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• Systematic review of magnesium in asthma
  Oliver J Rackham
  Published on: 22 March 2016
• Magnesium sulfate and moderate/severe versus severe/very severe asthmatics
  Kathy K Boutis
  Published on: 22 March 2016

• Published on: 22 March 2016

  Systematic review of magnesium in asthma

  • Oliver J Rackham, Doctor

  Dear Editor,

  I was very interested to read the meta-analysis of the use of intravenous magnesium in asthma [1] having recently conducted a systematic review on this subject. I was pleased to see that both produced the same primary outcome of a reduction in hospitalisation with an overall number needed to treat (NNT) of four and a good safety profile. However, there were a number of differences that I was somewhat surpri...

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  Dear Editor,

  I was very interested to read the meta-analysis of the use of intravenous magnesium in asthma [1] having recently conducted a systematic review on this subject. I was pleased to see that both produced the same primary outcome of a reduction in hospitalisation with an overall number needed to treat (NNT) of four and a good safety profile. However, there were a number of differences that I was somewhat surprised to see. Other than personal contact with authors and specialists it was not clear what methods were used to identify unpublished data. My search strategy yielded 179 references (compared to 152) and the review considered six eligible papers [2-7] (compared to five [2-6]) involving 215 participants (compared to 182). As there was no detail regarding reasons for exclusion of studies identified in the initial search it is not clear whether the authors did not identify the study by Santana et al [6] or deemed it ineligible. This study does include a third arm that received intravenous salbutamol but data are available for the comparisons between the placebo group and the magnesium group.

  The overall conclusion is that magnesium may be effective but calls only for further studies without making any recommendation for use now. Part of the reservation seems to be due to heterogeneity of co-therapies and the fact that the trial by Scarfone et al [7] was the largest study yet failed to show a benefit. All studies were randomised control trials and gave regular nebulised bronchodilator and systemic corticosteroid to all participants. One study [4] also gave intravenous aminophylline to both all participants. The differences between the trial by Scarfone et al [7] and the other studies are not discussed by the authors. In that trial, children were enrolled if they met entry criteria at presentation rather than after initial treatment with three doses of nebulised bronchodilator. This makes it likely that the lack of effect represents important information about the correct target population for treatment with magnesium. This is in keeping with adult studies, eg Green,[8] Tiffany. [9]

  The authors planned to stratify by illness severity but did not because all studies included children with moderate to severe asthma. However, it is appropriate to sub-analyse those studies including children who were eligible after initial bronchodilator treatment. This further reduces the risk of hospital admission, giving a number needed to treat of three to prevent one admission when this, more realistic target population is used.

  As discussed in "Atoms" [10] there was no mention of the effect on length of stay. This was reported in two studies. One [4] showed a shorter hospital stay, the other, [6] no significant difference, with pooled data showing a small but statistically significant reduction in length of stay (weighted mean difference (WMD) 5.3 hours [95% confidence interval (CI) 1.2 to 9.5]). With increasing emphasis on the speed of emergency department treatment and the scarcity of hospital beds this is an important result.

  Improvement in lung function was a stated outcome measure of this meta-analysis but few details on reported results were given. There was a greater improvement in all measured parameters at the end of the treatment in the magnesium group compared to placebo: peak expiratory flow rate (PEFR), WMD 43% (95%CI 9-79%); forced vital capacity, WMD 65% (95%CI 31-98%); forced expiratory volume in one second, WMD 75% (95%CI 70-80%). The one trial [4] that reported on lung function tests beyond this period showed a significantly higher PEFR in the magnesium group at 1, 2, 3 and 7 hours after the infusion. These findings are in keeping with the higher than expected rate of discharge from the emergency department and a reduced length of stay.

  Magnesium is already included in the British Thoracic Society guideline on the management of asthma [11] and the Advanced Paediatric Life Support guidelines [12]. Intravenous magnesium used in these suggested doses (25-40 mg/kg over 20-30 minutes) has a good safety profile. In all studies the drug was well tolerated with only minor side effects. This is to be expected as early signs of magnesium toxicity do not appear until serum magnesium levels exceed 6.5 mmol/l and severe toxic effects (such as abnormalities in cardiac conduction, absent reflexes, muscle weakness, respiratory depression) are seen only above 10 mmol/l [13]. In the three studies reporting serum magnesium concentration [2,4,6] the mean level rose to within or just above normal (0.9 to 1.7 mmol/l). Given the safety, the low cost of magnesium sulphate (2.5g (10mmol), the maximum recommended dose in most studies, costs £2.39 [14] [US$ 4.50, €3.35]) and the low number to treat, the recommendations from such a systematic review should be stronger. It is true that further work is needed to explore, among other things, the most effective dose, other routes of administration and the use of multiple doses. In the meantime, children age from six to eighteen presenting with a moderate to severe exacerbation of asthma who fail to respond to initial treatment with bronchodilators and corticosteroids should be considered for treatment with intravenous magnesium.

  References

  (1). Cheuk DKL, Chau TCH, Lee SL. A meta-analysis on intravenous magnesium sulphate for treating acute asthma. Arch Dis Child 2005;90:74-77.

  (2). Ciarallo L, Sauer AH, Shannon MW. Intravenous magnesium therapy for moderate to severe pediatric asthma: results of a randomized, placebo-controlled trial. J.Pediatr.1996;129:809-14.

  (3). Ciarallo L, Brousseau D, Reinert S. Higher-dose intravenous magnesium therapy for children with moderate to severe acute asthma. Arch.Pediatr.Adolesc.Med. 2000;154:979-83.

