Terry P. Klassen

Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses?

BACKGROUND Few meta-analyses of randomised trials assess the quality of the studies included. Yet there is increasing evidence that trial quality can affect estimates of intervention efficacy. We investigated whether different methods of quality assessment provide different estimates of intervention efficacy evaluated in randomised controlled trials (RCTs). METHODS We randomly selected 11 meta-analyses that involved 127 RCTs on the efficacy of interventions used for circulatory and digestive diseases, mental health, and pregnancy and childbirth. We replicated all the meta-analyses using published data from the primary studies. The quality of reporting of all 127 clinical trials was assessed by means of component and scale approaches. To explore the effects of quality on the quantitative results, we examined the effects of different methods of incorporating quality scores (sensitivity analysis and quality weights) on the results of the meta-analyses. FINDINGS The quality of trials was low. Masked assessments provided significantly higher scores than unmasked assessments (mean 2.74 [SD 1.10] vs 2.55 [1.20]). Low-quality trials (score < or = 2), compared with high-quality trials (score > 2), were associated with an increased estimate of benefit of 34% (ratio of odds ratios [ROR] 0.66 [95% CI 0.52-0.83]). Trials that used inadequate allocation concealment, compared with those that used adequate methods, were also associated with an increased estimate of benefit (37%; ROR=0.63 [0.45-0.88]). The average treatment benefit was 39% (odds ratio [OR] 0.61 [0.57-0.65]) for all trials, 52% (OR 0.48 [0.43-0.54]) for low-quality trials, and 29% (OR 0.71 [0.65-0.77]) for high-quality trials. Use of all the trial scores as quality weights reduced the effects to 35% (OR 0.65 [0.59-0.71]) and resulted in the least statistical heterogeneity. INTERPRETATION Studies of low methodological quality in which the estimate of quality is incorporated into the meta-analyses can alter the interpretation of the benefit of intervention, whether a scale or component approach is used in the assessment of trial quality.

What contributions do languages other than English make on the results of meta-analyses?

Including only a portion of all available evidence may introduce systematic errors into the meta-analytic process and threaten its validity. We set out to examine whether language restricted meta-analyses, compared to language inclusive meta-analyses, provide different estimates of the effectiveness of interventions evaluated in randomized trials. We identified and retrieved all 79 meta-analyses from several disease areas in which explicit eligibility criteria regarding trial selection were reported. General characteristics and quality of reporting of the meta-analyses were assessed using a validated instrument. We explored the effects of language of publication of the randomized trials on the quantitative results using logistic regression analyses. Language restricted meta-analyses, compared to language inclusive meta-analyses, did not differ with respect to the estimate of benefit of the effectiveness of an intervention (ROR = 0.98; 95% CI: 0.81-1.17). These results were also robust after a series of sensitivity analyses. This study provides no evidence that language restricted meta-analyses lead to biased estimates of intervention effectiveness. We encourage others to replicate this study using different sampling frames, clinical topics and interventions.

Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction : meta-analysis

Abstract Objective To conduct a systematic review of the efficacy and safety of exogenous melatonin in managing secondary sleep disorders and sleep disorders accompanying sleep restriction, such as jet lag and shiftwork disorder. Data sources 13 electronic databases and reference lists of relevant reviews and included studies; Associated Professional Sleep Society abstracts (1999 to 2003). Study selection The efficacy review included randomised controlled trials; the safety review included randomised and non-randomised controlled trials. Quality assessment Randomised controlled trials were assessed by using the Jadad Scale and criteria by Schulz et al, and non-randomised controlled trials by the Downs and Black checklist. Data extraction and synthesis One reviewer extracted data and another reviewer verified the data extracted. The inverse variance method was used to weight studies and the random effects model was used to analyse data. Main results Six randomised controlled trials with 97 participants showed no evidence that melatonin had an effect on sleep onset latency in people with secondary sleep disorders (weighted mean difference −13.2 (95% confidence interval −27.3 to 0.9) min). Nine randomised controlled trials with 427 participants showed no evidence that melatonin had an effect on sleep onset latency in people who had sleep disorders accompanying sleep restriction (−1.0 (−2.3 to 0.3) min). 17 randomised controlled trials with 651 participants showed no evidence of adverse effects of melatonin with short term use (three months or less). Conclusions There is no evidence that melatonin is effective in treating secondary sleep disorders or sleep disorders accompanying sleep restriction, such as jet lag and shiftwork disorder. There is evidence that melatonin is safe with short term use.

