Description of the condition
Asthma is a chronic respiratory condition characterised by airway inflammation, constriction of airway smooth muscle and structural alteration of the airways, that is at least partially reversible. Common symptoms include cough, wheezing, difficulty breathing, reduced exercise tolerance and chest tightness. Asthma is thought to be caused by a genetic predisposition and over-sensitivity to environmental triggers. Common triggers include allergens, pollutants and viral infections, though endogenous factors have also been identified. The World Health Organisation recognises the global burden of asthma and estimates a worldwide prevalence of 300 million people of all ages, with 250,000 dying each year. Epidemiological data suggest prevalence to be greatest in the developed world, with the prevalence amongst adults in the USA at 8.2% (CDC) and 9% to 10% in the UK (DOH 2012).
Asthma can present with varying degrees of severity, and in the most severe cases it can cause daily chronic symptoms and frequent acute exacerbations (defined as an acute worsening of asthma symptoms). Overarching principles of treatment lie in controlling daily symptoms and preventing exacerbations through good education and appropriate use of inhalers. Short acting bronchodilators are given to relieve bronchospasm and corticosteroids for the underlying inflammation; both are usually delivered via inhalers. Depending on the persistence of symptoms, inhalers can be taken regularly (maintenance therapy), or on an as-needed basis (reliever therapy) (BTS/SIGN 2012; GINA 2011). Treatment guidelines recommend preventative management in the community and prompt interventions during acute exacerbations to reduce mortality and other negative outcomes (such as intubation and hospital admissions).
Description of the intervention
In severe exacerbations of asthma, which can be life-threatening, most guidelines recommend the use of oxygen, nebulised or intravenous beta
National guidelines also vary with respect to definitions of asthma severity, treatment boundaries between age groups, and the use of additional interventions. Table 1 offers a summary of treatment strategies recommended by some of these guidelines for the management of acute asthma.
How the intervention might work
Magnesium is an important intracellular and extracellular cation and plays an important role in intracellular enzymatic reactions. Its mechanism of action in the context of an exacerbation of asthma is not fully understood, but several theories have been proposed (Rowe 2013). It is believed to play a role in bronchial smooth muscle relaxation via its ability to stop calcium ion movement into smooth muscle cells by blocking the voltage-dependent calcium channels (Gourgoulianis 2001; Spivey 1990). Furthermore, there is some evidence that it may reduce the neutrophilic burst seen with the inflammatory response (Cairns 1996), and may also be involved in acetylcholine release from cholinergic nerve terminals and histamine release from mast cells (Dominguez 1998). The combination of these properties contributes to relieving airflow obstruction and provides the theoretical basis for its effectiveness.
Why it is important to do this review
Acute asthma presentations represent a significant burden on emergency departments and carry a substantial mortality risk, with 1143 deaths from asthma in the UK in 2010 (Asthma UK) and an estimated mortality rate of 1.1 deaths per 100,000 in the USA (CDC). In the UK, it is thought that "75% of hospital admissions for asthma are avoidable and as many as 90% of the deaths from asthma are preventable" (Asthma UK).
The financial burden is also significant, with a cost to the NHS of £1 billion a year, 80% of which is spent on the 20% of people with the most severe disease (DOH 2012).
Current guidelines advocate the use of magnesium sulfate in the treatment of acute severe asthma, but evidence in the literature remains inconclusive (Rowe 2009). New evidence from randomised controlled trials has been published since the last version of this review, which may change the conclusions.
To assess the safety and efficacy of intravenous magnesium sulfate in adults being treated for acute asthma in the emergency department.
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 adults (defined as being over 18 years of age) being treated in the emergency department for acute exacerbations of asthma. If studies recruited both adults and children, we will contact the authors to try to obtain the data from adults separately.
Types of interventions
We will include trials comparing any dose of intravenous magnesium sulfate with placebo. Because people with acute asthma exacerbations often require multiple medications, we will include studies that allow other treatments (for maintenance, for the acute exacerbation itself, or for other co-morbidities), provided they are not part of the randomised treatment.
Types of outcome measures
- Hospital admissions
- Emergency department treatment duration
- Intensive care admissions
- Vital signs (respiratory rate, oxygen saturations)
- Spirometry (PEFR, FEV1)
- Validated Symptoms Scores
- Adverse events
Reporting one or more of the outcomes listed here in the trial is not an inclusion criterion for the review.
Search methods for identification of studies
We will identify trials from the Cochrane Airways Review Group's 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 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 in Appendix 2.
We will also conduct a search of ClinicalTrials.gov (www.ClinicalTrials.gov) and the 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 relevant 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 report the date this was done within the review.
Data collection and analysis
Selection of studies
Three review authors (LK, CM, KK) will independently screen titles and abstracts for inclusion of all the citations identified by the search and code them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We will retrieve the full-text study reports/publication and the review authors will independently screen the full-text and identify studies for inclusion. We will identify and record reasons for exclusion of the ineligible studies. We will resolve any disagreement through discussion or, if required, we will consult a third person. We will identify and exclude duplicates and 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 'Characteristics of excluded studies' table.
Data extraction and management
We will use a data collection form for study characteristics and outcome data, which has been piloted on at least one study in the review. One review author (KK) will extract study characteristics from included studies and all 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 location, withdrawals, and date of study.
