Educational Aims
The reader will come to:
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Update the evidence on IV-MgSO4 efficacy and safety as a second line of treatment in children with acute asthma exacerbations.
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Understand that children with acute asthma exacerbations who receive IV-MgSO4 as second line of treatment have 85 % lower odds of hospitalization and their lung function improves by 26 % more than controls. Adverse events of IV-MgSO4 were very rare (0.3 %).
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Recognize that IV-MgSO4 appears to be safe and efficacious treatment in the pediatric population.
Abstract
Background
Asthma is the most prevalent chronic disease in children and constitutes a significant healthcare burden. First-line therapy for acute asthma exacerbations is well established. However, secondary treatments, including intravenous magnesium sulfate (IV-MgSO4), remain variable due to scarcity of data on its efficacy and safety.
Objective
To assess the effectiveness and safety of IV-MgSO4 as a second line of treatment in managing children with asthma exacerbations.
Methods
We searched five databases from inception until April 2023 on randomized clinical trials of IV-MgSO4 in children with acute asthma exacerbations. The primary outcomes were hospitalization rate and length, and change in the severity score. Secondary outcomes included percentage increase in peak expiratory flow rate (PEFR), hospital re-admission rate, need and length for pediatric intensive care unit (PICU) treatment, and adverse effects. Meta-analysis was performed for three outcomes with estimated odds ratios (ORs) or mean differences (MDs) and 95% confidence intervals (CIs).
Results
Eleven studies met the final criteria. In comparison to control, administration of IV-MgSO4 was associated with a reduced hospitalization risk (OR 0.15; 95%CI: 0.03, 0.73) in four studies, and improvement of lung function (MD 26.77% PEFR; 95%CI: 18.41, 54.79) in two studies. There were no significant differences in the length of stay between groups. Due to heterogeneity, a narrative synthesis of other outcomes was performed.
Conclusion
The use of IV-MgSO4 demonstrated a reduction in the hospitalization rate and PEFR improvement in children with asthma exacerbations. Adverse effects were rare. Further well-designed studies are needed to better determine the efficacy and safety profile of IV-MgSO4.
Introduction
Asthma is the most common chronic disease in the pediatric population, affecting around 4.7 million children in the U.S. . Worldwide, asthma in children aged 5–19 causes ∼209 disability-adjusted life years (DALYs) per 100,000, and 0.29 deaths per 100,000 . Acute exacerbations are a leading cause of asthma-related healthcare utilization, accounting for 750,000 emergency department (ED) visits, 200,000 hospitalizations, and $50 billion in healthcare costs annually in the U.S. . First-line therapy for acute asthma exacerbations is well established and consists of inhaled short-acting beta2-agonists and systemic corticosteroids . The addition of multiple doses of inhaled ipratropium bromide to beta2-agonists is indicated as the standard treatment in children and adolescents with moderate to severe exacerbations of asthma in the ED . However, the use of second-line therapies for exacerbations refractory to initial therapies varies widely, partly due to the lack of robust evidence.
Secondary therapies include intravenous (IV) bronchodilators like albuterol/salbutamol, magnesium sulfate (MgSO4), terbutaline, or aminophylline, as well as inhaled therapies like nebulized MgSO4, Heliox, and non-invasive or invasive ventilatory support . National and international guidelines vary in their recommendations . A survey of pediatric emergency physicians in the UK/Ireland reported that over half preferred IV-albuterol/salbutamol, 28 % IV-MgSO4, and 15 % aminophylline , while an earlier survey in Australia/New Zealand found that aminophylline was used by 45 %, IV-MgSO4 by 55 %, and IV-albuterol/salbutamol by 87 % . More recently, a prospective study in 24 EDs in the UK/Ireland reported that 55.6 % used albuterol/salbutamol as first-line IV, 29.2 % used MgSO4, and 15.2 % aminophylline; roughly half gave these sequentially depending on response, while 16.8 % gave them concurrently . In contrast, a recent multicenter retrospective cohort study from 7 EDs in US (n = 22,495) showed that IV-MgSO4 was administered in 25.7 % (range by site from 15.9 % to 50.6 %) of children during ED visits resulting in hospitalization after ED treatment . And the use of IV-MgSO4 in status asthmaticus had almost doubled across children’s units across the US over the past decade .
One of the main concerns for clinicians is the lack of adequate evidence on the safety and efficacy of some of these treatments . A recent international survey from three pediatric emergency medicine research networks reported that only ∼ 18 % of ED physicians agreed that “there is adequate evidence that children with acute asthma refractory to first-line therapy, and who attain a satisfactory and sustained response to IV-MgSO4, can be safely discharged home”, with the proportion differing markedly among networks (58 % agreed in Canada vs. 5.7 % in UK/Ireland vs. 9.4 % in Australia/New Zealand) .
