This systematic review and meta-analysis aimed to evaluate the efficacy of intravenous (IV) and nebulized magnesium sulfate for acute asthma in children. Ten randomized and quasi-randomized trials (6 IV, 4 nebulized) were identified through search of databases (PubMed, Cochrane Library, and EMBASE). Intavenous magnesium sulfate treatment was associated with significant effects on respiratory function (standardized mean difference 1.94; 95% CI 0.80,3.08; P=0.0008) and hospital admission (RR 0.55; 95% CI 0.31,0.95; P=0.03). But nebulized magnesium sulfate treatment showed no significant effect on respiratory function (standardized mean difference 0.19; 95% CI –0.01, 0.40; P=0.07) or hospital admission (RR 1.11; 95% CI 0.86,1.44; P=0.42). Authors concluded that IV magnesium sulfate is an effective treatment in children, with significant improvement in pulmonary function and decrease in hospitalization and need for further treatment, but nebulized magnesium sulfate treatment showed no significant effect on respiratory function or hospital admission and further treatment.

Relevance: In recent years, magnesium sulphate therapy has gained popularity for managing acute asthma exacerbations in adults and children, on account of its perceived efficacy, mechanism of action distinct from conventional bronchodilator(s), and relative safety. A Pubmed search on 13 January 2017 using the terms ‘magnesium (acute asthma)’ with filter for ‘Child: birth-18 years’ yielded 21 citations with the ‘Systematic Review’ filter, and 26 citations using the ‘Randomized Controlled Trial’ filter. Among the 21 citations, a recent Cochrane systematic review [1], including five double blind, placebo-controlled randomized trials, reported that IV magnesium decreased hospitalization, but had no impact on hospital revisits. A 2013 systematic review [2] showed that IV magnesium decreased both hospital admissions, and also resulted in better lung function parameters. The same review showed that nebulized magnesium improved both these outcomes in adults, although not in children [2]. A recent analysis of multiple systematic reviews on management of acute asthma in children confirmed the beneficial effect of IV magnesium on hospitalization rates and pulmonary function parameters [3].

However, the 2016 GINA (Global Initiative for Asthma) guidelines explicitly stated that IV magnesium sulfate is not recommended in children, although it could work in children who do not respond to initial therapy [4]. Similarly, the guideline did not recommend nebulized magnesium sulfate, although it improved lung function parameters in children with severe exacerbations [4]. The 2014 British guideline [5] also recommended against using nebulized magnesium sulfate in children with asthma exacerbations, citing the need for more robust evidence on the subject. This position was reiterated in the September 2016 revision of the guideline [6]. For IV magnesium, the 2014 guideline [5] reported the intervention to be safe, but did not explicitly recommend its usage; whereas the 2016 guideline [6] recommended 40 mg/kg IV magnesium for those not responding to initial treatment. However, guarded language was used viz to consider IV magnesium as first-line IV treatment for those who do not respond adequately to first-line treatment. The reason for the ambiguous statement is unclear, despite the latest evidence available.

Against this backdrop, yet another systematic review by Su, et al. [7] evaluating efficacy of magnesium sulfate (intravenous and nebulized) has been published.

Critical appraisal: At the outset, the need for a new systematic review has to be considered carefully. The Cochrane review [1] on IV magnesium, published in April 2016 included literature search till 23 February 2016. In contrast, Su et al, [7] included studies on intravenous magnesium till June 2015. Thus, for IV magnesium, the Cochrane review [1] is the most up-to-date evidence. The immediate online publication of Cochrane reviews meeting the stringent publication criteria of the Cochrane Collaboration greatly facilitates them to be up-to-date. Since the Cochrane review protocol was published in April 2014 [8], the justification for undertaking a new review on IV magnesium is unclear.

In contrast, the last systematic review on nebulized magnesium was published in 2013 [2], and included only one pediatric trial with 62 children. Hence, the updated review on nebulized magnesium by Su, et al. [7] is timely. Table I present a critical appraisal of the systematic review using one of the various tools available for the purpose [9]. Overall, the review met the major criteria for a good quality review.