CATCH: a clinical decision rule for the use of computed tomography in children with minor head injury

Background: There is controversy about which children with minor head injury need to undergo computed tomography (CT). We aimed to develop a highly sensitive clinical decision rule for the use of CT in children with minor head injury. Methods: For this multicentre cohort study, we enrolled consecutive children with blunt head trauma presenting with a score of 13–15 on the Glasgow Coma Scale and loss of consciousness, amnesia, disorientation, persistent vomiting or irritability. For each child, staff in the emergency department completed a standardized assessment form before any CT. The main outcomes were need for neurologic intervention and presence of brain injury as determined by CT. We developed a decision rule by using recursive partitioning to combine variables that were both reliable and strongly associated with the outcome measures and thus to find the best combinations of predictor variables that were highly sensitive for detecting the outcome measures with maximal specificity. Results: Among the 3866 patients enrolled (mean age 9.2 years), 95 (2.5%) had a score of 13 on the Glasgow Coma Scale, 282 (7.3%) had a score of 14, and 3489 (90.2%) had a score of 15. CT revealed that 159 (4.1%) had a brain injury, and 24 (0.6%) underwent neurologic intervention. We derived a decision rule for CT of the head consisting of four high-risk factors (failure to reach score of 15 on the Glasgow coma scale within two hours, suspicion of open skull fracture, worsening headache and irritability) and three additional medium-risk factors (large, boggy hematoma of the scalp; signs of basal skull fracture; dangerous mechanism of injury). The high-risk factors were 100.0% sensitive (95% CI 86.2%–100.0%) for predicting the need for neurologic intervention and would require that 30.2% of patients undergo CT. The medium-risk factors resulted in 98.1% sensitivity (95% CI 94.6%–99.4%) for the prediction of brain injury by CT and would require that 52.0% of patients undergo CT. Interpretation: The decision rule developed in this study identifies children at two levels of risk. Once the decision rule has been prospectively validated, it has the potential to standardize and improve the use of CT for children with minor head injury.

Effectiveness of a home-based balance-training program in reducing sports-related injuries among healthy adolescents: a cluster randomized controlled trial

Background: Sport is the leading cause of injury requiring medical attention among adolescents. We studied the effectiveness of a home-based balance-training program using a wobble board in improving static and dynamic balance and reducing sports-related injuries among healthy adolescents. Methods: In this cluster randomized controlled trial, we randomly selected 10 of 15 high schools in Calgary to participate in the fall of 2001. We then recruited students from physical education classes and randomly assigned them, by school, to either the intervention (n = 66) or the control (n = 61) group. Students in the intervention group participated in a daily 6-week and then a weekly 6-month home-based balance-training program using a wobble board. Students at the control schools received testing only. The primary outcome measures were timed static and dynamic balance, 20-m shuttle run and vertical jump, which were measured at baseline and biweekly for 6 weeks. Self-reported injury data were collected over the 6-month follow-up period. Results: At 6 weeks, improvements in static and dynamic balance were observed in the intervention group but not in the control group (difference in static balance 20.7 seconds, 95% confidence interval [CI] 10.8 to 30.6 seconds; difference in dynamic balance 2.3 seconds, 95% CI 0.7 to 4.0 seconds). There was evidence of a protective effect of balance training in over 6 months (relative risk of injury 0.2, 95% CI 0.05 to 0.88). The number needed to treat to avoid 1 injury over 6 months was 8 (95% CI 4 to 35). Interpretation: Balance training using a wobble board is effective in improving static and dynamic balance and reducing sports-related injuries among healthy adolescents.

Epinephrine and Dexamethasone in Children with Bronchiolitis

BACKGROUND Although numerous studies have explored the benefit of using nebulized epinephrine or corticosteroids alone to treat infants with bronchiolitis, the effectiveness of combining these medications is not well established. METHODS We conducted a multicenter, double-blind, placebo-controlled trial in which 800 infants (6 weeks to 12 months of age) with bronchiolitis who were seen in the pediatric emergency department were randomly assigned to one of four study groups. One group received two treatments of nebulized epinephrine (3 ml of epinephrine in a 1:1000 solution per treatment) and a total of six oral doses of dexamethasone (1.0 mg per kilogram of body weight in the emergency department and 0.6 mg per kilogram for an additional 5 days) (the epinephrine-dexamethasone group), the second group received nebulized epinephrine and oral placebo (the epinephrine group), the third received nebulized placebo and oral dexamethasone (the dexamethasone group), and the fourth received nebulized placebo and oral placebo (the placebo group). The primary outcome was hospital admission within 7 days after the day of enrollment (the initial visit to the emergency department). RESULTS Baseline clinical characteristics were similar among the four groups. By the seventh day, 34 infants (17.1%) in the epinephrine-dexamethasone group, 47 (23.7%) in the epinephrine group, 51 (25.6%) in the dexamethasone group, and 53 (26.4%) in the placebo group had been admitted to the hospital. In the unadjusted analysis, only the infants in the epinephrine-dexamethasone group were significantly less likely than those in the placebo group to be admitted by day 7 (relative risk, 0.65; 95% confidence interval, 0.45 to 0.95, P=0.02). However, with adjustment for multiple comparisons, this result was rendered insignificant (P=0.07). There were no serious adverse events. CONCLUSIONS Among infants with bronchiolitis treated in the emergency department, combined therapy with dexamethasone and epinephrine may significantly reduce hospital admissions. (Current Controlled Trials number, ISRCTN56745572.)

