Intravenous magnesium sulfate for treating children with acute asthma in the emergency department

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the safety and efficacy of intravenous magnesium sulfate in children treated for acute asthma in the emergency department.

Background

Description of the condition

Asthma is a chronic respiratory condition characterised by inflammation of the airways and partially reversible airflow obstruction. Common symptoms include cough, wheezing, difficulty breathing, reduced exercise tolerance and chest tightness. The condition is characterised by airway inflammation and bronchospasm (contraction of the smooth muscle lining the airways) leading to airflow obstruction. Asthma follows a varying course in individuals that is driven by genetic and environmental triggers.

Asthma symptoms vary in severity and frequency. Asthma can cause daily chronic symptoms and exacerbations. An exacerbation is defined as an acute worsening of asthma symptoms. Overarching principles of treatment consist of controlling daily symptoms and preventing exacerbations by providing good education and appropriate inhaler usage. National and international guidelines have been published for the treatment of asthma exacerbations (BTS/SIGN 2012; GINA 2011).

Short-acting bronchodilators are given to relieve bronchospasm, and symptoms of inflammation are treated with corticosteroids; 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). Beta2-agonists are recognised as most effective in relieving bronchospasm (Teoh 2012); however, anticholinergic inhalers have also proved effective in the treatment of acute asthma (Griffiths 2013).

Children with asthma are managed most often in primary care; however in severe cases, secondary level care by a paediatrician may be necessary. The goal of treatment is to allow a good quality of life while avoiding asthma exacerbations requiring visits to the emergency department and hospital admission.

In severe exacerbations, which can be life threatening, further medications may be required, such as oral or intravenous corticosteroids (BTS/SIGN 2012; GINA 2011; Rowe 2001). Intravenous bronchodilators and magnesium sulfate have also been used to treat children with severe asthma exacerbations.

Description of the intervention

Recent clinical guidelines advise that a single dose of intravenous magnesium sulfate can be considered for children five years of age and older with acute severe asthma who have not responded to inhaled bronchodilator therapy and for those with life-threatening or near-fatal asthma (BTS/SIGN 2012).

Magnesium sulfate has been used in a nebulised form in the treatment of acute severe asthma; this is the subject of a separate review (Powell 2012). For the purposes of this review, only the use of intravenous magnesium sulfate will be considered. Dosage in children is usually based on weight. The British National Formulary for Children (BNFc) advises 20 mg/kg up to a maximum total dose of 2 grams, delivered by intravenous infusion over 20 minutes. However, larger doses of up to 75 mg/kg have been reported in the literature (Scarfone 2000).

How the intervention might work

The mechanism of action of intravenous magnesium sulfate in the context of an exacerbation of asthma is not fully understood. 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 (Spivey 1990). Some evidence has also been found of its role in reducing the inflammatory response (Cairns 1996). The combination of smooth muscle relaxation and anti-inflammatory properties provides a theoretical basis for the use of magnesium sulfate in cases of acute asthma.

Why it is important to do this review

One in 11 children in the UK suffer from asthma. Asthma presentations in emergency departments are common, peaking at 26,969 admissions in 2006/2007 (Millet 2013). A total of 1143 deaths from asthma were reported in the UK in 2010; 16 of these individuals were children 14 years of age or younger (Asthma UK). In fact between 2005 and 2010, 1% to 4.2% of all admissions to paediatric intensive care units (PICUs) in the UK were due to asthma; this translates to 1640 admissions (in 1410 patients). Furthermore, the number of admissions to PICUs in the UK due to asthma is rising. Asthma-related admissions increased by 67% (195 to 327 admissions) between 2005 and 2010 (Nyman 2011).

Although current guidelines advocate the use of intravenous magnesium sulfate in the treatment of acute asthma (see Table 1), it is acknowledged that evidence in the literature has provided conflicting results. An earlier version of this review (Rowe 2000) found little evidence in children to support the use of intravenous magnesium sulfate based on results from seven studies (five adult and two paediatric). It is important to examine these conclusions in the light of any new evidence that has emerged over the past 14 years to help inform future practice for paediatric patients.