Table I: Critical Appraisal of the Trial

One of the main limitations with the literature search strategy in the review [7] is the lack of clarity about the Comparator against which magnesium (both IV and nebulized) was evaluated. The Cochrane review on intravenous magnesium [1] included only placebo-controlled trials; whereas Su, et al, [7] did not state this. They included a study by Torres [10] which is a non-placebo controlled trial (shown in the meta-analysis as Silvio 2012), which suggests that they did not intend to exclude non-placebo trials. In fact, the authors stated only the exclusion of trials comparing IV magnesium versus beta-2 agonist. But, this does not explain the exclusion of the trial by Singhi, et al. [11], comparing IV magnesium versus terbutaline and aminophylline. The arm comparing magnesium versus aminophylline would be eligible for the review (although the trial outcome was treatment success, hence different from the systematic review outcomes). All such difficulties could have been avoided if authors had framed and reported a clear clinical question in the PICO format.

The issue about the trial eligibility criteria is more than academic, as the lack of clarity enabled Su, et al. [7] to include data from the trial by Torres, et al [10] in their meta-analysis on hospitalization. Torres, et al. [10] reported about children requiring ventilation support, which Su, et al. [7] included in the outcome of ‘hospitalization’ as a subgroup analysis. The inappropriate clubbing of a clearly distinct outcome resulted in an apparently more impressive pooled outcome (RR 0.55) compared to pooled RR of 0.70 for trials reporting hospitalization. Further, inclusion of the Torres trial [10] makes the review by Su, et al. [7] ‘look different’ from the Cochrane review on IV magnesium as there appear to be six trials compared to five in the Cochrane review. Another ‘cosmetic difference’ is the choice of ‘risk ratio’ for reporting outcomes in contrast to ‘odds ratio’ stated a priori in the Cochrane review protocol [8].

Another major limitation is that Su, et al. [7] did not specify the timing of administering magnesium as a criterion for including trials. Given that IV magnesium was already shown to be efficacious [5,6] when administered to children who do not respond to standard first-hour therapy, it is of great relevance to know whether the authors intended to study magnesium administered after initial therapy, or with initial therapy (note emphasis). The Cochrane review on intravenous magnesium [1] included four trials administering IV magnesium to children who did not respond to initial treatment (three doses of nebulized bronchodilator). The fifth trial included children who did not respond to one dose of nebulized salbutamol combined with IV methyl prednisolone. Since Su, et al. [7] included the same trials as the Cochrane review; the difficulty about the timing of administration is overcome. The sixth trial [10] included by them enrolled children who did not responded to three doses of inhaled salbutamol and IV methyl prednisolone. This suggests that the various trials included in the systematic review did not have uniform protocols for initial therapy (i.e. before using magnesium). The issue has greater importance considering that the more recent trials and current therapy protocols include systemic steroid administration within the first hour itself, whereas the older trials so not.

Therefore, one can argue that since the real role of magnesium (by any route) is after initial therapy has failed; hence it is important to compare it against other options used in the second hour, rather than placebo. This aspect has been studied only by Singhi et al, [11] who randomized non-responders to IV magnesium or IV terbutaline or aminophylline. They demonstrated greater therapeutic success and less side effects with magnesium compared to either of the other two medications. This firmly places IV magnesium as the preferred agent for children who do not respond to initial treatment.

In addition to these limitations in the systematic review [7], there are some errors in data extraction. Some of these (such as lack of intention-to-treat analysis, incorrect entry of mean/standard deviation) could affect the results marginally, while others (interchange of data of two trials in the forest plot reporting hospitalization with intravenous magnesium) do not.

The abstract of the review [7] mentions a third outcome viz need for further treatment, but there is no mention if this subsequently. One would also expect a systematic review of interventions to report on safety (in addition to efficacy). Although magnesium is generally well tolerated and hence deemed safe, some outcomes related to safety (such as side effects, tolerance) should have been incorporated.

