General Paediatrics•

Role of nebulised magnesium sulfate in treating acute asthma in children: a systematic review and meta-analysis

Abstract

Objectives To review the efficacy of nebulised magnesium sulfate (MgSO4) in acute asthma in children.

Methods The authors searched Medline, Embase, Web of Science and Cochrane Library for randomised controlled trials (RCTs) published until 15 December 2023. RCTs were included if they compared the efficacy and safety of nebulised MgSO4 as a second-line agent in children presenting with acute asthma exacerbation. A random-effects meta-analysis was performed, and the Risk of Bias V.2 tool was used to assess the biases among them.

Results 10 RCTs enrolling 2301 children with acute asthma were included. All trials were placebo controlled and administered nebulised MgSO4/placebo and salbutamol (±ipratropium bromide). There was no significant difference in Composite Asthma Severity Score between the two groups (6 RCTs, 1953 participants; standardised mean difference: −0.09; 95% CI: −0.2 to +0.02, I2=21%). Children in the MgSO4 group have significantly better peak expiratory flow rate (% predicted) than the control group (2 RCTs, 145 participants; mean difference: 19.3; 95% CI: 8.9 to 29.8; I2=0%). There was no difference in the need for hospitalisation, intensive care unit admission or duration of hospital stay. Adverse events were minor, infrequent (7.3%) and similar among the two groups.

Conclusions There is low-certainty evidence that nebulised MgSO4 as an add-on second-line therapy for acute asthma in children does not reduce asthma severity or a need for hospitalisation. However, it was associated with slightly better lung functions. The current evidence does not support the routine use of nebulised MgSO4 in paediatric acute asthma management.

PROSPERO registration number CRD42022373692.

What is already known on this topic

  • Global initiative for Asthma (GINA) 2023 update suggests using nebulized MgSO4 as a second line therapy for children aged 2 years and above with acute asthma.

What this study add

  • Evidence from this systematic review and meta-analysis suggests that add-on-therapy with nebulized MgSO4 might not reduce asthma severity.

  • Nebulized MgSO4 possibly improves lung functions; however, it does not translate into clincial benefits.

How this study might affect reserach, practice and policy

  • Existing evidence does not favour routine use of nebulized MgSO4 in acute asthma management in chidren. Future guidelines should incorporate this evidence.

Introduction

Asthma is the most common chronic disease of childhood, affecting nearly 22 million children worldwide.1 Acute exacerbation is the leading cause of mortality and morbidity in children with asthma and accounts for almost 13 000 deaths and 5 million disability-adjusted life years, along with a huge healthcare cost.1 2 The first-line therapy for acute exacerbation of childhood asthma is well established and comprises systemic corticosteroids and inhaled short-acting β2-agonists (SABAs) along with controlled oxygen.2 3 However, many children do not respond to these agents and hence necessitate additional therapy (second line). The role of intravenous and nebulised magnesium sulfate (MgSO4) has been explored as second-line therapy for acute exacerbation; however, the controversy on its route and timing still exists.3 4

The Global Initiative for Asthma (GINA) 2021 update suggests using intravenous MgSO4 (not nebulised) for patients with severe exacerbation not responding to initial treatment; however, the 2023 update suggests nebulised isotonic MgSO4 as a second-line therapy for children aged 2 years and above.3 4 In a recent systematic review, intravenous MgSO4 as a second-line therapy was associated with reduced hospitalisation and improved lung functions.2 Previous systematic reviews on nebulised MgSO4 showed variable and contradictory results, adding further uncertainty.5–7 Recently, the role of nebulised MgSO4 as second-line therapy in asthma exacerbation has been further explored in many more trials, necessitating an update on this aspect.8–11

In this systematic review and meta-analysis, we aimed to update the evidence on the efficacy and safety of inhaled/nebulised MgSO4 as second-line therapy in children and adolescents (up to 18 years) with acute asthma exacerbation.

Methods

Protocol registration and reporting

The protocol was prospectively registered with PROSPERO (CRD42022373692, available at https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=373692). The review was done as per the methodology described in the Cochrane Handbook for Systematic Reviews of Interventions and is being reported as per the updated Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.12

Research question

Does inhaled/nebulised MgSO4 as an adjunct to SABA, compared with standard therapy, help reduce asthma severity score in children presenting with acute asthma exacerbation?

