Safety and Effectiveness of Magnesium Sulphate for Severe Acute Asthma Management Among Under-five Children: Systematic Review and Meta-analysis

Introduction

Asthma is a common, chronic inflammatory airway disease that is associated with airway hyper-responsiveness.1 It is the most common chronic inflammatory diseases in children which affects the airways and is characterized by airflow obstruction. Globally, the prevalence of pediatric asthma varies from 10% to 30%.2 Its symptoms range from chronic cough to life-threatening bronchospasm.1,3 The most common triggers of asthma exacerbations in both younger and older children are viral respiratory tract infections, exposure to allergens, tobacco smoke, air pollutants, cold or dry air, and poorly controlled asthma.1,4 Poorly controlled asthma in children leads to significant morbidity, mortality, and socioeconomic problems.2 During emergency room management, all patients with acute severe asthma may initially receive standard treatment with nebulized β2-agonists, systemic corticosteroids, nebulized anticholinergics and general management with oxygen therapy. However, bronchodilators act within minutes and corticosteroids may require hours. Sometimes, these standard treatments and general management in children with moderate to acute severe asthma may not result in adequate response, leading to severe morbidity and mortality.

Rationale

There is an increasing need for a new and effective bronchodilating agents to improve the outcomes of moderate to acute severe asthma. The use of magnesium sulphate (MgSO4) in treating asthma was noted about 60 years ago and several case reports were published on its impact in decreasing admissions and endotracheal intubations.3 MgSO4 is considered an alternative therapeutic option in patients resisting standard therapies.2,5,6 It is an intracellular cation and important coenzyme for various enzyme activities with the following important actions in the management of acute severe asthma: blocks intracellular calcium entry, facilitates calcium release and activation of Na+-Ca2+ pumps, promotes muscle relaxation (inhibition of myosin and calcium interaction), reduces inflammatory mediators (inhibition of degranulation of mast cells and T cells stabilization), depresses the irritability of muscle fibers, and inhibits prostacyclin and nitric oxide synthesis. These mechanisms lead to reduction in the symptoms of acute severe asthma.7

MgSO4 has been used in its intravenous (IV) and nebulized dosage forms. The nebulized route offers a potential advantage of quick onset of action and reduced incidence of systemic side-effects.8 Studies indicated that nebulized MgSO4 is not significantly associated with improved respiratory function or hospital admission, further need of treatment and it is equally effective as nebulized salbutamol for managing severe acute asthma in children.1,2,9 The use of MgSO4 is resulted in improved hospitalization and decreased the need of further treatment among children with severe acute asthma. Intravenous magnesium sulfate is the most effective therapy for children with significant impact on pulmonary function.6,10,11 However, studies conducted on the clinical impacts of IV and nebulized MgSO4 among asthmatic children under five had already generated inconsistent results.2

Objective

This review was aimed to evaluate the safety and effectiveness of MgSO4 in the treatment of acute asthmatic attacks in children under five.

Methods

A systematic and comprehensive literature search was conducted to identify controlled clinical trials of MgSO4 conducted among pediatric patients diagnosed with severe acute asthma. Such trials evaluated the impacts of MgSO4 on hospitalization, short-term pulmonary function, symptom scores, and treatment related adverse effects. Electronic searches were conducted in PubMed, MEDLINE, Google Scholar and Cochrane Library. The key terms used were “magnesium sulphate”, and “safety”, “effectiveness” and “asthma” and “children.” The search strategy “magnesium sulphate” OR “MgSO4” AND “safety” AND “effectiveness” AND “asthma” OR “asthmatic” OR “chronic respiratory disease” AND “Children” AND “under five years old” OR “below five years” was employed to effectively locate appropriate trials.

Eligibility Criteria

Randomized controlled trials, published in English language from 2001 to 2021, examined the effectiveness or safety of IV or nebulized MgSO4 among children under-five with acute asthmatic attack were included. Whereas, review articles, cross-sectional, cohort, and case-control studies, clinical protocols, case reports, and randomized controlled trials conducted among patients age >5 years were excluded.

Critical Appraisal and Data Extraction

TAM and HG conducted critical appraisal using JBI critical appraisal tools for systematic reviews. HD managed the disagreements between the above independent reviewers whereas; HH and KL extracted the data using Excel spread sheet. Data were extracted on the following variables: name of the authors, year of publication, type of outcomes, number of events, and total number of participants form experimental and standard treatment groups.

Risk of Bias Assessment and Statistical Analysis

RevMan statistical data analysis software for systematic reviews was used to assess the risk of bias and the report was generated along with the safety or effectiveness data. The risk of bias was reported based on the following domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and others. Each potential source of bias was graded as high, low, or unclear risk. The risk of bias was reported along with the study findings.

Data were analyzed using RevMan statistical software. The risk ratio (RR) with its 95% confidence interval (CI) was calculated to describe the effects of MgSO4 on the intended outcomes. Data were presented by forest plot along with its interpretation. Heterogeneity across the trials was assessed and reported using I2. The assessed outcomes include respiratory distress and hospitalization, as defined by the trials.

Outcomes

Safety of intravenous or nebulized MgSO4 is defined as development of serious adverse events such as hypotension requiring medical intervention or admission to pediatric intensive care unit.

Effectiveness of intravenous or nebulized MgSO4 is defined as reduction in the use of mechanical ventilation and need of supplemental oxygen treatment, medical intervention or admission to pediatric intensive care unit.

Results

Extensive literature search using title and abstract retrieved 639 potential records. After excluding 636 articles based on the eligibility criteria shown in Figure 1, only three (one IV, two nebulized) randomized placebo-controlled trials were included in the meta-analysis. The mean and median age of the participants was less than five years.