Randomized trial of salbutamol in acute bronchiolitis

To test whether nebulized salbutamol (albuterol) is safe and efficacious for the treatment of young children with acute bronchiolitis, we enrolled 83 children (median age 6 months, range 1 to 21 months) in a randomized, double-blind clinical trial. Participants received two treatments at 30-minute intervals of either nebulized salbutamol (0.10 mg/kg in 2 ml 0.9% saline solution) or a similar volume of 0.9% saline solution placebo. Outcome measures were the respiratory rate, pulse oximetry, and a clinical score based on the degree of wheezing and retractions. Patients in the salbutamol arm had significantly greater improvement in clinical scores after the initial treatment (p = 0.04). There was no difference between the groups in oxygen saturation (p = 0.74); patients treated with salbutamol had a small increase in heart rate after two treatments (159 +/- 16 vs 151 +/- 16; p = 0.03). We conclude that salbutamol is safe and effective for the initial treatment of young children with acute bronchiolitis.

A randomized trial comparing the efficacy of epinephrine with salbutamol in the treatment of acute bronchiolitis

This randomized, double-blind trial compared the efficacy of nebulized epinephrine with salbutamol in the treatment of infants with acute bronchiolitis. The mean percent oxygen saturation at 60 minutes was significantly higher in the epinephrine group. Thirty-three percent of the patients in epinephrine group were admitted to the hospital compared with 81% of the salbutamol group (p = 0.003). We conclude that nebulized epinephrine is more efficacious than salbutamol for infants with acute bronchiolitis seen in an emergency department.

Community-based injury prevention interventions.

Community-based interventions offer a promising solution for reducing child and adolescent unintentional injuries. By focusing on altering behavior, promoting environmental change within the community, or passing and enforcing legislation, these interventions seek to change social norms about acceptable safety behaviors. This article systematically reviews 32 studies that evaluated the impact of community-based injury prevention efforts on childhood injuries, safety behaviors, and the adoption of safety devices. Interventions targeted schools, municipalities, and cities. Most relied on an educational approach, sometimes in combination with legislation or subsidies, to reduce the cost of safety devices such as bicycle helmets. Results indicate that community-based approaches are effective at increasing some safety practices, such as bicycle helmet use and car seat use among children. The evidence is less compelling that such interventions increase child pedestrian safety, increase adolescent vehicle safety by reducing drinking and driving behaviors, or reduce rates of several categories of childhood injuries. Strong evidence supporting the effectiveness of community-based interventions is lacking, in part because few studies used randomized controlled designs or examined injury rates among children and youths as outcome measures. Nonetheless, this review identifies common elements of successful community-based approaches that should be replicated in future studies. First, the use of multiple strategies grounded in a theory of behavior change is critical. Second, to maximize success, interventions should be integrated into the community and approaches should be tailored to meet unique community needs. Third, community stakeholders should be included in the development of community-based strategies. This community involvement and ownership of the intervention increases the likelihood of modeling and peer pressure, leading to widespread adoption of a safety behavior. Finally, when possible, a randomized controlled design should be used to maximize the trustworthiness of reported findings and aid decisions about where to invest resources in community-based approaches to injury prevention.

Dexamethasone in salbutamol-treated inpatients with acute bronchiolitis: a randomized, controlled trial.

OBJECTIVE To determine the clinical benefit of oral dexamethasone in children admitted to the hospital with bronchiolitis treated with nebulized salbutamol. METHODS Randomized, double-blind, placebo-controlled trial in the inpatient wards of a pediatric tertiary care hospital. The participants, children aged 6 weeks to 15 months, admitted with first-time wheezing, were eligible if their oxygen saturation was less than 95% on admission to the hospital and their Respiratory Distress Assessment Instrument (RDAI) score was greater than 6. Patients were excluded if they had any one of the following: an underlying disease that might affect cardiopulmonary status, asthma, recent treatment with steroids (within 2 weeks), or any history of adverse reaction to steroids. Patients were randomly assigned to receive either orally administered dexamethasone with 0.5 mg/kg as the first dose and 0.3 mg/kg for the next 2 mornings, or an equal volume of an orally administered placebo with an identical appearance. All patients received nebulized salbutamol at 0.15 mg/kg every 4 hours for the first 24 hours. The primary outcome measure was the change from baseline in the RDAI score at 24 hours. Secondary outcome measures were oxygen saturation, respiratory rate, RDAI measurement twice daily for the first 4 days, and the length of hospitalization. RESULTS At 24 hours the mean change (SD) from baseline in the RDAI score was 1.6 (2.3) in the placebo group (n = 28) and 1.4 (2.0) in the dexamethasone group (n = 33; p = 0.74). There were no significant differences between the two groups in change in oxygen saturation, respiratory rate, and RDAI score at any assessment period. The median length of stay (95% confidence interval) for the placebo group was 48 (42, 54) hours compared with 57 (38, 76) hours in the dexamethasone group (p = 0.19). CONCLUSIONS Oral dexamethasone therapy does not affect the clinical course of children hospitalized with bronchiolitis and therefore cannot be recommended in this clinical situation.