PROJECT SUMMARY ABSTRACT Asthma is the most common chronic illness of childhood and a leading cause of hospitalization and healthcare costs for children. Most children hospitalized for asthma first receive breathing treatments and steroid medicines in an emergency department (ED) according to national guidelines. An additional medicine, intravenous magnesium sulfate (IVMg), may help severely sick children avoid hospitalization. National asthma guidelines recommend IVMg for severely sick children, but note a lack of consistent evidence to support this recommendation. Only about one in four children hospitalized for asthma received IVMg in the ED. Estimates of the potential effects of broader use of IVMg on hospitalization are limited by the small size of prior trials, but increased use could potentially avoid 18,000 hospitalizations each year, producing direct cost savings of $65 million yearly in addition to saving significant indirect costs of missed school and parental work. A few major questions remain about IVMg. First, it has not been tested early in ED treatment, when the impact on hospitalization would be greatest. Second, the clinical impact of hypotension, a driver of low utilization, is not characterized in prior trials or clinical databases. Third, no trials have compared different IVMg doses or measured serum magnesium levels to optimize dosing, so the most effective dose is unknown. All prior trials of IVMg in children with asthma have been small. A large randomized, placebo-controlled clinical trial of IVMg that could answer whether IVMg can reduce hospitalization might be challenging for a few reasons. First, enrolling patients fast enough to give IVMg early in ED treatment is challenging. Second, understanding blood pressure changes after IVMg is essential to plan safety monitoring for a larger trial. Third, little pharmacologic information has been gathered to guide the doses of IVMg to be tested. We must conduct a small pilot clinical trial to test our procedures and gather necessary information to plan the large trial. The Pediatric Emergency Care Applied Research Network (PECARN) is a network of children’s EDs that has conducted similar research involving acutely ill children. Our goals in this project are to: 1. Demonstrate the feasibility of enrolling children in the ED with severe acute asthma in a multicenter, randomized, controlled trial of placebo, low-dose IVMg, or high-dose IVMg. 2. Demonstrate the feasibility of timely delivery of study medication to enrolled patients and assessment of blood pressure and associated adverse events in a standardized protocol. 3. Externally validate a previously constructed PK model and develop a combined PK/PD model for IVMg using magnesium (total and ionized) serum concentrations and their correlation with measures of safety and respiratory distress in children with asthma. After completing this pilot trial in three sites, we will plan a multi-center randomized trial of IVMg in chi...