Effect of protocolized MAGNesium replacement in critically ill patients On mortaLIty and Atrial fibrillation: protocol for the MAGNOLIA randomized controlled trial

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 health record (EHR) at 6 hospitals across 2 health networks in Ontario, Canada, with a shared EHR. We will include patients aged 16 years or older who have ICU admission orders, including an order for the magnesium replacement protocol. Patients with pre-eclampsia, sustained ventricular tachycardia, or neuromuscular junction disease will be excluded. Because both targets lie within the standard of care, we will use an opt-out consent approach. Screening will be integrated with the EHR, such that when a patient meets inclusion criteria, a pop-up will appear to allow the ordering clinician to confirm eligibility or indicate the relevant exclusion. After the clinician confirms eligibility, patients will be randomly assigned to a magnesium target. 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. For analyses, we will use Bayesian regression with weakly skeptical priors and an intention-to-treat approach. Outcome ascertainment will occur within the EHR. Discussion: This randomized controlled trial addresses an important uncertainty regarding routine care in the ICU with an EHR-embedded design. The innovative EHR-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. Trial registration: ClinicalTrials.gov, NCT07173855 . Registered 12 September 2025, https://clinicaltrials.gov/study/ NCT07173855 .