Information sources and eligibility criteria

We searched Medline (via PubMed), Embase, Web of Science and CENTRAL for randomised controlled trials (RCTs) published from inception until 15 December 2023. The search was further updated on 15 February 2024. We did not use any language restrictions or filters during the database search. The electronic search was supplemented by a manual search of the bibliography of relevant reports to identify additional citations. We also searched various registries (until 15 December 2023), namely ClinicalTrials.gov (https://ClinicalTrials.gov/ct2/home), Clinical Trial Registry of India (http://ctri.nic.in/), Australian and New Zealand Clinical Trials Registry (https://www.anzctr.org.au/) and the European Union Clinical Trials Register (https://www.clinicaltrialsregister.eu/). We included studies if they meet all the following criteria: (1) population: children aged 1–18 years with acute asthma, (2) intervention: inhaled/nebulised MgSO4, (3) control: either placebo with standard therapy or standard therapy alone, (4) study design: parallel-group RCTs. Studies will be excluded if they meet any of the following criteria: (1) population: adults, (2) intervention: oral or intravenous MgSO4, (3) study design: non-RCT/crossover RCT, and studies published in non-English language or as abstract only.

Outcomes

The primary outcome was the asthma severity. There are multiple scores for assessing asthma severity, namely the Pulmonary Index Score,13 Pediatric Asthma Severity Score,14 Childhood Asthma Score15 and the Pediatric Respiratory Assessment Measure.16 All these scores are on an ordinal scale where increasing scores mean increasing disease severity. We combined studies reporting similar scores. If different scores were reported across studies, then we combined them using standardised mean difference (SMD) calculated by the following formula17:

Display Formula

Secondary outcomes included pulmonary function tests (forced expiratory volume in 1 s (FEV1), peak expiratory flow rate (PEFR)), need for hospitalisation, intensive care unit (ICU) admission, length of hospital stay, effect on physiological parameters (heart rate, respiratory rate and oxygen saturation) and adverse events, including mortality before discharge.

Search strategy and selection process

The authors used a peer-reviewed database-specific search strategy for electronic search (online supplemental table 1). The articles retrieved by this search strategy were imported to Rayyan software (https://www.rayyan.ai/) to remove duplicates. Two reviewers (JPG and PK) independently reviewed the remaining unique records to identify the studies meeting all inclusion criteria. A hand search of the bibliography of the potentially relevant reports was done to identify additional citations. The full texts of eligible studies were retrieved and were independently assessed by two authors (JPG and PK). Any discrepancy between the two reviewers was resolved through discussion or involving the third reviewer (JK). Two reviewers (JPG and PK) independently extracted data in a duplicate and blinded manner to a predesigned Microsoft Excel proforma. The extracted data include but are not limited to the authors’ name, year of publication, country, study design, setting, detailed methodological characteristics, study population (age, gender, severity of asthma), details of the intervention and control group (dose, duration, frequency, route of administration, cumulative dose, adjunct therapy), and outcomes. The disagreement between the two reviewers was resolved through a discussion with a third reviewer (JK). The extracted data were rechecked for accuracy and completeness by another reviewer (JK). Two authors (JPG and JK) independently assessed the risk of bias using the Risk of Bias tool, V.2 (RoB2).18 After the assessment, the trials were rated to be either at low or high risk of bias or to have some concerns. Disagreements, if any, were resolved through mutual discussion.

Statistical analysis

We used the Review Manager (RevMan) computer program V.5.4 (Cochrane Collaboration, 2020) for data synthesis and meta-analysis. We calculated the mean difference (MD) with 95% CIs for continuous variables and relative risk (with 95% CI) for dichotomous variables. As explained above, studies using different scales to measure the same outcome were combined using the generic inverse variance approach.17

We used a random-effects model to account for slight variability in the disease severity and dose of the intervention. Heterogeneity in studies was explored by inspection of forest plots as well as using the Χ2 test on Cochran’s Q statistics and I² statistics. We did a sensitivity analysis to assess the effect of studies with high-risk bias on outcomes. We planned a subgroup analysis based on asthma severity. Wherever data permitted, we planned meta-regression to quantify the impact of various covariates (disease severity, age and cumulative dose) on the primary outcome. Publication bias was assessed by examining funnel plot asymmetry. We followed updated Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) recommendations to evaluate the certainty of the evidence and used GRADEPro software (https://gdt.gradepro.org) to generate the summary of the findings table.19 Two reviewers (JK and JPG) independently assessed the certainty of the evidence. In case of disagreement, a third researcher (JM) was involved.

Results

We retrieved 499 records (394 from database searching and 105 from registers), of which 237 were duplicates (figure 1). We assessed 197 reports for full text, of which only 10 met all inclusion criteria and were included. A detailed list of excluded studies is provided in online supplemental table 2. The foremost reasons for exclusion were review articles, different interventions (intravenous or oral MgSO4) or different populations (adults or children with other diseases).

