus group of EBM experts (clinical and ambulatory settings). No expert was involved in guideline production during the review period. RESULTS: Methodological appraisal: 16 out of guidelines were in accordance with the formal minimal standard with a wide range within the following domains: "description of the development process", "declaration of authors' independence", "explicit link between recommendations and the supporting evidence", "management options", "tools for implementation". The focus group recommended for future national asthma guidelines to rely on the following procedures: (1) to formulate the recommendations using standardized, clearly described consensus methods basing on evidence retrieved and selected in a systematic way (2) to prove links between recommendations and supporting evidence (3) to develop guideline versions for health care professionals as well as for consumer/patients (4) to develop guideline-based education tools (5) to ensure periodical updates of the asthma guideline (6) to consider the methodological recommendations and to give reasons for deviations from the methodological recommendations. APPRAISAL OF GUIDELINES CONTENT: None of the guidelines identified comprised information about all of the following key topics considered to be relevant for a German national guideline by the focus group: (1) intended guideline users/goals, (2) definition (3) cause of disease, (4) form of disease, (5) severity, (6) diagnosis, (7) therapeutic goals, (8) prevention, (9) pharmacotherapy, (10) non-pharmacotherapy, (11) therapy control and compliance, (12) emergency treatment, (13) rehabilitation, (14) comorbidity, (15) special aspects, (16) coordination of care, (17) quality assurance/quality management, (18) implementation. SUMMARY POINTS: For quality promotion of bronchial asthma management in Germany, the development of a national evidence-based guideline, using the internationally accepted quality criteria for clinical practice guidelines, was recommended by an expert group of the German Guideline Clearinghouse. The experts identified and peer-reviewed 16 out of 54 guidelines, which might be useful as benchmarks and examples for a German asthma guideline. From the peer review results, the expert group identified 18 key topics for a national asthma guideline.

Ursodeoxycholic acid and/or antibiotics for prevention of biliary stent occlusion.

BACKGROUND: Malignant biliary obstruction, which requires endoscopic stenting as palliative therapy, is often complicated by clogging of the stent with subsequent jaundice and/or cholangitis. Stent clogging may be caused by microbiological adhesion and biliary stasis. Therefore, antibiotics and choleretic agents like ursodeoxycholic acid (UDCA) have been investigated to see whether they prolong stent patency. OBJECTIVES: To evaluate if UDCA and/or antibiotics may prolong stent patency and survival in patients with strictures of the biliary tract and endoscopically inserted stents. SEARCH STRATEGY: The Trials Register of The Cochrane Hepato-Biliary Group, The Cochrane Library, MEDLINE, Current Contents, EMBASE, and CancerLit were searched until June 2001. Reference lists of the identified articles were checked for further trials. SELECTION CRITERIA: All randomised or quasi-randomised clinical trials investigating UDCA and/or antibiotics in patients with biliary stents were considered for inclusion, regardless of blinding, language, and publication status. DATA COLLECTION AND ANALYSIS: Trial inclusion, quality assessment, and data extraction were performed independently by two reviewers. Principal investigators were contacted for further information. Survival data were combined by using hazard ratios (with 95% confidence interval (95% CI)). MAIN RESULTS: Five non-blinded randomised trials with 258 patients with malignant strictures treated with polyethylene stents were included. Three trials, including 152 patients, investigated a combination of UDCA and antibiotics versus no treatment. The meta-analysis of these three trials does not show a significant treatment effect on the duration of stent patency (hazard ratio (random effects model) 0.58, 95% CI 0.22 to 1.54) or mortality (hazard ratio (fixed effect model) 0.99, 95% CI 0.68 to 1.43). Two trials with 106 patients compared antibiotics with no treatment, one of these trials used a combination of antibiotics and rowachol (an 'alternative' drug of the 'mint' family). The pooled results of these two trials do not show significant effects of antibiotics on the duration of stent patency (hazard ratio (fixed effect model) 0.69 (95% CI 0.37 to 1.30)) or mortality (hazard ratio (fixed effect model) 1.23 (95% CI 0.72 to 2.08). Data concerning duration of hospital stay, frequency of cholangitis, and rate of infectious complications due to selection of antibiotic resistant bacteria strains were not available. REVIEWER'S CONCLUSIONS: Treatment with UDCA and/or antibiotics to prevent clogging of biliary stents in patients with malignant stricture of the biliary tract cannot be recommended routinely on the basis of the existing randomised clinical trials. Further trials are needed with rigorous methodology and sufficient statistical power.

Intravenous aminophylline for acute severe asthma in children over 2 years using inhaled bronchodilators.

BACKGROUND: Intravenous aminophylline was the bronchodilator of choice for many years until supplanted by more effective bronchodilators in the treatment of acute paediatric asthma. Recently there has been renewed interest in this therapy for children with acute severe asthma. OBJECTIVES: To determine whether addition of intravenous aminophylline produces a beneficial effect in children with acute severe asthma receiving oxygen, maximised inhaled bronchodilators and oral/intravenous glucocorticoids. SEARCH STRATEGY: The Cochrane Airways Group register of trials (based on MEDLINE, EMBASE, CINAHL and hand searched respiratory journals) and reference lists of relevant articles were used to identify relevant studies. The latest search was carried out in October 2000. SELECTION CRITERIA: Only randomised-controlled trials comparing intravenous aminophylline with placebo in children treated with inhaled bronchodilators and systemic glucocorticoids for acute asthma were considered for this review. DATA COLLECTION AND ANALYSIS: Full text of 35 trials were anonymized for author, date and publication and two blinded independent reviewers selected eligible studies for inclusion. Disagreement was resolved through consensus. Seven trials met the inclusion criteria. Attempts were made to contact authors to verify accuracy. Results were reported as weighted mean differences (WMD) or relative risk (RR) with 95% confidential intervals (CI). MAIN RESULTS: Patients in these trials were predominantly school-aged children hospitalised for acute severe asthma with a baseline FEV1 at 35-40% of predicted and/or a baseline Pulmonary Index of 6-7. Aminophylline significantly improved percentage predicted FEV1 by 6 - 8 hours (WMD 8.4%; 95% CI: 0.82, 15.92%). The effect was maintained for 24 hours. Improvements were also seen in symptom scores at 6-8 hours (WMD= -0.71; 95% CI: -0.82,-0.60). There was no reduction in hospital stay or in number of nebulisers required. Vomiting was more likely with aminophylline therapy (Relative Risk = 3.69; 95% CI: 2.15, 6.33). REVIEWER'S CONCLUSIONS: Addition of intravenous aminophylline should be considered early in the treatment of children hospitalised with acute severe asthma with sub optimal response to the initial inhaled bronchodilator therapy. Although the improvement is sustained for 24 hours, there is no apparent reduction in length of hospital stay or number of inhaled beta2-agonists nebulisations. Treatment with aminophylline is associated with an increased risk of vomiting.