Figure 1 PRISMA flow diagram showing the selection of trials included in the review.

The characteristics of the included trials are described in Table 1. The sample size of the studies ranges from 50 to 816. All patients who enrolled in to the clinical trials had similar asthma severity defined by inadequate response to standard treatment; ie, severe acute asthma. Based on the quality assessment, two trials had low risk of bias and one had high risk of bias in the domain of blinding of participants. The dose response relationship was not evaluated and one study concluded that nebulizing MgSO4 was not superior to standard treatment among children with severe acute asthma with no significant adverse effects.1 Another study found that nebulizing MgSO4 has a greater clinical effect in children with more severe asthma exacerbation. It has shortened symptom duration and no significant adverse events.12 A study on IV MgSO4 also reported that early administration of intravenous MgSO4 achieved a rapid clinical response with excellent prognosis and no significant adverse effects among children with acute severe asthma which is refractory to standard treatment13 (Table 1).

Table 1 Characteristics of the Included Trials for the Safety and Efficacy Analysis of MgSO4

Effectiveness and Safety of IV MgSO4

A study reported the outcome of 33 patients (17 IV MgSO4 group and 16 standard treatment group). In this study, five patients (two from MgSO4 and three from the standard treatment group) required mechanical ventilation. The pooled result indicated, treatment with IV MgSO4 was not associated with improved respiratory function (RR=1.09, 95%CI: 0.81–1.45) (Figure 2).

Figure 2 The effectiveness of IV MgSO4 for managing acute severe asthma among children under five.

According to the study by Santana et al,13 tachycardia was reported among eight patients (three from MgSO4 and five from standard treatment group). The meta-analysis result indicated that safety of IV MgSO4 was not statistically different from standard treatment (RR=0.38, 95%CI: 0.08−1.67) (Figure 3). Two studies; involving the data of 1321 patients (660 from MgSO4 and 661 from standard treatment group), were used for analyzing the efficacy of nebulized MgSO4. In the studies, 409 (200 from MgSO4 and 209 from standard treatment group) of 1321 participants were hospitalized for persistent respiratory distress or needed supplemental oxygen therapy within 24 h of randomization. According to the meta-analysis, nebulized MgSO4 did not significantly improve respiratory function (RR=1.05, 95%CI: 0.71–1.19) (Figure 4) with an acceptable degree of heterogeneity (I2=55%).

Figure 3 The safety of IV MgSO4 for managing acute severe asthma among children under five.

Figure 4 The effectiveness of nebulized MgSO4 for managing acute severe asthma among children under five.

The data of 1323 participants were included in the analysis for the safety of nebulized MgSO4. The studies reported that serious adverse events; defined as hypotension requiring medical intervention or admission to pediatric intensive care unit, were reported among 34 participants (eight from MgSO4 and 26 from standard treatment group). The meta-analysis analysis result indicated that nebulized MgSO4 was safer than placebo. It resulted in 69% lower risk of adverse effects (RR=0.31, 95%CI: 0.14–0.68) (Figure 5) compared to the standard treatment.

Figure 5 The safety of nebulized MgSO4 for managing acute severe asthma among children under five.

Discussion

In this systematic review and meta-analysis, the authors attempted to synthesize the most comprehensive evidence for the safety and effectiveness of magnesium sulfate among children under five with severe acute asthma. According to this study, IV MgSO4 was not superior to standard treatment (bronchodilators and steroids) among children under five hospitalized with severe acute asthma. It was neither safe nor effective than the standard treatment. In clinical practice, IV MgSO4 is often used in combination with other IV bronchodilators (salbutamol and aminophylline).14 Another systematic review and meta-analyses confirmed that supplementing IV MgSO4 among children with severe acute asthma was not more effective than the standard therapy.14 Similarly, nebulized MgSO4 did not show significant effect on respiratory function or hospitalization.1 This result is consistent with previous studies.1,2,9

According to the current study, nebulized MgSO4 is safer than standard treatment. A recent double-blind, randomized, controlled study demonstrated that there was no serious adverse reaction associated with nebulized MgSO4 among Thai children with moderate asthma exacerbation.16 However, Tassalpa D et al found that the use of nebulizing and IV MgSO4 has no statistically significant impact on the safety and efficacy of the treatment.15 Other studies confirmed that, MgSO4 has a low risk of serious adverse effects, minor side effects, such as epigastric or facial warmth, flushing, pain and numbness at infusion site, dry mouth, and malaise.2,10,12,13 Santana, et al13 concluded that IV MgSO4 is associated with low risk of tachycardia than salbutamol. This could be due to the variation in mechanism action, as MgSO4 is one of the vasodilating agents.

Our meta-analysis has several limitations that must be taken into consideration. Firstly, inclusion of small number of studies, as only few trials with the target population are retrieved. Secondly, only RCTs are included in this study, which may undermine the actual scenario of the clinical practice. Thirdly, as the studies are nearly all from high income nations, the finding cannot be generalized to the all children with severe acute asthma. Hence, we suggest the need for further investigation with appropriate and adequate properly designed studies to identify the true impact and factors affecting the safety and effectiveness of MgSO4 in this population.

Conclusion

This study revealed that intravenous and nebulized MgSO4 were not more effective than the standard treatment among children with severe acute asthma. Besides, both formulations had statistically insignificant effect in reducing the risk of hospitalization and clinical symptoms of severe acute asthma among children under five. However, this study indicated that nebulized MgSO4 was safer than the standard treatment among children under five with severe acute asthma. This finding indeed contradicts the earlier results; therefore the authors suggest the need of further investigation with properly designed trials and adequate sample size.

Data Sharing Statement

All relevant data are within the manuscript.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.

References

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