Figure 1
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Figure 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.

Study characteristics

We include 10 RCTs enrolling 2301 children of 2–17 years age range with acute asthma exacerbation.8–11 20–25 All trials used nebulised MgSO4 along with SABA (±ipratropium bromide). All were done in the emergency room setting except one,11 which was done in the paediatric ICU. There was wide variation in the frequency and cumulative dose of the intervention (online supplemental table 3).

Risk of bias

We used the RoB2 tool for the risk of bias assessment. Three trials were at low risk of bias in all domains,9 11 21 and six trials8 10 20 22–24 have some concerns in the selection of reported results (mostly due to lack of availability of protocol in the public domain and/or inadequate information on analysis reporting). One trial had concerns about the allocation concealment and the selection of reported results.25 None of the trials were considered at high risk of bias. Detailed graphical light plots and summary plots are shown in figure 2.

Figure 2
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Figure 2

Risk of bias of included studies A). Judgments about each risk of bias item; b) Risk of bias summary.

Primary outcome

The primary outcome was asthma control, assessed by a Composite Asthma Severity Score and reported in six trials.8–10 21–23 There was no significant difference in the Composite Asthma Severity Score between the two groups (6 RCTs, 1953 participants; SMD: −0.09; 95% CI: −0.2 to +0.02, I2=21%) (figure 3A and table 1). Individual trials used different asthma severity scores, so we also compared them. The two groups had no significant difference regarding individual scores (figure 3B).

Figure 3
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Figure 3

Forest plot showing comparison of Composite Asthma Severity Score (A) and Asthma Severity Score (B) in children with and without inhaled MgSO4. MgSO4, magnesium sulfate; PRAM, Pediatric Respiratory Assessment Measure.

Table 1
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Summary of outcomes and certainty of the evidence

Secondary outcomes

Children who received MgSO4 have significantly better PEFR (presented as % predicted) than the control group (2 RCTs, 145 participants; MD: 19.3; 95% CI: 8.9 to 29.8; I2=0%) (figure 4A). However, there was no significant difference in FEV1 (MD: 8.1; 95% CI: −3 to +19). We also compared the effect of MgSO4 and placebo on physiological parameters (heart rate, respiratory rate and oxygen saturation). Infants who received MgSO4 have slightly lower respiratory rates than the control group (MD: 0.9; 95% CI: −1.4 to −0.4); however, having any clinical significance was unlikely. There was no significant difference in heart rate and oxygen saturation (figure 4B). There was no significant difference in the need for hospitalisation, ICU admission or hospital stay (table 1 and online supplemental figures 1–3). There are some concerns that MgSO4 can lead to respiratory depression, hypotension and bradycardia; therefore, we compared adverse events between the two groups as a safety outcome. We did not observe any increased adverse event rates with MgSO4 (online supplemental figure 4 and table 1).

Figure 4
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Figure 4

Forest plot showing comparison of pulmonary function test (A) and physiological parameters (B) in children with and without inhaled MgSO4. FEV1, forced expiratory volume in 1 s; MgSO4, magnesium sulfate.

Sensitivity and subgroup analysis

We aimed to assess the effect of studies with high-risk bias on all outcomes. However, none of the included studies were at high risk of bias, precluding this analysis. Similarly, there was significant overlap in age groups and asthma severity (most have moderate to severe asthma), precluding subgroup analysis based on these variables. Because of the above reasons, these variables could not be included in the meta-regression analysis. We did a meta-regression analysis for a cumulative dose of MgSO4 (in mg) for the primary outcome. There was no significant relationship between asthma control and MgSO4 dose (coefficient: −0.00009; 95% CI: −0.0004 to 0.00002, p=0.4). Seven studies9 11 20 22–25 used salbutamol alone in both groups (along with intervention/placebo), whereas three studies8 10 21 used ipratropium bromide as an additional therapy. This difference in intervention might introduce heterogeneity and affect the outcomes.5 Therefore, we decided to do subgroup analysis (post hoc) to explore the effect of ipratropium bromide. No significant subgroup differences were observed with or without ipratropium bromide addition (online supplemental table 4).

Publication bias

Though there were limited studies for publication bias, we did funnel plot analysis considering that six studies (a minimum requirement) were available for the primary outcome. There was no evidence of publication bias (online supplemental figure 5). However, due to a limited number of studies, the test may not be able to identify the true bias (if any); hence, it should be interpreted cautiously.

Certainty of evidence

We followed updated GRADE recommendations to evaluate the certainty of the evidence and described it in table 1. Evidence for most outcomes was of low or very low certainty only.