- Participants: N, mean age, age range, gender, asthma severity*, diagnostic criteria, co-morbidities, co-medications, 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 are entered correctly by comparing the data presented in the systematic review with the study reports. A second review author (LK or CM) will spot-check study characteristics for accuracy against the trial report.
Assessment of risk of bias in included studies
All 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 any disagreements by discussion. We will assess the risk of bias according to the following domains:
- Random sequence generation.
- Allocation concealment.
- Blinding of participants and personnel.
- Blinding of outcome assessment.
- Incomplete outcome data.
- Selective outcome reporting.
- Other bias.
We will grade each potential source of bias as high, low or unclear and provide a quote from the study report together with a justification for our judgment 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 where necessary (e.g. for unblinded outcome assessment, risk of bias for hospital admissions may be very different than for a patient-reported scale). Where 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 the 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 report any deviations form 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 difference or standardised mean difference. 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 increase precision. We will enter data presented 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 where this is meaningful, i.e. if the treatments, participants and the underlying clinical question are similar enough for pooling to make sense.
Where 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 patients rather than events as the unit of analysis (i.e. number of adults admitted to hospital rather than number of admissions per adult). It is not envisaged that we will find cluster randomised trials, but if we do, the unit of analysis will be the randomised centre and we will deal with them in accordance with the Cochrane Handbook and in consultation with the statistical editor (Higgins 2011).
Dealing with missing data
We will contact investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when a study is identified as abstract only). Where 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 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 it and 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 perform a sensitivity analysis with random effects where significant heterogeneity is observed (I² greater than 30%).
'Summary of findings' table
We will create a 'Summary of findings' table for all seven 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 which contribute data to the meta-analyses for the prespecified outcomes (http://www.gradeworkinggroup.org/). 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 down- or up-grade the quality of studies using footnotes and we will make comments to aid readers' understanding of the review where necessary.
Subgroup analysis and investigation of heterogeneity
We plan to carry out the following subgroup analyses:
- Baseline severity (mild, moderate and severe exacerbations*)
- Mean age (≤ and > 65 years)
- Co-medications (maximal and minimal**)
We will use the formal test for subgroup differences in Review Manager (version 5.2) (Review Manager (RevMan)).
*Since there is no single accepted metric for assessing asthma severity we will extract baseline data relevant to the severity criteria stated in the BTS guidelines (BTS/SIGN 2012), i.e.:
- Clinical features e.g. ability to complete sentences, respiratory effort, conscious level, signs of exhaustion
- Previous intensive care unit admissions
- Blood pressure
- Respiratory rate
- Pulse oximetry
- Peak flow
- Arterial blood gas
A subgroup analysis by severity was informed by conclusions drawn in the previous Cochrane Review (Rowe 2009), that the intervention may be more effective in acute, severe or life-threatening asthma. Study populations will be labelled as mild, moderate or severe exacerbations based on the available data, as judged by an independent assessor blinded to the study IDs.
**For co-medications, maximal will refer to studies where patients have been given short-acting beta
Ipratropium is included in most guidelines, but it is unclear whether this is adopted in all emergency departments. Griffiths 2013 has demonstrated that it is an effective adjunct to SABA in children with asthma exacerbations in the acute setting.
We plan to carry out the following sensitivity analyses:
- Studies at high risk of bias for blinding
- Unpublished data
We will base our conclusions only on findings from the quantitative or narrative synthesis of included studies for this review. We will avoid making recommendations for practice and our implications for research will suggest priorities for future research and outline what the remaining uncertainties are in the area.
We acknowledge Chris Cates for his help with the protocol.
full name] was the Editor for this review and commented critically on the review.
Appendix 1. Sources and search methods for the Cochrane Airways Group Specialised Register (CAGR)
Electronic searches: core databases
Handsearches: core respiratory conference abstracts
MEDLINE search strategy used to identify trials for the CAGR
1. exp Asthma/
3. (antiasthma$ or anti-asthma$).mp.
4. Respiratory Sounds/
6. Bronchial Spasm/
8. (bronch$ adj3 spasm$).mp.
10. exp Bronchoconstriction/
11. (bronch$ adj3 constrict$).mp.
12. Bronchial Hyperreactivity/
13. Respiratory Hypersensitivity/
14. ((bronchial$ or respiratory or airway$ or lung$) adj3 (hypersensitiv$ or hyperreactiv$ or allerg$ or insufficiency)).mp.
15. ((dust or mite$) adj3 (allerg$ or hypersensitiv$)).mp.
Filter to identify RCTs
1. exp "clinical trial [publication type]"/
2. (randomised or randomised).ab,ti.
11. 9 not (9 and 10)
12. 8 not 11
The MEDLINE strategy and RCT filter are adapted to identify trials in other electronic databases.
Appendix 2. Search strategy to identify relevant trials from the CAGR
#2 MeSH DESCRIPTOR Asthma Explode All
#4 #1 or #2 or #3
#7 #5 or #6
#8 #4 and #7
#9 (#8) AND (INREGISTER)
[Note: in search line #1, MISC1 refers to the field in which the reference record has been coded for condition, in this case, asthma]
Contributions of authors
Liza Kirtchuk and Clare Michell wrote the background and managed the clinical implications of the methods, with input from Ben Griffiths. Kayleigh Kew wrote the methods.
Declarations of interest
Sources of support
- No sources of support supplied
- National Institute for Health Research (NIHR), UK.Programme grant funding