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Effect of Nebulized Magnesium vs Placebo Added to Albuterol on Hospitalization Among Children With Refractory Acute Asthma Treated in the Emergency DepartmentA Randomized Clinical Trial

Educational Objective
To learn about the treatment of children with acute moderate to severe asthma.
1 Credit CME
Key Points

Question  What is the effectiveness of nebulized magnesium in children and adolescents with acute asthma in the emergency department who remain in moderate or severe respiratory distress after evidence-based standardized initial therapy?

Findings  In this randomized clinical trial that included 816 patients, nebulized magnesium with albuterol, compared with placebo with albuterol, did not significantly decrease the rate of hospitalization for asthma within 24 hours (43.5% vs 47.7%, respectively).

Meaning  The findings do not support use of nebulized magnesium with albuterol among children with refractory acute asthma.

Abstract

Importance  While intravenous magnesium decreases hospitalizations in refractory pediatric acute asthma, it is variably used because of invasiveness and safety concerns. The benefit of nebulized magnesium to prevent hospitalization is unknown.

Objective  To evaluate the effectiveness of nebulized magnesium in children with acute asthma remaining in moderate or severe respiratory distress after initial therapy.

Design, Setting, and Participants  A randomized double-blind parallel-group clinical trial from September 26, 2011, to November 19, 2019, in 7 tertiary-care pediatric emergency departments in Canada. The participants were otherwise healthy children aged 2 to 17 years with moderate to severe asthma defined by a Pediatric Respiratory Assessment Measure (PRAM) score of 5 or greater (on a 12-point scale) after a 1-hour treatment with an oral corticosteroid and 3 inhaled albuterol and ipratropium treatments. Of 5846 screened patients, 4332 were excluded for criteria, 273 declined participation, 423 otherwise excluded, 818 randomized, and 816 analyzed.

Interventions  Participants were randomized to 3 nebulized albuterol treatments with either magnesium sulfate (n = 410) or 5.5% saline placebo (n = 408).

Main Outcomes and Measures  The primary outcome was hospitalization for asthma within 24 hours. Secondary outcomes included PRAM score; respiratory rate; oxygen saturation at 60, 120, 180, and 240 minutes; blood pressure at 20, 40, 60, 120, 180, and 240 minutes; and albuterol treatments within 240 minutes.

Results  Among 818 randomized patients (median age, 5 years; 63% males), 816 completed the trial (409 received magnesium; 407, placebo). A total of 178 of the 409 children who received magnesium (43.5%) were hospitalized vs 194 of the 407 who received placebo (47.7%) (difference, −4.2%; absolute risk difference 95% [exact] CI, −11% to 2.8%]; P = .26). There were no significant between-group differences in changes from baseline to 240 minutes in PRAM score (difference of changes, 0.14 points [95% CI, −0.23 to 0.50]; P = .46); respiratory rate (0.17 breaths/min [95% CI, −1.32 to 1.67]; P = .82); oxygen saturation (−0.04% [95% CI, −0.53% to 0.46%]; P = .88); systolic blood pressure (0.78 mm Hg [95% CI, −1.48 to 3.03]; P = .50); or mean number of additional albuterol treatments (magnesium: 1.49, placebo: 1.59; risk ratio, 0.94 [95% CI, 0.79 to 1.11]; P = .47). Nausea/vomiting or sore throat/nose occurred in 17 of the 409 children who received magnesium (4%) and 5 of the 407 who received placebo (1%).

Conclusions and Relevance  Among children with refractory acute asthma in the emergency department, nebulized magnesium with albuterol, compared with placebo with albuterol, did not significantly decrease the hospitalization rate for asthma within 24 hours. The findings do not support use of nebulized magnesium with albuterol among children with refractory acute asthma.

Trial Registration  ClinicalTrials.gov Identifier: NCT01429415

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Corresponding Author: Suzanne Schuh, MD, Pediatric Emergency Medicine, The Hospital for Sick Children, 555 University Ave, Toronto, M5G 1X8, ON, Canada (suzanne.schuh@sickkids.ca).

Accepted for Publication: September 21, 2020.

Author Contributions: Dr Schuh had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Schuh, Coates, Willan, Zemek, Plint, Gravel, Ducharme, Johnson, Black, Curtis, Klassen, Nicksy, Freedman.

Acquisition, analysis, or interpretation of data: Sweeney, Rumantir, Willan, Stephens, Atenafu, Finkelstein, Thompson, Zemek, Plint, Gravel, Black, Curtis, Beer, Nicksy, Freedman.

Drafting of the manuscript: Schuh, Stephens, Curtis, Nicksy, Freedman.

Critical revision of the manuscript for important intellectual content: Schuh, Sweeney, Rumantir, Coates, Willan, Stephens, Atenafu, Finkelstein, Thompson, Zemek, Plint, Gravel, Ducharme, Johnson, Black, Curtis, Beer, Klassen, Freedman.

