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Three Part Question

In a [child with acute severe asthma] does [the addition of nebulised magnesium sulphate to standard treatment regimes] improve [outcome]?

Clinical Scenario

A nine year old boy is brought into the emergency department by his parents. He is a known asthmatic and has become acutely short of breath. He is struggling to talk in full sentences and his PEFR is less than 50% predicted. You suspect acute severe asthma and begin the appropriate treatment in accordance with the BTS asthma guideline. You wonder if the addition of nebulised magnesium sulphate would improve his outcome.

Search Strategy

MEDLINE using the OVID interface 1966 to August 2015.

[nebulised OR inhaled OR aerosolized] AND [magnesium sulphate OR MgSO4] AND [asthma] AND [child filter] LIMIT to Human and English language.

Search Outcome

38 papers were found of which 5 were relevant to the question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Powell C et al. June 2013 UK	508 children aged 2-16 with acute severe asthma from 30 hospitals in the UK. Acute severe asthma was defined as per the BTS guidelines. 252 children received nebulised salbutamol 2.5 mg (ages 2-5 years) or 5 mg (ages ≥ 6 years) and ipratropium bromide 0.25 mg mixed with 2.5 ml of isotonic MgSO4 (250 mmol/l, tonicity 289 mOsm; 151 mg per dose) and 256 received nebulised salbutamol 2.5 mg (ages 2-5 years) or 5 mg (ages ≥ 6 years) and ipratropium bromide 0.25 mg mixed with 2.5 ml of isotonic saline. A total of three doses were administered at 20-minute intervals.	Double blind, randomised, placebo-controlled, multi-centre, parallel trial.	The Yung asthma severity score was measured at 60 minutes post randomisation. The ASS includes wheeze, accessory muscle use and heart rate. A high score correlated with a higher severity with a maximum score of 9.	The Mean Yung ASS at 60 minutes post randomisation was lower in the magnesium sulphate group (4.72) in comparison with the placebo group (4.95). The difference was small but statistically significant (p=0.034). They found that the difference was sustained for 4 hours post randomisation (p=0.042). The affect was more significant for those with the more severe asthma (p=0.034) and for children with symptoms for <6 hours (p=0.049).	The same dose of isotonic MgSO4 was used for all ages. Different nebulisers used at different centres.
			The 'stepping down' of treatment at one hour.	The percentage of children stepping down at one hour was higher in magnesium group (33% vs 30%); however, this was not statistically significant (p = 0.527).
			The Length of stay in hospital. The LOS in hospital was defined by the time from randomisation to treatment to discharge.	The median LOS for children in magnesium group was slightly shorter (26 hours) in comparison to the placebo group (27 hours). This was not statistically significant (p = 0.166).
			The requirement for IV bronchodilators.	The percentage of children requiring the addition of an IV bronchodilator was lower in the magnesium group (10% versus 12%); however, this was not a statistically significant difference (p = 0.527).
			The requirement for either intubation or ITU admission.	T0he percentage of children requiring intubation or an ITU admission was slightly higher in the magnesium group (9% versus 6%); however, this was not statistically significant (p=0.283).
			Paediatric quality of life measured at 1 month using the PedsQL™ Asthma Scales. This contains 28 items: asthma symptoms (11 items), treatment problems (11 items), worry (three items) and communication (three items). High score correlates with a higher QoL.	The mean PedsQL™ asthma score was slightly higher (73.92) in the magnesium group than in the placebo (70.24) although this was not statistically significant (p=0.104).
			The number and frequency of additional salbutamol administrations.	The total number of additional salbutamol administrations was slightly lower in the magnesium group (8 versus 9); however this was not significant (p = 0.236).
