Timely Intravenous Magnesium for Asthma in Children

5.4.1 Acquisition The specific study agent to be used in this pilot trial is Magnesium Sulfate in Water for Injection, a sterile, nonpyrogenic solution of magnesium sulfate heptahydrate in water. Study agent will be acquired by each hospital's research pharmacy from Pfizer, Inc as a solution of magnesium sulfate in water at 80 mg/mL. Agent will be shipped directly from Pfizer to each study hospital pharmacy.

5.4.2 Preparation, Storage & Labeling Doses for each IVMg arm will be prepared in identical manner, by drawing a specified volume of Intravenous Magnesium Sulfate (IVMg) from the commercial container using sterile technique and mixing in a polyvinylchloride container with a specified volume of sterile water. For the 50 mg/kg arm, this will be accomplished by mixing 25 mL of IVMg (80 mg/mL) with 15 mL of sterile water for a final concentration of 50 mg/mL and volume of 40 mL. For the 75 mg/kg arm, this will be accomplished by mixing 37.5 mL of IVMg (80 mg/mL) with 2.5 mL of sterile water for a final concentration of 75 mg/mL and volume of 40 mL. For the placebo arm, 40 mL of 0.9% sodium chloride solution will be drawn into a polyvinylchloride container identical in appearance to the containers used for the IVMg arms. Each prepared dose will be labeled according to the sequential randomization scheme and stored according to local pharmacy procedure. Unused doses prepared locally will be replaced after one week of storage.

5.4.3 Dosing Schedule

After randomization the institutional pharmacist will draw equivolumetric dosages (1 mL/kg, with max of 40 mL) from previously prepared vials. Enrolled subjects will be randomized to one of three arms:

• IVMg 75 mg/kg arm: 75 mg/kg (max 3 gm) infused over 20 minutes through a peripheral IV catheter
• IVMg 50 mg/kg arm: 50 mg/kg (max 2 gm) infused over 20 minutes through a peripheral IV catheter
• Placebo arm: 1 mL/kg (max 40 ml) of normal saline over 20 minutes through a peripheral IV catheter 5.4.4 Dose Modification for Potential Toxicity Clinicians will not administer IVMg to enrolled subjects outside of the study protocol until study outcomes have been determined 2 hours after the start of the infusion. The half-life of IVMg is approximately 2 hours.49 Repeated-dose protocols in an ICU setting that gave as much as 125 mg/kg IVMg to children with asthma over two hours produced no hypotension or other serious adverse effects.47 Because of this margin of safety, open-label IVMg 50 mg/kg can be administered safely 2 hours after the study infusion under strict study monitoring protocols without need for unblinding.

Inclusion criteria

are:

• A prior physician diagnosis of asthma confirmed by a treating physician in the ED who has spoken with the patient and family and reviewed the medical record (ED attending or fellow physician)
• Severe acute asthma, defined as a Pediatric Respiratory Assessment Measure (PRAM) score of 7 or greater as assessed by a treating physician at the time of screening using the study scoring instrument, which takes 60 seconds to complete
• Children 2-17 years of age

Exclusion criteria

are:

• Known pregnancy (by patient or parent report) or positive pregnancy test on females 12 years of age and older
• Age-adjusted hypotension at presentation using age-based Pediatric Advanced Life Support parameters (children >1 year to 10 years, systolic blood pressure (SBP)<(70 + 2 x age in years); >10 years, SBP < 90 mmHg)71
• Known severe renal impairment (by parent or patient report)
• Application of assisted ventilation before enrollment assessment (intubated, bi-level positive airway pressure, continuous positive airway pressure)
• Received IVMg within 24 hours prior to screening (by parent or patient report or medical record review)
• Enrollment assessment is 60 minutes after the start of ED treatment (start of first albuterol treatment)
• Previous enrollment in the same trial (by research coordinator review of trial records)