Background
Asthma attacks are common in adults and children. People having an attack may need to be treated in a hospital emergency department (A&E). Even with the best treatment, some people need to be admitted to hospital or even into the intensive care unit. Some guidelines suggest that giving magnesium sulfate, either by injection or inhaled straight into the lungs, may be beneficial. In this review we focused on inhaled (or 'nebulised') magnesium sulfate. We were particularly interested in finding out the effects of magnesium sulfate on lung function (breathing tests), severity scores and hospital admissions. We also wanted to know if it was safe.
Study characteristics
We looked for studies in adults and children attending the emergency department with an asthma attack. We included studies which compared giving inhaled magnesium sulfate, plus standard treatment, with standard treatment alone. We also included studies that compared inhaled magnesium sulfate directly with standard treatment. We included studies carried out anywhere in the world, at any time and written in any language.
Key results
We found 25 studies in total, which included nearly 3000 people with asthma attacks. This latest update of the review includes several large trials that were carried out to a very high standard. We found that adding inhaled magnesium sulfate to standard treatments may result in small benefits in terms of lung function, hospital admission and severity scores, but we are uncertain about these findings. This is because many of the studies were carried out in different ways and measured different outcomes at different times so it was quite hard to combine the results from individual studies. Inhaled magnesium sulfate did not seem to cause any serious side effects in the studies we found. We did not find evidence that using inhaled magnesium sulfate instead of standard treatment is beneficial.
Quality of the evidence
We used a scoring system to rate how confident we are in the findings presented. Our scores ranged from high confidence to very low confidence, but most outcomes we rated as low or very low. This is because we had concerns about the way in which some of the studies were carried out: for example, it was perhaps not clear how people were chosen for the two different treatment groups in the study; or it was unclear whether the patients or people running the trial knew who was getting which treatment. Another factor that reduced our confidence was uncertainty about the combined results: for example in some cases we could not tell whether magnesium sulfate was better, worse or the same.
Key message
There is some limited evidence that inhaled magnesium sulfate may have a small benefit for people having asthma attacks when added to standard treatment. However, the most recent, high-quality trials did not generally show important benefits. Also, we cannot be sure if some groups may benefit more than other, for example those having more severe attacks.
Treatment with nebulised MgSO₄ may result in modest additional benefits for lung function and hospital admission when added to inhaled β₂-agonists and ipratropium bromide, but our confidence in the evidence is low and there remains substantial uncertainty. The recent large, well-designed trials have generally not demonstrated clinically important benefits. Nebulised MgSO₄ does not appear to be associated with an increase in serious adverse events. Individual studies suggest that those with more severe attacks and attacks of shorter duration may experience a greater benefit but further research into subgroups is warranted.
Despite including 24 trials in this review update we were unable to pool data for all outcomes of interest and this has limited the strength of the conclusions reached. A core outcomes set for studies in acute asthma is needed. This is particularly important in paediatric studies where measuring lung function at the time of an exacerbation may not be possible. Placebo-controlled trials in patients not responding to standard maximal treatment, including inhaled β₂-agonists and ipratropium bromide and systemic steroids, may help establish if nebulised MgSO₄ has a role in acute asthma. However, the accumulating evidence suggests that a substantial benefit may be unlikely.
Asthma exacerbations can be frequent and range in severity from mild to life-threatening. The use of magnesium sulfate (MgSO₄) is one of numerous treatment options available during acute exacerbations. While the efficacy of intravenous MgSO₄ has been demonstrated, the role of inhaled MgSO₄ is less clear.
To determine the efficacy and safety of inhaled MgSO₄ administered in acute asthma.
Specific aims: to quantify the effects of inhaled MgSO₄ I) in addition to combination treatment with inhaled β₂-agonist and ipratropium bromide; ii) in addition to inhaled β₂-agonist; and iii) in comparison to inhaled β₂-agonist.
We identified randomised controlled trials (RCTs) from the Cochrane Airways Group register of trials and online trials registries in September 2017. We supplemented these with searches of the reference lists of published studies and by contact with trialists.
RCTs including adults or children with acute asthma were eligible for inclusion in the review. We included studies if patients were treated with nebulised MgSO₄ alone or in combination with β₂-agonist or ipratropium bromide or both, and were compared with the same co-intervention alone or inactive control.
Two review authors independently assessed trial selection, data extraction and risk of bias. We made efforts to collect missing data from authors. We present results, with their 95% confidence intervals (CIs), as mean differences (MDs) or standardised mean differences (SMDs) for pulmonary function, clinical severity scores and vital signs; and risk ratios (RRs) for hospital admission. We used risk differences (RDs) to analyse adverse events because events were rare.
Twenty-five trials (43 references) of varying methodological quality were eligible; they included 2907 randomised patients (2777 patients completed). Nine of the 25 included studies involved adults; four included adult and paediatric patients; eight studies enrolled paediatric patients; and in the remaining four studies the age of participants was not stated. The design, definitions, intervention and outcomes were different in all 25 studies; this heterogeneity made direct comparisons difficult. The quality of the evidence presented ranged from high to very low, with most outcomes graded as low or very low. This was largely due to concerns about the methodological quality of the included studies and imprecision in the pooled effect estimates.
Inhaled magnesium sulfate in addition to inhaled β₂-agonist and ipratropium
We included seven studies in this comparison. Although some individual studies reported improvement in lung function indices favouring the intervention group, results were inconsistent overall and the largest study reporting this outcome found no between-group difference at 60 minutes (MD −0.3 % predicted peak expiratory flow rate (PEFR), 95% CI −2.71% to 2.11%). Admissions to hospital at initial presentation may be reduced by the addition of inhaled magnesium sulfate (RR 0.95, 95% CI 0.91 to 1.00; participants = 1308; studies = 4; I² = 52%) but no difference was detected for re-admissions or escalation of care to ITU/HDU. Serious adverse events during admission were rare. There was no difference between groups for all adverse events during admission (RD 0.01, 95% CI −0.03 to 0.05; participants = 1197; studies = 2).
Inhaled magnesium sulfate in addition to inhaled β₂-agonist
We included 13 studies in this comparison. Although some individual studies reported improvement in lung function indices favouring the intervention group, none of the pooled results showed a conclusive benefit as measured by FEV1 or PEFR. Pooled results for hospital admission showed a point estimate that favoured the combination of MgSO₄ and β₂-agonist, but the confidence interval includes the possibility of admissions increasing in the intervention group (RR 0.78, 95% CI 0.52 to 1.15; participants = 375; studies = 6; I² = 0%). There were no serious adverse events reported by any of the included studies and no between-group difference for all adverse events (RD −0.01, 95% CI −0.05 to 0.03; participants = 694; studies = 5).
Inhaled magnesium sulfate versus inhaled β₂-agonist
We included four studies in this comparison. The evidence for the efficacy of β₂-agonists in acute asthma is well-established and therefore this could be considered a historical comparison. Two studies reported a benefit of β₂-agonist over MgSO₄ alone for PEFR and two studies reported no difference; we did not pool these results. Admissions to hospital were only reported by one small study and events were rare, leading to an uncertain result. No serious adverse events were reported in any of the studies in this comparison; one small study reported mild to moderate adverse events but the result is imprecise.