Ricardo M. Fernandes

Steroids and bronchodilators for acute bronchiolitis in the first two years of life: systematic review and meta-analysis.

Objective To evaluate and compare the efficacy and safety of bronchodilators and steroids, alone or combined, for the acute management of bronchiolitis in children aged less than 2 years. Design Systematic review and meta-analysis. Data sources Medline, Embase, Central, Scopus, PubMed, LILACS, IranMedEx, conference proceedings, and trial registers. Inclusion criteria Randomised controlled trials of children aged 24 months or less with a first episode of bronchiolitis with wheezing comparing any bronchodilator or steroid, alone or combined, with placebo or another intervention (other bronchodilator, other steroid, standard care). Review methods Two reviewers assessed studies for inclusion and risk of bias and extracted data. Primary outcomes were selected by clinicians a priori based on clinical relevance: rate of admission for outpatients (day 1 and up to day 7) and length of stay for inpatients. Direct meta-analyses were carried out using random effects models. A mixed treatment comparison using a Bayesian network model was used to compare all interventions simultaneously. Results 48 trials (4897 patients, 13 comparisons) were included. Risk of bias was low in 17% (n=8), unclear in 52% (n=25), and high in 31% (n=15). Only adrenaline (epinephrine) reduced admissions on day 1 (compared with placebo: pooled risk ratio 0.67, 95% confidence interval 0.50 to 0.89; number needed to treat 15, 95% confidence interval 10 to 45 for a baseline risk of 20%; 920 patients). Unadjusted results from a single large trial with low risk of bias showed that combined dexamethasone and adrenaline reduced admissions on day 7 (risk ratio 0.65, 0.44 to 0.95; number needed to treat 11, 7 to 76 for a baseline risk of 26%; 400 patients). A mixed treatment comparison supported adrenaline alone or combined with steroids as the preferred treatments for outpatients (probability of being the best treatment based on admissions at day 1 were 45% and 39%, respectively). The incidence of reported harms did not differ. None of the interventions examined showed clear efficacy for length of stay among inpatients. Conclusions Evidence shows the effectiveness and superiority of adrenaline for outcomes of most clinical relevance among outpatients with acute bronchiolitis, and evidence from a single precise trial for combined adrenaline and dexamethasone.

Predictors of severe H1N1 infection in children presenting within Pediatric Emergency Research Networks (PERN): retrospective case-control study.

Objective To identify historical and clinical findings at emergency department presentation associated with severe H1N1 outcome in children presenting with influenza-like illness. Design Multicentre retrospective case-control study. Setting 79 emergency departments of hospitals associated with the Pediatric Emergency Research Networks in 12 countries. Participants 265 children (<16 years), presenting between 16 April and 31 December 2009, who fulfilled Centers for Disease Control and Prevention criteria for influenza-like illness and developed severe outcomes from laboratory confirmed H1N1 infection. For each case, two controls presenting with influenza-like illness but without severe outcomes were included: one random control and one age matched control. Main outcome measures Severe outcomes included death or admission to intensive care for assisted ventilation, inotropic support, or both. Multivariable conditional logistic regression was used to compare cases and controls, with effect sizes measured as adjusted odds ratios. Results 151 (57%) of the 265 cases were male, the median age was 6 (interquartile range 2.3-10.0) years, and 27 (10%) died. Six factors were associated with severe outcomes in children presenting with influenza-like illness: history of chronic lung disease (odds ratio 10.3, 95% confidence interval 1.5 to 69.8), history of cerebral palsy/developmental delay (10.2, 2.0 to 51.4), signs of chest retractions (9.6, 3.2 to 29.0), signs of dehydration (8.8, 1.6 to 49.3), requirement for oxygen (5.8, 2.0 to 16.2), and tachycardia relative to age). Conclusion These independent risk factors may alert clinicians to children at risk of severe outcomes when presenting with influenza-like illness during future pandemics.

The Placebo Response in Studies of Acute Migraine

OBJECTIVES To characterize the magnitude of the placebo response in trials of migraine therapy in children and adolescents, and to identify its determinants. STUDY DESIGN MEDLINE and CENTRAL were searched through November 2006 for randomized controlled trials or controlled clinical trials of pediatric acute migraine pharmacologic treatment that included a placebo comparator group. The main outcomes were headache relief and pain-free response, and effect estimates for risk differences were calculated whenever possible. The influence of placebo response determinants was studied using subgroup analysis. A total of 13 trials (1324 participants in the placebo groups) were included in the analysis. RESULTS The pooled placebo responses for pain relief and pain-free at 2 hours were 46% (range, 38% to 53%) and 21% (range, 17% to 26%). Parallel studies conducted in North American centers demonstrated a significantly higher placebo response, as did trials that used 4-point pain scales. Other placebo determinants did not influence the effect estimate, although insufficient data were available to study some of them. CONCLUSIONS There is a widely variable placebo response in pediatric migraine trials, supporting the continued use of placebo groups and suggesting the need for more research into the placebo effect in the pediatric population.