Mahajan et al. 2004 Detroit, Michigan	62 patients aged 5-17 with acute mild-moderate asthma exacerbation defined as FEV1 between 45% and 75% predicted. Intervention group: 31 patients received 2.5 mL Isotonic (6.3%) MgSO4 solution with Albuterol 2.5mg Control group: 31 patients received 2.5 mL normal saline with Albuterol 2.5mg. Patients received a single dose only. Both groups also received corticosteroids (2mg/kg).	Double blind, prospective randomised controlled parallel trial.	Percentage(%) change in FEV1 measured at 0, 10 and 20 minutes following treatment.	The percentage(%) difference in FEV1 was significant at both 10 and 20 minutes in the magnesium sulphate group (1.41L versus 1.13L, respectively, p = 0.03).	Also reported a clinical severity score but not reported in sufficient detail to included. Did not describe incomplete outcome data so unclear risk of outcome bias.
			Hospital admission rates.	No significant reduction in hospital admissions were found.
Ashtekar et al. 2008 Cardiff, Wales	17 patients aged 2-16 with acute severe asthma presenting to the University Hospital of Wales, Cardiff. Severe asthma defined as saturations <93% on room air. Intervention: 7 patients received 2.5 mL isotonic MgSO4 (151 mg /dose) with 500 mcg Ipratropium bromide and 2.5 mg salbutamol or 5 mg salbutamol (2-5 and >5 years) three times in one hour. Control group: 10 patients recieved 2.5 mL of isotonic saline) with 500 mcg Ipratropium bromide and either 2.5 mg salbutamol or 5 mg salbutamol (2-5 and >5 years) three times in one hour. Both groups also received 2mg/kg oral prednisolone.	Double blind parallel randomised controlled pilot study	The Yung ASS measured at 60 minutes also the area under the ASS curve over 240 minutes (score was measured on 6 occasions over 4 hours and plotted onto a graph).	There were no significant differences in mean (SD) ASS at 60 minutes between the magnesium group and the placebo: 5.3 (2.0) v 6.1 1.3) (diff 0.8, 95%CI diff -0.87, 2.5; p=0.3). The area under the curve for ASS showed no differences between the two groups, 151 (56.4) v 151 (36.7) (diff 0.29, 95% CI diff -47.6, 48.2, p=0.99).	The results for the studies secondary outcomes including the number and frequency of additional inhaled or nebulised salbutamol and the length of stay in hospital were not reported in the publication. Small patient group.
Khashabi et al. 2008 Urmia, Iran	40 children with a mean age of 3.55 years. The treatment group (10 children) were given two doses of nebulised Isotonic MgSO4 with nebulised salbutamol. The control group (10 children) were given 2 doses of 2.5 mL normal saline with nebulised salbutamol.	Double blinded randomised controlled parallel trial	Reduced mean duration of oxygen therapy required.	The mean hours of oxygen therapy in magnesium sulphate group was less than for the saline group (15.2 ± 12.5, 95% CI: 9.3-21.5 vs. 19 ± 14.3, 95% CI: 12.35-25.8 respectively) (p=000).	The severity of asthma exacerbations included was not specified. The method of blinding was not described. Small sample size.
			Change in respiratory distress score measured one hour before and one hour after the second dose of treatment.	The difference in improvement of the mean respiratory distress scores for the magnesium sulfate and saline groups was insignificant (2.8±1, 95%CI: 2.8-1.9 vs. 2 ±1, 95% CI 2.8-1.8, p=0.97).
			Mean number of days of hospital stay.	The mean duration of inpatient stay in days was slightly lower in the magnesium sulphate group in comparison to the saline group (1.95 ± 0.9, 95%CI: -1.28 to 1.28 vs.2.1 ± 8.6, 95%CI: -1.35 to 1.35 respectively). Although this was not statistically significant (p=0.73).
Meral et al. 1996 Izmur, Turkey	40 patients with a moderate to severe exacerbation of asthma with a mean age of 10.8. 20 patients received 2 mL MgSO4 (280 mmol/L 258 mOsm, pH 6.7) and 20 patients received Salbutamol 2.5 mg in 2.5 mL . Only a single dose was given to each treatment group.	Randomised controlled trial	Percentage (%) change in PEF measured using a wright peak flow meter at 5, 15, 30, 60, 180, 240 and 360 minutes after treatment.	Lung function at 5, 60 and 360 minutes was significantly greater in the salbutamol group.	No control group. Method of randomisation not described. Unclear if blinded as no details given.
			Respiratory distress score (RR, HR and BP) measured at 5, 15, 30, 60, 180, 240 and 360 minutes post treatment.	No statistical differences were found between the groups for respiratory rate, heart rate and BP.