  (4). Devi PR, Kumar L, Singhi SC, Prasad R, Singh M. Intravenous magnesium sulfate in acute severe asthma not responding to conventional therapy. Indian Pediatr. 1997;34:389-97.

  (5). Gurkan F, Haspolat K, Bosnak M, Dikici B, Derman O, Ece A. Intravenous magnesium sulphate in the management of moderate to severe acute asthmatic children nonresponding to conventional therapy. Eur.J.Emerg.Med. 1999;6:201-5.

  (6). Santana JC, Barreto SS, Piva JP, Garcia PC. Randomized clinical trial of intravenous magnesium sulfate versus salbutamol in early management of severe acute asthma in children. J.Pediatr.(Rio J.)2001;77:279-87.

  (7). Scarfone RJ, Loiselle JM, Joffe MD, Mull CC, Stiller S, Thompson K et al. A randomized trial of magnesium in the emergency department treatment of children with asthma. Ann.Emerg.Med.2000;36:572-8.

  (8). Green SM,.Rothrock SG. Intravenous magnesium for acute asthma: failure to decrease emergency treatment duration or need for hospitalization. Ann.Emerg.Med. 1992;21:260-5.

  (9). Tiffany BR, Berk WA, Todd IK, White SR. Magnesium bolus or infusion fails to improve expiratory flow in acute asthma exacerbations. Chest 1993;104:831-4.

  (10). Bauchner H. Reducing admission for asthma, but no impact on inpatient stay. Arch Dis Child 2005;90:1a.

  (11). Scottish Intercollegiate Guidelines Network,.The British Thoracic Society. British guideline on the management of asthma. Thorax 2003;58(Suppl 1):i1-94.

  (12). Mackway-Jones K, Molyneux E, Phillips B, Wieteska S. Advanced Paediatric Life Support: The practical Approach. 2001.

  (13). Monem GF, Kissoon N, DeNicola L. Use of magnesium sulfate in asthma in childhood. Pediatr.Ann. 1996;25:136, 139-6, 144.

  (14). Joint Formulary Committee. British National Formulary. London: 2004.

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  Conflict of Interest:
  None declared.

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• Published on: 22 March 2016

  Magnesium sulfate and moderate/severe versus severe/very severe asthmatics

  • Kathy K Boutis, Pediatric Emergency Physician

  Dear Editor,

  This article addressed a very important question in the field of paediatric emergency medicine. The prevalence of asthma has risen and there are chronic shortages of inpatient beds in many centres worldwide. Therefore, if intravenous magnesium sulfate added to standard therapy reduces admission rates in asthmatics without significant side effects, this would be very welcome information. This me...

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  Dear Editor,

  This article addressed a very important question in the field of paediatric emergency medicine. The prevalence of asthma has risen and there are chronic shortages of inpatient beds in many centres worldwide. Therefore, if intravenous magnesium sulfate added to standard therapy reduces admission rates in asthmatics without significant side effects, this would be very welcome information. This meta-analysis meets many of the standards that have been developed for such studies and demonstrates a favourable treatment effect of intravenous magnesium sulphate in children with asthma exacerbations and demonstrated a reduction in hospitalisation with an overall number needed to treat (NNT) of four and a good safety profile.[1]

  An issue in clinical practice application of the results of this meta -analysis is that in clinical practice in many paediatric centres in Canada and the USA, intravenous magnesium sulfate is currently reserved for those asthmatics that are severe to very severe and most often have failed to respond to the traditional therapy of bronchodilators and corticosteroids. Individual studies included in this meta-analysis included children with moderate to severe disease, and in the study that represented 30% of the total sample size of pooled results, very severe asthmatics were excluded.[2] In addition, the definition of “moderate to severe” varied in each study. And, while the study mentioned the heterogeneity present in the inclusion criteria, they did not control for them. For example, in the Scarfone et al study, children were assessed after 1 treatment of standard therapy (ventolin) while in the Ciarallo studies, children were assessed after 3 treatments of standard therapy.[3,4] Children assessed to be “moderately to severely” ill after 1 treatment may have included some children that were less ill and therefore the Scarfone study would be less likely to find any differences. The inclusion of milder asthmatics may have diluted the treatment effect and under-emphasized the population that may benefit the most from magnesium sulphate, the severe asthmatics, which would be consistent with the prior evidence found in the Cochrane review published on this area.[5]

  Overall, the results of this study do encourage the more liberal use of intravenous magnesium sulfate in children with a moderate to severe exacerbation of asthma, and perhaps future studies will address more specifically those children with severe to very severe disease and/or those who fail to respond to traditional therapy.

  References

  (1) Cheuk DKL, Chau TCH, Lee SL. A meta-analysis on intravenous magnesium sulphate for treating acute asthma. Arch Dis Child 2005;90:74- 77.

  (2) Scarfone RJ, Loiselle JM, Joffe MD, Mull CC, Stiller S, Thompson K et al. A randomized trial of magnesium in the emergency department treatment of children with asthma. Ann.Emerg.Med.2000;36:572-8

  (3) Ciarallo L, Sauer AH, Shannon MW. Intravenous magnesium therapy for moderate to severe pediatric asthma: results of a randomized, placebo- controlled trial. J.Pediatr.1996;129:809-14.

  (4) Ciarallo L, Brousseau D, Reinert S. Higher-dose intravenous magnesium therapy for children with moderate to severe acute asthma. Arch.Pediatr.Adolesc.Med. 2000;154:979-83.

  (5) Rowe BH, Bretzleff JA, Bourdon C, et al. Magnesium sulfate for treating exacerbations of acute asthma in the emergency department. Cochrane Database Systematic Reviews 2003;1

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  Conflict of Interest:
  None declared.

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