A systematic review of the characteristics and validity of monitoring technologies to assess Parkinson’s disease

BackgroundThere is growing interest in having objective assessment of health-related outcomes using technology-based devices that provide unbiased measurements which can be used in clinical practice and scientific research. Many studies have investigated the clinical manifestations of Parkinson’s disease using such devices. However, clinimetric properties and clinical validation vary among the different devices.MethodsGiven such heterogeneity, we sought to perform a systematic review in order to (i) list, (ii) compare and (iii) classify technological-based devices used to measure motor function in individuals with Parkinsons disease into three groups, namely wearable, non-wearable and hybrid devices. A systematic literature search of the PubMed database resulted in the inclusion of 168 studies. These studies were grouped based on the type of device used. For each device we reviewed availability, use, reliability, validity, and sensitivity to change. The devices were then classified as (i) ‘recommended’, (ii) ‘suggested’ or (iii) ‘listed’ based on the following criteria: (1) used in the assessment of Parkinson’s disease (yes/no), (2) used in published studies by people other than the developers (yes/no), and (3) successful clinimetric testing (yes/no).ResultsSeventy-three devices were identified, 22 were wearable, 38 were non-wearable, and 13 were hybrid devices. In accordance with our classification method, 9 devices were ‘recommended’, 34 devices were ‘suggested’, and 30 devices were classified as ‘listed’. Within the wearable devices group, the Mobility Lab sensors from Ambulatory Parkinson’s Disease Monitoring (APDM), Physilog®, StepWatch 3, TriTrac RT3 Triaxial accelerometer, McRoberts DynaPort, and Axivity (AX3) were classified as ‘recommended’. Within the non-wearable devices group, the Nintendo Wii Balance Board and GAITRite® gait analysis system were classified as ‘recommended’. Within the hybrid devices group only the Kinesia® system was classified as ‘recommended’.

CPAP and High-Flow Nasal Cannula Oxygen in Bronchiolitis

Severe respiratory failure develops in some infants with bronchiolitis because of a complex pathophysiologic process involving increased airways resistance, alveolar atelectasis, muscle fatigue, and hypoxemia due to mismatch between ventilation and perfusion. Nasal CPAP and high-flow nasal cannula (HFNC) oxygen may improve the work of breathing and oxygenation. Although the mechanisms behind these noninvasive modalities of respiratory support are not well understood, they may help infants by way of distending pressure and delivery of high concentrations of warmed and humidified oxygen. Observational studies of varying quality have suggested that CPAP and HFNC may confer direct physiologic benefits to infants with bronchiolitis and that their use has reduced the need for intubation. No trials to our knowledge, however, have compared CPAP with HFNC in bronchiolitis. Two randomized trials compared CPAP with oxygen delivered by low-flow nasal cannula or face mask and found some improvements in blood gas results and some physiologic parameters, but these trials were unable to demonstrate a reduction in the need for intubation. Two trials evaluated HFNC in bronchiolitis (one comparing it with headbox oxygen, the other with nebulized hypertonic saline), with the results not seeming to suggest important clinical or physiologic benefits. In this article, we review the pathophysiology of respiratory failure in bronchiolitis, discuss these trials in detail, and consider how future research studies may be designed to best evaluate CPAP and HFNC in bronchiolitis.