Discussion

This systematic review and meta-analysis assessed the efficacy and safety of adjuvant nebulised/inhaled MgSO4 as a second-line therapy for acute exacerbation in childhood asthma. Overall, 10 RCTs enrolling 2301 children with asthma were included. Low-certainty evidence suggests that add-on therapy with inhaled MgSO4 in acute exacerbation of childhood asthma does not decrease the severity of asthma exacerbation and hence does not improve the immediate asthma exacerbation control. It does not reduce the need for hospitalisation, ICU admission or length of hospital stay (low to very low certainty). However, it does benefit the pulmonary functions in terms of improved PEFR (low-certainty evidence). There is very low-certainty evidence that adjuvant inhaled MgSO4 does not increase adverse events like hypotension, bradycardia or respiratory depression.

MgSO4 has many mechanisms through which it was thought to have possible beneficial effects on asthma. MgSO4 inhibits calcium ion influx, acetylcholine and histamine release from cholinergic motor nerve terminals and mast cells.2 5 26 Simultaneously, it promoted the synthesis of nitric oxide and prostacyclin.5 These actions lead to bronchodilation, an essential aspect of asthma management. Also, it may augment the responsiveness of β-receptors to salbutamol and hence can play a complementary role.2 Furthermore, it stabilises T cells, neutrophils and mast cells, and has anti-inflammatory properties. By virtue of these potential actions, its use has increased significantly in asthma management despite the absence of strong evidence favouring it.

Intravenous and nebulised preparations have been extensively used in various clinical trials in children and adults.2 5 26 27 There are conflicting reports on the efficacy of intravenous MgSO4 in adults and paediatric asthma.2 6 27 A recent systematic review in adults with asthma found no significant effect of intravenous MgSO4 on critical clinical outcomes.27 In contrast, a review in children suggests that it may reduce the need for hospitalisation and improve lung functions.2 However, the later evidence is based on extremely limited data and is subject to extreme uncertainty.2

Recent GINA updates (2023) suggest against routine use of intravenous MgSO4, but at the same time, advocate considering it in patients with severe asthma who do not respond to first-line treatment.4 Though robust data do not support this recommendation, one may argue that there are some potential beneficial effects on pulmonary functions and clinical outcomes, like hospitalisation, without any significant increase in adverse event rates. Hence, it may be justified until better therapies are available. However, the same guideline from GINA suggests considering nebulised MgSO4 as an adjuvant to salbutamol and ipratropium in children aged >2 years with severe exacerbation.4 The evidence does not support this recommendation well. The index systematic review did not observe any significant effect on critical clinical outcomes. The lack of efficacy was consistently seen across almost all studies included in the review, adding to the robustness of the results. Similar observations were reported in previous systematic reviews on nebulised MgSO4 in children.5 7 There was significant improvement (though of lesser magnitude) in PEFR with nebulised MgSO4, as observed with intravenous MgSO4 as well, but there was no significant change in FEV1.2 However, unlike intravenous MgSO4, it does not translate to improved clinical outcomes. These findings suggest that the 2023 GINA recommendations might not be in coherence with the updated review and need a revisit on this aspect.

Strengths and limitations

This systematic review and meta-analysis was performed using standard Cochrane methodology and is reported as per appropriate guidelines. All studies used a placebo and were double-blind, adding to their robustness. Most studies enrolled children with similar disease severity (moderate to severe exacerbation) from similar settings (emergency room), reducing the clinical heterogeneity and making the results more robust and widely applicable. However, there are certain limitations. Most of the studies had small sample sizes, hence, had wide CIs, reducing the level of certainty. The asthma severity scores used in different studies varied greatly. Though we used an appropriate approach to summarise them, it still affects our certainty in results. Unfortunately, there is a shortage of data for subgroup analyses based on disease severity or age group. Though adverse events were rare, they were not reported consistently.

Due to these limitations, the certainty of the evidence for most outcomes was low or very low. This certainty can be improved by adding larger, adequately powered, placebo-controlled multicentric RCTs. Until larger trials are available, the current evidence does not support the routine use of nebulised MgSO4 as an add-on therapy in children presenting with acute exacerbation of asthma not responding to inhaled SABAs and systemic steroids.

Conclusions

Treatment with nebulised MgSO4 as an adjunct to SABA (±ipratropium) compared with standard therapy does not lead to better control of asthma exacerbation or reduce the need for hospitalisation among the children presenting with acute asthma exacerbation. It significantly improves pulmonary functions (PEFR) and is not associated with increased adverse events. However, our confidence in the evidence is low, and substantial uncertainty remains. There is a need for large RCTs on this aspect to improve the certainty of the evidence.

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