Comment(s)

It is evident that there are very few high quality studies, comparing the addition of nebulised magnesium sulphate to standard treatment regimes, for children with an acute severe exacerbation of asthma. Five randomised controlled trials were included in this best evidence review. Several of the studies included did not directly answer the question. The study by Meral et al. did not include have control group, instead they directly compared nebulised magnesium sulphate alone to nebulised salbutamol alone. In addition, not all of the studies included patients with only asthma exacerbations classified as severe. The study by Mahajan et al. used patients with mild to moderate asthma exacerbations. In addition, the severity of asthma exacerbations for the children included in the study by Kashabi et al. was not specified. It is evident that nebulised magnesium sulphate cannot be used as a substitute to standard asthma treatment. However, there is some evidence that the addition of magnesium sulphate to the current asthma treatment regimes may be of benefit to some children. Three of the four studies comparing the addition of magnesium sulphate to standard treatment regimes support the use of nebulised salbutamol. Khasbai et al. found that the addition of magnesium sulphate reduced the mean duration of oxygen therapy required. The study by Mahajan et al. found that the addition of nebulised magnesium sulphate significantly increased the FEV1 in the short term. The MAGNETIC trial by Powell at al. is the largest most recent study to date. Their study found that three doses of nebulised isotonic magnesium, given in addition to the standard therapy (nebulised salbutamol and ipratropium bromide) resulted in a significant difference reduction in the asthma severity score at 60 minutes post treatment, in comparison to the control group. This difference although small, was statistically significant. They also found that the effect continues to be statistically significant for up to 240 minutes after initial treatment. Interestingly they found that the addition of nebulised magnesium sulphate was particularly beneficial for a particular subset of patients. They found that it was most beneficial for the children with the more severe asthma exacerbations as well as those with a short duration of onset of symptoms. This study measured several other secondary outcomes. For these outcomes there were no statistically significant benefits for the addition of nebulised magnesium sulphate. However, in the majority of the secondary outcomes measured, the addition of nebulised magnesium sulphate resulted in a better outcome. Although the question did not directly ask about the side effect profile or cost effectiveness; all of the studies found that the side effects profile of nebulised magnesium sulphate is minimal and the treatment is cost effective. These are important factors when considering the inclusion of a new medication. There were several limitations identified which should be considered. Each of the studies have used different doses of nebulised magnesium sulphate, but given the same dose to all ages. In addition they have used different frequencies of administration and total number of doses and nebulised magnesium sulphate has been administered in a number of different combinations with other treatments. These differences make these studies less combinable. Also, a few of the studies have an unclear risk of bias as they have not stated the method of blinding and randomisation. With the exception of the study by Powell et al. the studies included only small sample sizes which impacts upon the power of the studies. More high powered studies are required to investigate the benefit of nebulised magnesium sulphate further.

Clinical Bottom Line

There is some evidence that the addition of nebulised magnesium sulphate to standard treatment regimes for paediatric asthma is beneficial. Particularly for those with more severe asthma and a shorter duration of onset of symptoms. Given the safety profile and cost effectiveness, use should be considered for these patients.

References

1. CVE Powell, R Kolamunnage-Dona, J Lowe, A Boland, S Petrou, I Doull, K Hood and PR Williamson on behalf of the MAGNETIC study group. MAGNEsium Trial In Children (MAGNETIC): a randomised, placebo-controlled trial and economic evaluation of nebulised magnesium sulphate in acute severe asthma in children. Health technology assessment 17 (45) (pp v-vi, 1-216), 2013. Date of Publication: Oct 2013.
2. Mahajan P, Haritos D, Rosenberg N, Thomas R. Comparison of nebulised magnesium sulphate plus albuterol plus saline in children with exacerbations of mild to moderate asthma. J Emerg Med 2004;27:21–5
3. Ashtekar CS, Powell C, Hood K, Doull I. Magnesium nebuliser trial (magnet): a randomised double-blind placebo controlled pilot study in severe acute asthma. Archives of Disease in Childhood 2008;93:A1
4. Khashabi J, Asadolahi S, Karamiyar M, Salari Lak S. Comparison of magnesium sulfate to normal saline as a vehicle for nebulized salbutamol in children with acute asthma: a clinical trial. European Respiratory Society Annual Congress 2008:[4597].
5. Meral A, Coker M, Tanac R. Inhalation therapy with magnesium sulfate and salbutamol in bronchial asthma. Turkish Journal of Pediatrics 1996;38(2):169–75.