Earlier systematic reviews concluded that using IV-MgSO4 during acute asthma exacerbations in children may decrease hospital admission and may improve lung function; however, the more recent Cochrane review noted that the number and size of studies limited the evidence on efficacy and safety. The aim of this systematic review is to update the evidence on IV-MgSO4 efficacy and safety as a second line of treatment in children with acute asthma exacerbations.
Methods
Seach strategy
Five bibliographic databases were searched (PubMed, Embase, Web of Science, Latin American & Caribbean Health Sciences Literature [LILACS] and Cochrane Library) from inception to April 04, 2023. Search terms in each database included all subject headings, abstracts, and/or full texts associated with acute asthma exacerbations, acute wheezing episodes, and magnesium. The full PubMed search strategy can be found in the Online Repository. Reference lists were checked for any additional relevant studies. All extracted citations were imported into the EndNote® reference manager (Version X9, Clarivate Analytics, 2018). After removing the duplicates, four reviewers (DA, AA, IO, JACR) independently screened the retrieved titles and abstracts. Subsequently, all potentially relevant publications were assessed in full text. At each stage, uncertainty about the eligibility of studies was resolved through discussion and obtaining consensus by other reviewers (EF, WF), if necessary. The protocol for this review was registered in the National Institute for Health Research’s PROSPERO (CRD42022334390), and reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines .
Eligibility criteria
The main eligibility criteria were: 1) randomized controlled trial (RCT) study design; 2) age group under 18 years; 3) clinical presentation described as severe asthma exacerbation; and 4) IV-MgSO4 administration as a second line of treatment during the ED or hospital management compared to any of the following control groups: placebo, no intervention, or any other standard treatment. Exclusion criteria included e.g. duplicate publications and multiple publications regarding the same study group, non-human studies, secondary analysis of not eligible RCTs, retrospective studies, studies without any randomization procedures. Actions were taken to contact corresponding authors when additional clarification or further data were required.
Our primary outcomes included: (a) hospital admissions, (b) change in the severity score at any point assessed, and (c) length of the hospital stay for those hospitalized. Secondary outcomes included (a) lung function, (b) re-admission rate to a hospital or ED at any time assessed, (c) proportion of patients needing pediatric intensive care unit (PICU) treatment and length of stay in PICU, and (d) adverse effects.
Study extraction and quality assessment
Data were extracted from each included clinical trial for the following parameters: (a) study origin, (b) study design, population, and sample size, (c) intervention, (d) comparator, (e) primary and secondary outcomes, (f) results, and (g) potential confounding factors. Two independent reviewers (AA, IO) assessed the risk of bias in each of the included studies without being blinded to the authors or journal. A revised Cochrane risk-of-bias tool for randomized trials was used (RoB 2) . Encountered discrepancies were resolved through discussion with all the reviewers. The RoB 2 tool is structured into five bias domains, which enables judging the randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result. The judgments for each domain were to choose between “low risk of bias”, “some concerns”, or “high risk of bias”. In conclusion, the overall bias was determined by reflecting the individual marks.
Data analysis and synthesis
Data collection and curation were performed using Microsoft Excel. A meta -analysis was undertaken where possible (at least two studies considering the same quantitative outcome in similar populations). However, given the small number of studies utilizing similar methodologies and assessing similar outcomes, meta‐analysis was not possible for all our outcomes. Consequently, in those, a narrative synthesis method was used. Review Manager (RevMan) v5.3 software from the Cochrane Collaboration was used to perform meta -analyses, generate forest and funnel plots, and calculate the I 2 statistic. Dichotomous variables were expressed using pooled statistics of odds ratio (OR) and their 95 % confidence interval (CI), with a random-effects model using a Mantel-Haenszel method depending on heterogeneity. In the studies that reported continuous variables as means, mean difference (MD) was extracted and calculated where not given. Heterogeneity was assessed using the I 2 statistic defined by the Cochrane Handbook for Systematic Reviews, and substantial heterogeneity was defined as I 2 value > 50 %. Several sensitivity analyses were conducted to test the robustness of the main findings and assess the potential sources of heterogeneity. First, a fixed-effect meta -analysis was conducted to evaluate the consistency of the main results from a random-effect model. Secondly, the individual study estimates one at a time were excluded to examine the impact of each study on the overall OR. Prediction intervals were calculated, where appropriate, to show the expected range of true effects can be observed in future studies on this subject . The calculations were performed using R .