Systematic reviews, overviews of reviews and comparative effectiveness reviews: a discussion of approaches to knowledge synthesis

BACKGROUND The Cochrane Collaboration has been at the forefront of developing methods for knowledge synthesis internationally. OBJECTIVES We discuss three approaches to synthesize evidence for healthcare interventions: systematic reviews (SRs), overviews of reviews and comparative effectiveness reviews. METHODS We illustrate these approaches with examples from knowledge syntheses on interventions for bronchiolitis, a common acute paediatric condition. Some of the differences among these approaches are subtle and methods are not necessarily mutually exclusive to a single review type. RESULTS AND CONCLUSIONS Systematic reviews bring together evidence from multiple studies in a rigorous fashion for a single intervention or group of interventions. Systematic reviews, as they have developed within healthcare, often focus on single or select interventions and direct pairwise comparisons; therefore, end-users may need to read several individual SRs to inform decision making. Overviews of reviews compile information from multiple SRs relevant to a single health problem. Overviews provide the end-user with a quick overview of the available evidence; however, overviews are dependent on the methods and decisions employed at the SR level. Furthermore, overviews do not often integrate evidence from different SRs quantitatively. Comparative effectiveness reviews, as we define them here, synthesize relevant evidence from individual studies to describe the relative benefits (or harms) of a range of interventions. Comparative effectiveness reviews may use statistical methods (network meta-analysis) to incorporate direct and indirect evidence; therefore, they can provide stronger inferences about the relative effectiveness (or safety) of interventions. While potentially more expensive and time-consuming to produce, a comparative effectiveness review provides a synthesis of a range of interventions for a given condition and the relative efficacy across interventions using consistent and standardized methodology.

Standard 4: Determining Adequate Sample Sizes

* Abbreviations: CINV — : chemotherapy-induced nausea and vomiting RCT — : randomized controlled trial RSV — : respiratory syncytial virus There are many challenges to be faced when conducting randomized controlled trials (RCTs) in pediatric research. One important challenge is the determination of an appropriate sample size. Recruiting more children than necessary risks unnecessary overexposure of children to an inferior treatment, whereas underestimating the sample required will lead to inconclusive or unreliable results. Both options pose important ethical dilemmas for the pediatric researcher. Reviews have concluded that sample size calculations are frequently based on inaccurate assumptions regarding the key pieces of information needed.1,2 For example, a recent “failed” pediatric RCT highlighted the commonly encountered problem of underestimating the SD of a continuous primary outcome variable.3 This leads to underestimation of the necessary sample size, inadequate statistical power, and, consequently, an unanswered study question. Similarly, an incorrect estimation of the frequency with which a dichotomous outcome, or event, occurs in the control group of a trial (known as the control or baseline event rate) will also lead to incorrect sample size estimation. This standards article uses a series of scenarios to assist pediatric researchers in not only determining an adequate trial sample size but also how to proceed when this sample size may be difficult to achieve. Recommendations for practice are summarized in Table 1. View this table: TABLE 1 Recommendations for Practice Methods to calculate adequate sample sizes are described for superiority, noninferiority, and cluster-randomized trials with various types of primary outcome variables, including continuous, dichotomous, or time-to-event data.4–10 In this article, we focus primarily on superiority trial designs with continuous or dichotomous outcomes. Information on noninferiority or equivalence designs, as well as on cluster-randomized designs, can be found in the literature.9,10 RCTs generally have many outcomes of interest, but the number of patients required (and the main statistical analysis) should be based on … Address correspondence to Martin Offringa, MD, PhD, Senior Scientist and Program Head, Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8. E-mail: martin.offringa{at}sickkids.ca

What guidance is available for researchers conducting overviews of reviews of healthcare interventions? A scoping review and qualitative metasummary

BackgroundOverviews of reviews (overviews) compile data from multiple systematic reviews to provide a single synthesis of relevant evidence for decision-making. Despite their increasing popularity, there is limited methodological guidance available for researchers wishing to conduct overviews. The objective of this scoping review is to identify and collate all published and unpublished documents containing guidance for conducting overviews examining the efficacy, effectiveness, and/or safety of healthcare interventions. Our aims were to provide a map of existing guidance documents; identify similarities, differences, and gaps in the guidance contained within these documents; and identify common challenges involved in conducting overviews.MethodsWe conducted an iterative and extensive search to ensure breadth and comprehensiveness of coverage. The search involved reference tracking, database and web searches (MEDLINE, EMBASE, DARE, Scopus, Cochrane Methods Studies Database, Google Scholar), handsearching of websites and conference proceedings, and contacting overview producers. Relevant guidance statements and challenges encountered were extracted, edited, grouped, abstracted, and presented using a qualitative metasummary approach.ResultsWe identified 52 guidance documents produced by 19 research groups. Relatively consistent guidance was available for the first stages of the overview process (deciding when and why to conduct an overview, specifying the scope, and searching for and including systematic reviews). In contrast, there was limited or conflicting guidance for the latter stages of the overview process (quality assessment of systematic reviews and their primary studies, collecting and analyzing data, and assessing quality of evidence), and many of the challenges identified were also related to these stages. An additional, overarching challenge identified was that overviews are limited by the methods, reporting, and coverage of their included systematic reviews.ConclusionsThis compilation of methodological guidance for conducting overviews of healthcare interventions will facilitate the production of future overviews and can help authors address key challenges they are likely to encounter. The results of this project have been used to identify areas where future methodological research is required to generate empirical evidence for overview methods. Additionally, these results have been used to update the chapter on overviews in the next edition of the Cochrane Handbook for Systematic Reviews of Interventions.