Table 1. Summary of guideline treatment recommendations in acute asthma
 BTS/SIGNGINANACANAEPP
Oxygen
Inhaled beta2-agonist
Inhaled antimuscarinic
Sytemic steroids
IV beta2-agonist(✓) if nebulised form cannot be used reliablyx✓ if no response to inhaled formx
IV magnesium sulfate✓ IV or nebulised
Helioxxxx
IV aminophylline/theophylline(✓) limited evidence, only after senior consultation(✓) if inhaled beta2-agonist unavailable(✓) as an alternative to IV beta2-agonistx

Objectives

To assess the safety and efficacy of intravenous magnesium sulfate in children treated for acute asthma in the emergency department.

Methods

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

Primary outcomes
  1. Hospital admissions.

Secondary outcomes
  1. Emergency department treatment duration.

  2. Intensive care admissions.

  3. Hospital length of stay.

  4. Vital signs (respiratory rate, oxygen saturations).

  5. Spiromety (peak expiratory flow rate (PEFR), forced expiratory volume in one second (FEV1)).

  6. Validated paediatric symptom scores.

  7. Adverse events.

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

Electronic searches

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.

  1. 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.

  2. Participants: N, mean age, age range, gender, asthma severity*, diagnostic criteria, baseline lung function, inclusion criteria and exclusion criteria.

  3. Interventions: intervention, dose, comparison, concomitant and failed treatments and excluded medications.

  4. Outcomes: primary and secondary outcomes specified and collected, and time points reported.

  5. 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.

  1. Random sequence generation.

  2. Allocation concealment.

  3. Blinding of participants and personnel.

  4. Blinding of outcome assessment.

  5. Incomplete outcome data.

  6. Selective outcome reporting.

  7. Other bias.

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.

Data synthesis

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.

  1. Baseline severity of exacerbation (moderate, severe, life threatening*).

  2. 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).

  1. Ability to speak and eat.

  2. Breaths per minute.

  3. Pulse.

  4. Pulse oximetry.

  5. Peak flow.

  6. 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.

Sensitivity analysis

We plan to carry out the following sensitivity analyses.

  1. Studies at high risk of bias for blinding.

  2. Studies including children < 18 months of age.

  3. Unpublished data.

Acknowledgements

Chris Cates was the Editor for this protocol and commented critically on the protocol.

Appendices

Appendix 1. Sources and search methods for the Cochrane Airways Group Specialised Register (CAGR)

Electronic searches: core databases

Database Frequency of search
CENTRALMonthly
MEDLINE (Ovid)Weekly
EMBASE (Ovid)Weekly
PsycINFO (Ovid)Monthly
CINAHL (EBSCO)Monthly
AMED (EBSCO)Monthly

 

Handsearches: core respiratory conference abstracts

Conference Years searched
American Academy of Allergy, Asthma and Immunology (AAAAI)2001 onwards
American Thoracic Society (ATS)2001 onwards
Asia Pacific Society of Respirology (APSR)2004 onwards
British Thoracic Society Winter Meeting (BTS)2000 onwards
Chest Meeting2003 onwards
European Respiratory Society (ERS)1992, 1994, 2000 onwards
International Primary Care Respiratory Group Congress (IPCRG)2002 onwards
Thoracic Society of Australia and New Zealand (TSANZ)1999 onwards

 

MEDLINE search strategy used to identify trials for the CAGR

Asthma search

1. exp Asthma/

2. asthma$.mp.

3. (antiasthma$ or anti-asthma$).mp.

4. Respiratory Sounds/

5. wheez$.mp.

6. Bronchial Spasm/

7. bronchospas$.mp.

8. (bronch$ adj3 spasm$).mp.

9. bronchoconstrict$.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.

16. or/1-15

Filter to identify RCTs

1. exp "clinical trial [publication type]"/

2. (randomised or randomised).ab,ti.

3. placebo.ab,ti.

4. dt.fs.

5. randomly.ab,ti.

6. trial.ab,ti.

7. groups.ab,ti.

8. or/1-7

9. Animals/

10. Humans/

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

#1 AST:MISC1

#2 MeSH DESCRIPTOR Asthma Explode All

#3 asthma*:ti,ab

#4 #1 or #2 or #3

#5 magnesium*

#6 MgSO4

#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

Ben Griffiths wrote the background and managed the clinical implications of the methods. Kayleigh Kew wrote the methods. Clare Michell and Liza Kirtchuk commented critically on the draft.

Declarations of interest

None known.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • NIHR, UK.

    Programme grant funding

Ancillary