Criteria for considering studies for this review
Types of studies
We will include randomised controlled trials (RCTs) of any follow-up duration. We will include studies reported as full text, those published as abstract only and unpublished data.
Types of participants
We will include studies of children (18 months to 18 years of age) treated in the emergency department for acute asthma (all severities). If studies recruited both adults and children, we will use data only if provided for children separately. As wheezy symptoms in children younger than 18 months may represent a different disease process (i.e. bronchiolitis), we will examine participant demographics in trials that include children younger than 18 months to determine percentage of the study population. If they make up more than 10% of the population, we will exclude the studies.
Types of interventions
We will include trials comparing any dose of intravenous magnesium sulfate versus placebo. Because children with acute asthma often require additional treatments, we will include studies that allow other medications provided they are not part of the randomly assigned treatment. We will present in the results a summary characteristics table that includes a list of medications given in each of the included studies.
Types of outcome measures
Emergency department treatment duration.
Intensive care admissions.
Hospital length of stay.
Vital signs (respiratory rate, oxygen saturations).
Spiromety (peak expiratory flow rate (PEFR), forced expiratory volume in one second (FEV1)).
Validated paediatric symptom scores.
Reporting in the trial one or more of the outcomes listed here is not an inclusion criterion for the review.
Search methods for identification of studies
We will identify trials from the Cochrane Airways Group Specialised Register (CAGR), which is maintained by the Trials Search Co-ordinator for the Group. The Register contains trial reports identified through systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED and PsycINFO, and by handsearching of respiratory journals and meeting abstracts (see Appendix 1 for further details). We will search all records in the CAGR using the search strategy provided in Appendix 2.
We will also conduct a search of ClinicalTrials.gov (www.ClinicalTrials.gov) and the World Health Organization (WHO) trials portal (www.who.int/ictrp/en/). We will search all databases from their inception to the present, and we will impose no restriction on language of publication.
Searching other resources
We will check reference lists of all primary studies and review articles for additional references. We will search relevant manufacturers' websites for trial information. We will also search for errata or retractions from included studies published in full text on PubMed (www.ncbi.nlm.nih.gov/pubmed) and will report within the review the date this was done.
Data collection and analysis
Selection of studies
Two review authors (BG and KMK) will independently screen titles and abstracts for inclusion of all citations identified by the search and will code them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We will retrieve the full-text study reports/publications, and both review authors will independently screen the full text and identify studies for inclusion. We will identify and record reasons for exclusion of ineligible studies. We will resolve disagreements through discussion, or, if required, we will consult a third person. We will identify and exclude duplicates and will collate multiple reports of the same study, so that each study rather than each report is the unit of interest in the review. We will record the selection process in sufficient detail to complete a PRISMA flow diagram and a 'Characteristics of excluded studies' table.
Data extraction and management
To record study characteristics and outcome data, we will use a data collection form that has been piloted on at least one study in the review. One review author (KMK) will extract study characteristics from included studies, and both review authors will independently extract outcome data. We will extract the following study characteristics.
Methods: study design, duration of observation and follow-up, details of any 'run-in' period, number of study centres and locations, withdrawals and date of study.
Participants: N, mean age, age range, gender, asthma severity*, diagnostic criteria, baseline lung function, inclusion criteria and exclusion criteria.
Interventions: intervention, dose, comparison, concomitant and failed treatments and excluded medications.
Outcomes: primary and secondary outcomes specified and collected, and time points reported.
Notes: funding for trial and notable conflicts of interest of trial authors.
We will note in the 'Characteristics of included studies' table if outcome data were not reported in a usable way. We will resolve disagreements by consensus or by involving a third person. One review author will transfer data into the Review Manager (RevMan) (version 5.2) file. We will double-check that data have been entered correctly by comparing data presented in the systematic review with information in the study reports. A second review author (BG) will spot-check study characteristics for accuracy against the trial report.
Assessment of risk of bias in included studies
Both review authors will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), resolving disagreements by discussion. We will assess the risk of bias according to the following domains.
Random sequence generation.
Blinding of participants and personnel.
Blinding of outcome assessment.
Incomplete outcome data.
Selective outcome reporting.
We will grade each potential source of bias as high, low or unclear and will provide a quote from the study report together with a justification for our judgement in the 'Risk of bias' table. We will summarise the risk of bias judgements across different studies for each of the domains listed. We will consider blinding separately for different key outcomes when necessary (e.g. for unblinded outcome assessment, risk of bias for hospital admissions may be very different than for a patient-reported scale). When information on risk of bias relates to unpublished data or correspondence with a trial author, we will note this in the 'Risk of bias' table.
When considering treatment effects, we will take into account the risk of bias for studies that contribute to that outcome.
Assesment of bias in conducting the systematic review
We will conduct the review according to this published protocol and will report any deviations from it in the 'Differences between protocol and review' section of the systematic review.
Measures of treatment effect
We will analyse dichotomous data as odds ratios and continuous data as mean differences or standardised mean differences. If studies report several validated symptom measures, or if different scales are reported across studies, we will analyse the data as standardised mean differences in one analysis to reduce measurement error and enhance precision. We will enter presented data as a scale with a consistent direction of effect. We will narratively describe skewed data reported as medians and interquartile ranges.
We will undertake meta-analyses only when this is meaningful (i.e. when treatments, participants and the underlying clinical question are similar enough for pooling to make sense).
When multiple trial arms are reported in a single trial, we will include only the relevant arms. If two relevant comparisons from a single study are combined in the same meta-analysis, we will halve the control group to avoid double-counting.
Unit of analysis issues
For dichotomous outcomes, we will use participants rather than events as the unit of analysis (i.e. number of children with any adverse events rather than the total number of events).
Dealing with missing data
We will contact investigators or study sponsors to verify key study characteristics and to obtain missing numerical outcome data when possible (e.g. when a study is identified as an abstract only). When this is not possible and the missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by performing a sensitivity analysis.
Assessment of heterogeneity
We will use the I² statistic to measure heterogeneity among the trials in each analysis. If we identify substantial heterogeneity, we will report this and will explore possible causes by prespecified subgroup analysis.
Assessment of reporting biases
If we are able to pool more than 10 trials, we will create and examine a funnel plot to explore possible small-study and publication biases. We will consider the impact of unpublished trials in the GRADE ratings for each outcome.
We will use a fixed-effect model and will perform a sensitivity analysis with random effects when significant heterogeneity is observed (I² > 30%).
Summary of findings table
We will create a 'Summary of findings' table for all five outcomes. We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of a body of evidence as it relates to the studies that contribute data to the meta-analyses for the prespecified outcomes. We will use methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) using GRADEpro software. We will justify all decisions to downgrade or upgrade the quality of studies using footnotes, and we will make comments to aid readers' understanding of the review when necessary.
Subgroup analysis and investigation of heterogeneity
Based on observations in previous versions of this review and to focus recommendations about the appropriateness of the intervention within specific patient groups, we plan to carry out the following subgroup analyses.
Baseline severity of exacerbation (moderate, severe, life threatening*).
Age (≤ and > five years).
We will use the formal test for subgroup differences in Review Manager (version 5.2).
*As no single metric has been accepted for assessing asthma severity in children, we will extract baseline data relevant to the following severity criteria as stated in the recent asthma guidelines (BTS/SIGN 2012).
Ability to speak and eat.
Breaths per minute.
Arterial (oxygen saturation).
Study populations will be labelled as moderate, severe and life threatening based on available data, as judged by an independent assessor blinded to the study results.
We plan to carry out the following sensitivity analyses.
Studies at high risk of bias for blinding.
Studies including children < 18 months of age.