Performance of the HAS-BLED high bleeding-risk category, compared to ATRIA and HEMORR2HAGES in patients with atrial fibrillation : a systematic review and meta-analysis

IntroductionAtrial fibrillation (AF) patients’ major bleeding risk should be evaluated through risk scores such as HAS-BLED, HEMORR2HAGES or ATRIA. These scores were validated in independent studies with different methods. Therefore, we aimed to review and estimate the value added by ATRIA and HEMORR2HAGES compared to HAS-BLED.MethodsMedline and Cochrane Library (July 2013) were searched, as well as reviews and references of obtained articles. We looked for studies reporting data for diagnostic accuracy of HAS-BLED with any of HEMORR2HAGES or ATRIA scores, concerning Major Bleeding events. We determined the sensitivity, specificity, and diagnostic odds ratio (DOR) of ATRIA and HEMORR2HAGES compared to HAS-BLED within the same studies. Random effects meta-analysis was performed in order to derive diagnostic accuracy estimates. Heterogeneity was assessed through I2 test.ResultsSix studies fulfilled inclusion criteria. Five studies evaluated simultaneously HAS-BLED and HEMORR2HAGES. Sensitivity, specificity, and DOR were respectively 0.53 (0.52–0.54), 0.65 (0.65–0.65) and 2.11 (1.91–2.35) for HAS-BLED, and 0.27 (0.26–0.27), 0.89 (0.89–0.89) and 2.90 (2.77–3.04) for HEMORR2HAGES. Four studies compared HAS-BLED with ATRIA. Sensitivity, specificity, and DOR were respectively 0.41 (0.35–0.48), 0.78 (0.76–0.79) and 2.22 (1.08–4.55) for HAS-BLED, and 0.23 (0.17–0.29), 0.91 (0.90–0.91) and 1.98 (1.29–3.03) for ATRIA.ConclusionsThe ‘high-risk’ categories of the evaluated major bleeding-risk scores are not sensitive. HAS-BLED, due to its sensitivity (compared to other scores) and ease to apply, is recommended for the assessment of AF patients’ major bleeding risk.

Validity of Bronchiolitis Outcome Measures

BACKGROUND: The Respiratory Distress Assessment Instrument (RDAI) and Respiratory Assessment Change Score (RACS) are frequently used in bronchiolitis clinical trials, but evidence is limited on their measurement properties. We investigated their validity, reliability, and responsiveness. METHODS: We included data from up to 1765 infants with bronchiolitis enrolled in 2 studies conducted in pediatric emergency departments. We assessed RDAI construct validity by testing hypotheses of associations with physiologic measures (respiratory rate, oxygen saturation) and with constructs related to hospitalization, using correlation coefficients, and multivariable analysis. RDAI/RACS responsiveness was evaluated by using anchors of change based on these constructs; measures of responsiveness included the area under the curve. RDAI test-retest agreement and interrater reliability were evaluated by using limits of agreement and intraclass correlation coefficients. RESULTS: Baseline RDAI scores were weakly correlated with respiratory rate (r = 0.38, P < .001), and scores increased in lower oxygen saturation categories (P < .001). Higher RDAI scores were associated with hospitalization (odds ratio: 1.36; 95% confidence interval: 1.26–1.47); scores differed between participants who were discharged, admitted, or stayed in the emergency department (P < .001). Our hypotheses were met, but the magnitude of associations was below our predefined thresholds. RDAI test-retest limits of agreement were −3.80 to 3.64 (20% of the range), whereas interrater reliability was good (intraclass correlation coefficient = 0.93). Formulated hypotheses for responsiveness were confirmed, with moderate responsiveness (area under the curve: RDAI, 0.64–0.70; RACS, 0.72). CONCLUSIONS: RDAI has poor to moderate construct validity, with good discriminative properties but considerable test-retest measurement error. The RDAI and RACS are responsive measures of respiratory distress in bronchiolitis but do not encompass all determinants of disease severity.