A Multi-Center Randomized Controlled Trial of Intravenous Magnesium for Sickle Cell Pain Crisis in Children

Introduction: There are approximately 18,000 hospitalizations and 75,000 hospitalization days annually in the United States for children experiencing sickle cell vasoocclusive crises. Despite advances in the management of other comorbidities of sickle cell disease, little has changed in the management of sickle cell pain crises. Magnesium, a known vasodilator, anti-inflammatory and pain reliever, has the potential to alter the pathophysiology of pain crises, shortening length of stay and decreasing opioid use. A previous pilot study showed IV magnesium shortened length of stay compared to historical controls. A randomized trial conducted in Canada showed no decrease in length of stay with the use of intravenous magnesium. In the MAGiC (MAGnesium for children in Crisis) study, we hypothesized that the addition of intravenous (IV) magnesium to standard therapy would shorten hospital length of stay, result in decreased opioid use and improve quality of life for pediatric patients hospitalized with sickle cell pain crises.

Methods: The MAGiC study was a multi-center, randomized, double-blind, placebo-controlled trial of IV magnesium versus normal saline for the treatment of pediatric sickle cell pain crisis conducted at 8 sites. Participating sites were members of the Pediatric Emergency Care Applied Research Network (PECARN), and collaborations between Pediatric Emergency Medicine physicians and Pediatric sickle cell experts facilitated enrollment. Children aged 4 to 21 years, with hemoglobin SS or hemoglobin SB° thalassemia were eligible if they required inpatient hospitalization after failing emergency department (ED) management for pain. Enrollment occurred at 8 sites between December 2010 and December 2013, with a total of 217 eligible site enrollment months. Children received 40 mg/kg of IV magnesium every eight hours for a total of 6 doses or normal saline placebo of equivalent volume (1 ml/kg). Randomization was stratified by site, age and hydroxyurea use. The primary outcome was length of stay from the time of first drug infusion until 12 hours after the last IV opioid dose or time of discharge, whichever occurred first. Secondary outcomes included opioid use, recorded as morphine equivalents, and quality of life, as measured using the PedsQL Sickle cell disease specific module, fatigue module and generic module. Side effects, specifically hypotension, weakness, warmth on infusion, or the development of acute chest syndrome (ACS) were documented. Using an intention-to-treat analysis, we compared length of stay using a Van Elteren test, stratified by the same factors used to stratify randomization.

Results: 208 children were enrolled. Four children were excluded prior to receipt of any study drug, resulting in 101 children receiving magnesium and 103 receiving placebo. The 2 groups were similar with respect to age, sex ,genotype, weight, history of ACS or asthma, previous hospitalizations within the past three years and days of pain prior to arrival. The median time from first ED opioid to first study drug infusion was 7.4 hours, similar between the two groups. The median (interquartile range) length of stay was 56.0 (27.0 - 109.0) hours in the magnesium group compared to 47.0 (24.0 - 99.0) hours in the placebo group, p = 0.264. Patients who received magnesium received 1.46 mg/kg of morphine equivalents compared to 1.28 mg/kg in the placebo group (p=0.11). Quality of life scores were similar between the two groups after 48 hours on study drug and one week after discharge (p > 0.10 at both time points). Safety analysis revealed no differences in hypotension (3% for magnesium versus 1% for placebo) or weakness (7% versus 4%) between the 2 groups. Of those who received magnesium, 26% reported warmth on infusion compared to 2% of children who received placebo, p < .0001. Other adverse events, serious adverse events, and rehospitalizations within 7 days were similar between the groups.

Conclusion: Intravenous magnesium does not shorten length of stay, lessen opioid use or improve quality of life in children who require hospitalization for sickle cell pain crisis. Close collaboration between Pediatric Emergency Medicine physicians and Pediatric Hematologists allows for the successful enrollment of large numbers of children in an acute intervention trial for children with sickle cell disease.