Results
After removing duplicate entries, 533 titles and abstracts were reviewed in the initial screening process, and 266 records were excluded as irrelevant to the search criteria. Thus, 267 papers were assessed for eligibility for inclusion, out of which 252 retrieved articles did not fulfill the inclusion criteria ( Fig. 1 for details). In the end, 11 studies (n = 672 children) were included in the final review and meta -analysis (see Table 1 ). Three studies were performed in the USA, two in India, and one in each of these countries: Turkey, Thailand, Brazil, Argentina, Paraguay and Venezuela. Sample sizes in the included studies ranged from 20 to 143 children. Nine studies were conducted in the ED and two in hospitalized patients. For three outcomes (two primary and one secondary), the data retrieved from the included studies was sufficient to conduct a meta -analysis; the remaining outcomes were summarized descriptively.
| Authors | Study design | Total NAge range (yrs) | Country | Settings | Experimental | Comparator | Outcome | D1 | D2 | D3 | D4 | D5 | Overall | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Ciarallo L et al. 1996 | Double-blind placebo-controlledrandomizedclinical trial | 31(6–18) | USA | Emergency department | Single dose of MgSO4 infusion (25 mg/kg max 2 g) over 20 min | Single dose placebo infusion over 20 min | Change in pulmonary function between enrollment at 50, 65,80, 95, 110 min (PEFR,FEV1, FVC) | Low risk | |||||||
| Devi PR et al.1997 | Double-blind placebo-controlledrandomizedclinical trial | 47(1–12) | India | Emergency department | Single dose of MgSO4 infusion (0,2 ml/kg, 50 %solution, max. 2 g) over35 min | Single dose placebo infusion over 35 min | Change in PPEFR and oxygen saturation starting from 30 min to next hours and change in asthma score | Some concerns | |||||||
| Gürkan F et al.1999 | Double-blind placebo-controlledrandomizedclinical trial | 20(6–16) | Turkey | Emergency department | Single dose of MgSO4 infusion (40 mg/kg, max. 2 g) over 20 min | Single dose of an equivalent volume of saline | Change in PEFR and asthma score | High risk | |||||||
| Ciarallo L et al.2000 | Double-blind placebo-controlledrandomizedclinical trial | 30(6–17.9) | USA | Emergency department | Single dose of MgSO4 infusion (40 mg/kg, max. 2 g) over 20 min | Single dose placebo infusion over 20 min | Change in PEFR from baseline to 110 min | ||||||||
| Scarfone RJ et al.2000 | Double-blind placebo-controlledrandomizedclinical trial | 54(1–18) | USA | Emergency department | Single dose of MgSO4 infusion (75 mg/kg, max. 2,5g) over 20 min | Single dose placebo infusion over 20 min | Mean change inPulmonary Index Score over 120 min | D1 | Randomisation process | ||||||
| Santana JC et al.2001 | Double-blind randomizedclinical trial | 50(>2 to < 13) | Brazil | Pediatric IntensiveCare Unit | Intravenous MgSO4 (2.5 mg/kg/min,diluted in saline, 20mins, total dose 50 mg/kg) | salbutamol (1mcg/kg/min, in saline, 20 min) or placebo (saline 1 ml/kg/h) | Days in PICU, need for mechanical ventilation,number of nebulizations | D2 | Deviations from the intended interventions | ||||||
| Torres S et al.2012 | Open-label randomizedcontrolled trial | 143(2–15) | Argentina | Emergency department | Single dose of MgSO4 infusion (25 mg/kg, max. 2 g) over 20 min, within the first hour | Further nebulized bronchodilators | Need for mechanical ventilation | D3 | Missing outcome data | ||||||
| Singhi S et al.2014 | Open-label randomizedcontrolled trial | 100(1–12) | India | Emergency department | Single dose of MgSO4 infusion (50 mg/kg) over 20 min | Single terbutaline infusion | Improvement of four or more points in the CAS score 1 h after the intervention | D4 | Measurement of the outcome | ||||||
| Irazuzta JE et al.2016 | Open-label randomizedcontrolled trial | 38(6–18) | Paraguay | Emergency department | Single dose of MgSO4 infusion (50 mg/kg) over > 1 h | HDMI | Discharge rate at 24 h | D5 | Selection of the reported result | ||||||
| Daengsuwan T et al. 2017 | Open-label randomizedcontrolled trial | 28(2–15) | Thailand | Hospital | Single dose of MgSO4 infusion (50 mg/kg) over 20 min | 3 doses of isotonic MgSO4 nebulizer (6 % solution, 2.5 ml) each given 20 min apart | The Wood’s ClinicalAsthma Score | ||||||||
| Kassisse E et al.2021 | Observer-blinded randomizedcontrolled, partly cross-over trial | 131(2–12) | Venezuela | Emergency department | Single dose of MgSO450 mg/kg, 30 mins | Rapid and then slow infusion of aminophylline at 5 mg/kg | Changes in mPIS, hospitalization rate |
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