Nebulised magnesium sulphate for asthma?

Acute asthma is a common presentation to the Paediatric Emergency Department. Treatment is adjusted depending on the child’s clinical acuity but commonly includes inhaled salbutamol (a beta-2 agonist), oral corticosteroids, and – in more severe cases – inhaled ipratropium (an anticholinergic). However, some moderate to severe asthma patients do not respond to this treatment.

 Magnesium sulphate is commonly used intravenously as an escalation of care, with evidence supporting reduced hospital admission in children. The 2019 NICE-accredited BTS / SIGN guideline on managing asthma suggests magnesium sulphate can be nebulised with salbutamol and ipratropium in children with a short duration or acute severe asthma with oxygen saturations below 92%. But how effective is nebulised magnesium sulphate?

Schuh S, Sweeney J, Rumantir M, et al. Effect of Nebulized Magnesium vs Placebo Added to Albuterol on Hospitalization Among Children With Refractory Acute Asthma Treated in the Emergency Department: A Randomized Clinical Trial. JAMA. 2020;324(20):2038–2047. doi:10.1001/jama.2020.19839

Clinical question

What is the effectiveness of nebulized magnesium added to inhaled short-acting beta-agonists in children and adolescents with acute asthma in the emergency department who remain in moderate or severe respiratory distress after evidence-based standardized initial therapy?

Design and setting

A randomized, double-blind parallel-group clinical trial conducted over eight years from September 2011 to November 2019 in seven tertiary-care paediatric emergency departments in Canada. Randomization allocations were concealed to maintain blinding.

Population

Children 2 to 17 years of age were eligible if they had a diagnosis of asthma made by a physician, had a previous episode of acute wheezing, and had persistent moderate to severe asthma after completing 1 hour of initial treatment. This treatment included systemic steroids, three doses of inhaled ipratropium bromide and three doses of inhaled salbutamol.

Intervention

Three consecutive nebulisers comprised 5 mg of salbutamol (known as albuterol in Canada) and 600 mg (1.2 mL) of magnesium sulphate.

Control

Three consecutive nebulisers comprised 5mg of salbutamol, but instead of magnesium sulphate, the nebulisers contained 1.2 mL of 5.5% saline placebo.

The magnesium and placebo solutions were identical in volume, colour, taste, and smell, both in the steady state and during nebulization. Study participants, research nurses, ED staff, and the analyst were blinded to the treatment assignment.

Outcome

The primary outcome was whether the treating physician decided to hospitalise children in the study due to persistent respiratory distress or the need for supplemental oxygen within 24 hours of randomisation.

The secondary outcomes included adverse effects, changes in PRAM score, respiratory rate, oxygen saturations or blood pressure, hospitalisation or revisits within 72 hours or administration of IV magnesium after the experimental therapy.

Exclusions

Several exclusion criteria were applied. Children requiring immediate airway management; children who received IV magnesium before enrolment; those with comorbidities such as chronic lung disease, cardiovascular, kidney, neurologic, or other systemic disease; and those with known hypersensitivity to magnesium. Families without adequate command of the English or French language, without telephone or e-mail contact information, and those previously enrolled were also excluded.

What is the PRAM score?

PRAM (Paediatric Respiratory Assessment Measure) is a 12-point clinical scoring system that captures a patient’s asthma severity using a combination of scalene muscle contraction, suprasternal retractions, wheezing, air entry and oxygen saturation. PRAM was originally developed for patients aged 3 – 6 years and subsequently validated in children aged 1 to 17 years old.

Asthma scores are commonly used in the USA and Canada. However, they are much less frequently used in the UK, Ireland, Australia and NZ. A recent PERUKI survey found that none of 59 hospitals routinely collected enough information to calculate a PRAM score for asthma patients.

A PRAM score of 4-7 is considered “moderate” asthma, while 8 or more suggests “severe” illness.

Analysis

Of a total of 5846 screened patients, 4332 met various exclusion criteria (the most common was the 2740 patients who had a PRAM score of 4 or less after initial therapy), 273 declined participation, and another 423 did not participate, mostly due to absence of a primary caretaker.

818 children were randomised, and the results of 816 children were analysed (two children were excluded, one from each group, because they were lost to follow or not eligible).

What did they find?

The primary outcome was hospital admission within 24 hours. 178 of the 409 children in the magnesium sulphate group (43.5%) were hospitalised, compared to 194 of the 407 children in the placebo group (47.7%). The difference between groups was 4.2%. However, the 95% confidence intervals range from -11% to 2.8%, suggesting that there may be no significant difference.

There were no differences in any secondary outcomes between the two groups: no difference in change in PRAM score from baseline at 240 minutes (4 hours); no difference in hospitalisations; no difference in revisits within 72 hours; and no difference in administration of IV magnesium after the experimental therapy.

There were relatively more adverse events in the magnesium group than in the placebo group, but more serious adverse events in the placebo group. All observed serious adverse events consisted of admissions to PICU, and none were attributed to the experimental therapy.

There was no difference in outcome between the intention-to-treat analysis (all patients enrolled in the study) and “per protocol” analysis (those who completed all three assigned treatments), and no difference was demonstrated for those with more severe asthma.

Clinical bottom line

Children with acute asthma who received nebulised magnesium with salbutamol did not have a significantly lower hospitalisation rate than those given salbutamol alone. This study suggests that patients who present with moderate to severe asthma will not benefit from nebulized magnesium sulphate added to salbutamol.

Will it change my practice? – Simon Craig

This is a well-conducted study from the Pediatric Emergency Research Canada (PERC) network and highlights how challenging it is to conduct high-quality research. The authors made an incredible effort to recruit over 800 patients from 7 hospitals over an 8-year period.

Although magnesium alone has some bronchodilator properties (compared to placebo), it doesn’t look like it’s worth adding to inhaled salbutamol for children who are still unwell after initial asthma therapy.

This study also makes me wonder how good IV magnesium really is… It will be very interesting to see the various paediatric emergency research networks trying to tackle large multicentre trials to answer some of the big “IV therapy for asthma” questions. Australian, UK and Irish guidelines don’t recommend inhaled magnesium, and I doubt they will change due to this study.

References

Chalut, D.S., Ducharme, F.M., & Davis, G.M. (2000). The preschool respiratory assessment measure (PRAM): A responsive index of acute asthma severity. Journal of Pediatrics, 137(6), 762-768.

Cheuk DK, Chau TC, Lee SL. Ameta-analysis on intravenous magnesium sulphate for treating acute asthma. Arch Dis Child. 2005;90(1):74-77. doi:10. 1136/adc.2004.050005

Ducharme FM, Chalut D, Plotnick L, Savdie C, Kudirka D, Zhang X, Meng L, McGillivray D. The Pediatric Respiratory Assessment Measure: a valid clinical score for assessing acute asthma severity from toddlers to teenagers. J Pediatr. 2008 Apr;152(4):476-80, 480.e1. doi: 10.1016/j.jpeds.2007.08.034. Epub 2007 Oct 31. PMID: 18346499.

Liu X, Yu T, Rower JE, Campbell SC, Sherwin CM, Johnson MD. Optimizing the use of intravenous magnesium sulfate for acute asthma treatment in children. Pediatr Pulmonol. 2016;51(12):1414-1421. doi:10.1002/ppul.23482

https://www.chusj.org/CORPO/files/32/32ba0b8c-4894-4d8e-87ca-a46e4c0924a5.pdf

https://www.asthmahandbook.org.au/acute-asthma/clinical/add-on-treatment