Nebulised Magnesium Sulphate – Hype or Hope?

By: Norwich PEM
On: February 5, 2021

Ask an anaesthetist any question, and they will probably tell you that the answer is magnesium.

Whilst that may be a little flippant, good old fashioned magnesium sulphate has a vast range of clinical uses: pre-eclampsia, neuroprotecting our neonates, converting arrhythmias, you name it, magnesium does it. As paediatricians, our main exposure to magnesium is using it as a second-line IV therapy for our wheezy children, and it seems to be pretty effective, though the jury is still out as to how effective compared to other IV bronchodilators.

So, some clever people came up with a theory: if IV magnesium is effective at treating asthmatic exacerbations, what about nebulised magnesium? Could this be the straw that broke the wheezy camel’s back?

Thankfully, instead of guessing, we can dive right into the recent paper from our friends in the PERC research network in Canada, looking at nebulised magnesium vs placebo in children with refractory acute asthma

What do we know about this currently?

The astute amongst you may have realised that nebulised magnesium has already made it into the SIGN/BTS Guidelines for treatment of acute asthma in children. It made it’s recommendations based on the MAGNETIC study, a large (n=508) randomised control trial comparing nebulised magnesium vs placebo when added to standard salbutamol/ipratropium therapy. It showed a statistically significant, but not clinically significant improvement in Asthma Severity Score at 60 minutes, and thus bought itself a Grade C recommendation to consider using it in severely wheezy kids in the first hour. Whilst encouraging, the data set from MAGNETIC was far from rock-solid, and encouraged further RCTs of nebulised magnesium.

Tell me about this new JAMA study then?

The PERC research group set out to try to answer a relevant clinical question:

Does the addition of nebulised magnesium sulphate reduce hospitalisation rates in children with persistant moderate/severe asthma, after 1hr of standardised therapy?

They did this by designing a randomised, double-blind, placebo-controlled trial, enrolling children 2-17 with a physician confirmed diagnosis of asthma, who had persistant moderate/severe asthma as scored on the PRAM score (an asthma severity score linked here) after 1hr of standardised therapy. This standard therapy was an oral steroid, ipratropium bromide, and 3 “back-to-back” β2 agonists (they used albuterol, the favoured β2 agonist on the other side of the pond, but this is essentially the same as good ol’ salbutamol).

Children requiring immediate airway management, children with significant systemic disease, and those who had received magnesium or were allergic to it were excluded.

The children were then randomised to receive either 3 consecutive nebulisers with albuterol + magnesium sulphate or albuterol + placebo. The placebo was identical in colour, smell, volume, taste and tonicity to the magnesium solution

The primary outcome was hospitalisation within 24hr of receiving therapy. Secondary outcomes were clinically significant changes in PRAM score or observations at up to 4hrs after randomisation, or the need for additional β2 agonists at up to 4hrs after randomisation.

And what did they find?

The team collected data from 7 PED departments over 8 years. During that time, they managed to randomise 818 patients, 409 to magnesium and 407 to placebo. 43.5% of patients receiving magnesium were hospitalised, compared to 47.7% of patients receiving placebo, which was not significant. There were no significant differences in any of the secondary outcomes.

Adverse outcomes were uncommon (36 in total across the arms), and generally not attributed to experimental therapy. All Serious Adverse Outcomes in the study were admission to PICU, and none were attributed to the experimental therapy.

So what does it all mean?

After finishing a paper, we tend to ask ourselves three questions:

Is the clinical question asked by this study relevant to us?

In a word, yes. Nebulised magnesium sulphate is a newer kid on the block, and the evidence for it prior to this trial was encouraging but weak. Good, well designed RCTs are the best way of assessing whether these therapies work, before they become entrenched and dogmatic.

Some may ask whether the primary outcome is relevant to us. Hospitalisation is a good primary outcome here. It’s binary, objective and therefore less susceptible to bias, leading us to be able to interpret the results more confidently. It should also be pointed out that none of the secondary outcomes showed any difference between the two arms.

Is the benefit big enough?

There was no benefit demonstrated in this study between the two arms. Though perhaps disappointing for the trial designers, it should be pointed out that negative trials are as important, if not more so than positive trials. Publication bias towards positive trials often lead clinicians into adopting novel therapies with shaky evidence bases, and it is important to provide balance when these therapies are proved ineffective. Often, with medicines with a fairly low side effect profile are studied, the temptation is to ask, what’s the harm? Well, consider the non-zero cost, non-zero impact on nursing time, pharmacy time, non-zero impact on evidence-based culture at your place of work, and zero benefit, and all of a sudden, the risk:benefit ratio tilts firmly towards harming not only your patient, but your other patients and your clinical practice.

Where does this fit in the context of other research?

This research adds excellent additional data to the questions posed by MAGNETIC. The summary for the original MAGNETIC trial used subgroup analysis to show that the effect size noted in their trial was larger in children with more severe asthma, and in those who were unwell for <6hrs, and propose that nebulised magnesium sulphate may play a clinically significant role in these children. This PERC paper did not support that. It did not find a difference between either arm, nor did it find a difference when looking specifically at children with severe asthma (PRAM score >8), though it should be pointed out the numbers in the severe category in both papers were low, and therefore both are underpowered to make absolute conclusions.

Clinical Bottom Line

The bottom line is that in children with moderate/severe asthma, nebulised magnesium sulphate has not been shown to be of benefit to any meaningful clinical outcomes. The subgroup analysis of MAGNETIC showing significance in severe asthma was not supported by this larger trial, but to be clear, a much larger sample size of patients with severe asthma would be needed to categorically prove it has no effect.

However, the burden of proof lies with nebulised magnesium sulphate. So, until it can be proven to be of benefit, its use is not justified in evidence based practice.