Original Article
Prospective Observational Study of Clinical Outcomes After Intravenous Magnesium for Moderate and Severe Acute Asthma Exacerbations in Children

https://doi.org/10.1016/j.jaip.2021.11.028Get rights and content

Background

There is limited knowledge regarding whether intravenous magnesium (IV-Mg) improves outcomes in children with acute asthma exacerbations.

Objective

To examine whether IV-Mg improves outcomes in children with moderate and severe exacerbations.

Methods

We performed a secondary analysis using data from a prospective observational cohort of children aged 5 to 17 years with moderate and severe exacerbations. Standardized treatment included systemic corticosteroid and inhaled albuterol, with consideration of IV-Mg (75 mg/kg) for patients with insufficient response after 20 minutes. Propensity score (PS) models were used to examine associations of IV-Mg treatment with change in the validated Acute Asthma Intensity Research Score, hospitalization rate, and time to spacing of inhaled albuterol of 4 hours or more among hospitalized participants.

Results

Among 301 children, median (interquartile range) age was 8.1 (6.4-10.2) years, 170 were Black (57%), 201 were male (67%), and 84 received IV-Mg (28%). In a PS covariate-adjusted multivariable linear regression model, IV-Mg treatment was associated with a 2-hour increase in the Acute Asthma Intensity Research Score (β-coefficient = 0.98; 95% confidence interval [CI], 0.20-1.77), indicating increased exacerbation severity. Three additional PS-based models yielded similar results. Participants receiving IV-Mg had 5.8-fold (95% CI, 2.8-11.9) and 6.8-fold (95% CI, 3.6-12.9) greater odds of hospitalization in PS-based multivariable regression models. Among hospitalized participants, there was no difference in time to albuterol of every 4 hours or more in a PS covariate-adjusted Cox proportional hazards model (hazard ratio = 1.2; 95% CI, 0.8-1.8).

Conclusions

Among children with moderate and severe exacerbations, IV-Mg is associated with increased exacerbation severity, increased risk for hospitalization, and no acceleration in exacerbation resolution among hospitalized participants.

Introduction

National Heart, Lung, and Blood Institute (NHLBI) expert guidelines recommend considering intravenous (IV) magnesium (IV-Mg) in children with moderate or severe asthma exacerbations who have an incomplete response to systemic corticosteroid (CCS) and inhaled albuterol.1 A 2020 focused update to these guidelines did not change this recommendation.2

The primary mechanism of action of IV-Mg is thought to be competition for the smooth muscle calcium channel, decreased cytosolic Ca2+ concentration, and smooth muscle relaxation.3 A Cochrane systematic review of randomized trials concluded that although fewer children treated with IV-Mg required hospital admission, the quality of evidence was poor owing to the small sample size and varying results among studies.4 In addition, the reviewers could not determine whether reduced hospitalizations were associated with exacerbation severity, age, or other treatments.

Moreover, recent studies showed that IV-Mg is typically administered late in the emergency department (ED) course, and most children are hospitalized after receiving IV-Mg.5,6 Yet despite limited evidence for the safety and efficacy of IV-Mg in children, the use of IV-Mg increased in the United States over the past decade.5

In a recently reported study, children with moderate or severe exacerbations after 1 hour of treatment with CCS and nebulized albuterol were randomized to an additional 1 hour of nebulized albuterol plus either nebulized Mg or saline placebo.7 After this nebulized treatment, ED physicians prescribed additional treatments as deemed necessary, including IV-Mg, and made hospitalization decisions. A post hoc analysis of these post-randomization data indicated that IV-Mg was associated with greatly increased odds of hospitalization.8 This association was also present among participants who achieved mild exacerbation severity at the time of disposition decision-making.

Furthermore, a recent study of patients using a large administrative database reported that IV-Mg was not associated with improved in-hospital outcomes such as noninvasive positive pressure ventilation, mechanical ventilation, duration of mechanical ventilation, or length of stay.9 That study and other retrospectively derived cohorts may have been limited by confounding by severity, a type of confounding by indication.10,11 Furthermore, administrative databases are unable to determine more granular clinical outcomes that include validated measures of pretreatment severity and response to treatment.

Limitations of those studies emphasize the need for prospectively derived cohorts that incorporate measures of clinical severity and response to treatment to examine the effectiveness of IV-Mg in children with acute asthma exacerbations. The objective of this study was to use data from a large prospective study of children with moderate and severe acute asthma exacerbations to examine whether IV-Mg administered early in ED management decreases exacerbation severity, hospitalizations, and time to spacing of inhaled albuterol to 4 hours or more in hospitalized patients.

Section snippets

Study population

We performed secondary analyses of data from a prospective, observational cohort of 933 children aged 5 to 17 years with doctor-diagnosed asthma and acute exacerbations in an urban tertiary children’s hospital ED.12,13 These analyses included participants with moderate and severe exacerbations defined using the validated Acute Asthma Intensity Research Score (AAIRS), as described subsequently (Figure 1).14,15 An exacerbation was defined as cough, dyspnea, wheezing, and/or chest pain, and the

Results

Among the cohort of 933 participants enrolled between April 2008 and February 2013, 570 had a pretreatment AAIRS of 7 or greater and 301 of those met study inclusion criteria and were available in the ED at 2 hours after treatment initiation (Figure 2). Those 301 participants were aged (median [IQR]) 8.1 [6.4-10.2] years, 170 were Black (57%), 201 were male (67%), and 84 received IV-Mg (28%). Table II lists demographic and asthma characteristics of the 301 children according to IV-Mg treatment

Discussion

The results of this investigation indicate that IV-Mg treatment is associated with increased exacerbation severity of approximately one point on the validated 17-point AAIRS. We have reported that a two point or greater decrease is clinically meaningful for decisions to deescalate treatment but have not examined the threshold for an increase in AAIRS that warrants escalation of treatment.15,18 Nonetheless, an increase of one point indicates an increase in clinical severity and is cause for

Acknowledgments

D.H. Arnold is the guarantor of the manuscript content, including the data and analysis. D.H. Arnold, W. Gong, J.W. Antoon, L.B. Bacharier, T.G. Stewart, D.P. Johnson, W.S. Akers, and T.V. Hartert made substantial contributions to the conception and design of the work; D.H. Arnold was responsible for acquisition of the data; W. Gong and T.G. Stewart were responsible for analysis of the data; and all coauthors made substantial contributions to the interpretation of data. D.H. Arnold, W. Gong,

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  • Cited by (6)

    This work was supported by the National Institutes of Health: National Heart, Lung, and Blood Institute Grant K23 HL80005 (D.H. Arnold), National Institute of Allergy and Infectious Diseases Grant K24 AI77930 (T.V. Hartert), and National Institutes of Health/National Center for Research Resources Grant UL1 RR024975 (Vanderbilt Clinical and Translational Science Awards).

    Conflicts of interest: L.B. Bacharier reports personal fees from GlaxoSmithKline, Genentech/Novartis, Merck, DBV Technologies, France, Teva, Boehringer Ingelheim, AstraZeneca, WebMD/Medscape, SanofiSanofi, France/Regeneron, Vectura, Circassia, Elsevier, Kinaset, and Vertex outside the submitted work. D.P. Johnson serves as a Quality Improvement consultant to LifePoint Corporate Services, General Partnership. The rest of the authors declare that they have no relevant conflicts of interest.

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