On the plus side, the authors [7] presented the review in simple, easy-to-understand language, without undue statistical (or other) jargon. They also acknowledged some of the limitations with methodology. However no efforts were made to evaluate publication bias.

Extendibility: The clinical problem, type of patients, therapeutic options and mode of administration (intravenous magnesium) is extendible to hospital-based settings in India. In fact, IV magnesium is already the standard of care in most pediatric emergency rooms. In contrast, the lack of clear benefit with nebulized magnesium precludes its application in routine practice.

Conclusion: IV magnesium is efficacious in children with asthma exacerbations who do not respond to first hour therapy. Limited data suggest that it is preferable to other options such as aminophylline or terbutaline infusions. However, there is insufficient evidence to support the use of nebulized magnesium.

Funding: None; Competing interest: None stated.

Joseph L Mathew

1. Griffiths B, Kew KM. Intravenous magnesium sulfate for treating children with acute asthma in the emergency department. Cochrane Database Syst Rev. 2016;4: CD011050.

2. Shan Z, Rong Y, Yang W, Wang D, Yao P, Xie J, et al. Intravenous and nebulized magnesium sulfate for treating acute asthma in adults and children: a systematic review and meta-analysis. Respir Med. 2013;107:321-30.

3. Castro-Rodriguez JA, Rodrigo GJ, Rodríguez-Martínez CE. Principal findings of systematic reviews of acute asthma treatment in childhood. J Asthma 2015;52:1038-45.

4. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2016. Available from: www.ginasthma.org. Accessed December 14, 2016.

5. British Thoracic Society Scottish Intercollegiate Guidelines Network. British Guideline on the Management of Asthma. A National Clinical Guideline. Revised 2014. Available from: https://www.brit-thoracic.org.uk/document-library/clinical-information/asthma/btssign-asthma-guideline-2014/. Accessed December 16, 2016.

6. British Thoracic Society Scottish Intercollegiate Guidelines Network. British Guideline on the Management of Asthma. A National Clinical Guideline. Revised 2016. Available from: https://www.brit-thoracic.org.uk/document-library/clinical-information/asthma/btssign-asthma-guideline-2016/. Accessed January 15, 2017.

7. Su Z, Li R, Gai Z. Intravenous and nebulized magnesium sulfate for treating acute asthma in children: A systematic review and meta-analysis. Pediatr Emerg Care. 2016 Oct 4 [Epub ahead of print].

8. Griffiths B, Kew KM, Michell CI, Kirtchuk L. Intravenous magnesium sulfate for treating children with acute asthma in the emergency department. Cochrane Database Syst Rev. 2014;4:CD011050.

9. Abalos E, Carroli G, Mackey ME, Bergel E. Critical appraisal of systematic reviews Available from: http://apps.who.int/rhlCritical%20appraisal%20of%20 systematic%20reviews.pdf. Accessed December 14, 2016.

10. Torres S, Sticco N, Bosch JJ, Iolster T, Siaba A, Rocca Rivarola M, et al. Effectiveness of magnesium sulfate as initial treatment of acute severe asthma in children, conducted in a tertiary-level university hospital: a randomized, controlled trial. Archivos Argentinos de Pediatria. 2012;110:291-6.

11. Singhi S, Grover S, Bansal A, Chopra K. Randomised comparison of intravenous magnesium sulfate, terbutaline and aminophylline for children with acute severe asthma. Acta Paediatrica. 2014;103:1301-6.

Funding: None; Competing interest: None stated.

Mandeep Walia

1. Griffiths B, Kew KM. Intravenous magnesium sulfate for treating children with acute asthma in the emergency department. Cochrane Database Syst Rev. 2016; 4:CD011050.

2. British Thoracic Society/Scottish Guidelines Intercollegiate Network. British Guideline on the Management of Asthma. 2014. Available from: http:// www.sign.ac.uk/pdf/SIGN141.pdf. Accessed December 25, 2016.