Effect of Protocolized Magnesium Replacement on Mortality and Atrial Fibrillation in Critically Ill Patients (MAGNOLIA)

Background: Measurement of serum magnesium levels, and administration of supplemental magnesium when levels are below target, is a common element of routine care for critically ill patients. However, targets for replacement vary, and the targets that lead to the best outcomes are unknown.

Methods: Multi-center open-label parallel group randomized controlled superiority trial of adult critically ill patients receiving protocolized magnesium replacement, comparing a higher target (\>0.95mmol/L) to a lower target (\>0.7mmol/L). The trial will be embedded into the electronic medical record (EMR) at 5 hospitals across 2 health networks in Ontario, Canada, with a shared EMR. Patients aged 16 years or older who have ICU admission orders and an order for the magnesium replacement protocol will be included. Patients with pre-eclampsia, sustained ventricular tachycardia, or neuromuscular junction disease will be excluded. The primary outcome will be an ordinal composite, evaluated at 30 days, composed of death and the number of days free of atrial fibrillation or flutter in ICU. Secondary outcomes will include ventricular arrhythmia and antiarrhythmics administered; receipt of vasopressors, ventilation, and new renal replacement therapy in ICU; lengths of ICU and hospital stay; hospital mortality at 60 and 90 days, magnesium levels, and magnesium supplementation. Analyses will use Bayesian regression with weakly skeptical priors and an intention-to-treat approach. Because both targets lie within the standard of care, the trial will use opt-out consent. Screening will be integrated with the EMR, such that when a patient meets inclusion criteria, a pop-up will appear for the ordering clinician. After the clinician confirms eligibility, the patient will be randomized and assigned to their target. Outcome ascertainment will occur within the EMR.

Discussion: This randomized controlled trial addresses an important uncertainty regarding routine care in the ICU with an EMR-embedded design. The innovative EMR-embedded design facilitates the large sample sizes and comprehensive, equitable recruitment needed for a trial evaluating a routine care intervention, and will lead to seamless integration with routine care upon trial completion.