Statistical analysis: Willan, Stephens, Atenafu.

Obtained funding: Schuh, Zemek, Plint, Gravel, Johnson, Curtis, Freedman.

Administrative, technical, or material support: Sweeney, Rumantir, Coates, Finkelstein, Thompson, Gravel, Ducharme, Black, Beer, Nicksy, Freedman.

Supervision: Schuh, Sweeney, Rumantir, Johnson, Beer, Klassen.

Conflict of Interest Disclosures: Dr Schuh reported receiving grants from the Canadian Institutes for Health Research (CIHR), Thrasher Research Fund, Physicians’ Services Incorporated Foundation, and Hospital for Sick Children and nonfinancial support from La Diffusion Technique Francaise during the conduct of the study. Dr Sweeney reported receiving grants from the Hospital for Sick Children during the conduct of the study. Dr Finkelstein reported receiving grants from CIHR during the conduct of the study. Dr Zemek reported holding competitively funded research grants from CIHR, Ontario Neurotrauma Foundation, Physicians’ Services Incorporated Foundation, CHEO Foundation, Ontario Brain Institute, Ontario SPOR Support Unit, National Football League, and Clinical Research Chair in Pediatric Concussion from the University of Ottawa. He has no commercial conflicts of interest to disclose. Dr Gravel reported receiving grants from CIHR during the conduct of the study. Dr Ducharme reported receiving unrestricted research funds from GlaxoSmithKline, AstraZeneca, Novartis, Teva, and Trudell Medical; grants from GlaxoSmithKline, Covis, Thorasys, and CIHR; and personal fees from Thorasys, Covis, and Teva outside the submitted work. No other disclosures were reported.

Funding/Support: This research was supported by grants from CIHR, the Thrasher Research Fund, the Physicians’ Services Incorporated Foundation, and the Hospital for Sick Children. Dr Freedman is supported by the Alberta Children’s Hospital Foundation Professorship in Child Health and Wellness.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The Pediatric Emergency Research Canada (PERC) Network members include the following: Suzanne Schuh, MD, Judy Sweeney, RN, BScN, Maggie Rumantir, MD, Allan L. Coates, MDCM, BEng, Andrew R. Willan, PhD, Derek Stephens, MSc, BSc, Yaron Finkelstein, MD, and Darcy Nicksy, BScPhM (The Hospital for Sick Children, Toronto, Ontario, Canada); Graham Thompson, MD, and Stephen B. Freedman, MDCM, MSc (Alberta Children’s Hospital, Calgary, Alberta, Canada); Darcy Beer, MD, and Terry Klassen, MD, MSc (Winnipeg Children’s Hospital, Winnipeg, Manitoba, Canada); Sarah Curtis, MD (Stollery Children’s Hospital, Edmonton, Alberta, Canada); Jocelyn Gravel, MD, MSc, and Francine Ducharme, MD, MSc (Sainte-Justine Pédiatrie, Montreal, Quebec, Canada); Roger Zemek, MD, and Amy Plint, MD, MSc (Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada); and Karen Black, MD, MSc (British Columbia Children’s Hospital, Vancouver, British Columbia, Canada).

Meeting Presentation: This study was accepted for a platform presentation at the annual conference of the Pediatric Academic Societies; May 2020; Philadelphia, Pennsylvania.

Additional Contributions: We thank the participants and their families for trusting us to conduct this trial; the trial investigators and support staff across all sites for their commitment to the successful conduct of the trial; the site coordinators, including Rena Papadimitropoulos (research coordinator, Children’s Hospital of Winnipeg), Arpita Majundar (MSc, Children’s Hospital of Winnipeg), Jianling Xie (MD, MPH, Alberta Children’s Hospital), Dale Dalgleish (RN, BHScN, CHEO), Candice McGahern (BA, CHEO), Ally Slattery (RN, British Columbia Children’s Hospital), Maryse Lagace (RN, BScN, CCRP, CHU Sainte-Justine, Montreal), Manasi Rajagopal (research coordinator, Stollery Children’s Hospital), and Nadia Dow (research coordinator, Stollery Children’s Hospital) for trial coordination; the emergency department physicians, nurses, and ancillary staff at all sites; the staff of the Pediatric Research Academic Initiative at SickKids Emergency (PRAISE) and of the SickKids Emergency Assistants for Research in Child Health (SEARCH) programs for identifying potentially eligible participants; Tanveer H. Collins (MD, The Hospital for Sick Children) for his help with the database; Aya Finkelstein (The Hospital for Sick Children) for her help with the study database; and Lejla Halilovic (BSc, The Hospital for Sick Children) for her administrative assistance with the manuscript preparation. The site coordinators and Dr Collins received financial compensation for their role in the study. The other contributors were not compensated.

Data Sharing Statement: See Supplement 6.

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