Timely Intravenous Magnesium for Asthma in Children (IMPACT-ED)

Children's Hospital of Philadelphia, Nationwide Children's Hospital, National Heart, Lung, and Blood Institute (NHLBI)

Many children currently being hospitalized with severe asthma could potentially avoid hospitalization and be sent home if their treatment in the emergency department was more effective. The investigators will conduct a pilot trial that will lead to a larger study to conclusively answer whether a simple and inexpensive medicine, intravenous magnesium sulfate, can be used in the emergency department to prevent hospitalization for these 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 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.

Doses will be prepared ahead of time by an investigational pharmacist, arms will be identical in appearance, and clinicians administering the study drug will be blinded to the study arm the patient receives.

Doses for each IVMg arm will be prepared in identical manner, by drawing a specified volume of IVMg from the commercial container using sterile technique and mixing in a polyvinylchloride container with a specified volume of sterile water. 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. After randomization the institutional pharmacist will draw equivolumetric dosages (1 mL/kg, with max of 40 mL) from previously prepared vials. The dose will be delivered by the clinical nurse over 20 minutes through a peripheral IV.

Doses for each IVMg arm will be prepared in identical manner, by drawing a specified volume of 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. After randomization the institutional pharmacist will draw equivolumetric dosages (1 mL/kg, with max of 40 mL) from previously prepared vials. The dose will be delivered by the clinical nurse over 20 minutes through a peripheral IV.

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. After randomization the institutional pharmacist will draw equivolumetric dosages (1 mL/kg, with max of 40 mL) from previously prepared vials. The dose will be delivered by the clinical nurse over 20 minutes through a peripheral IV.

A single dose of intravenous magnesium sulfate given over 20 minutes through a peripheral intravenous line. Two arms of the study will deliver intravenous magnesium, one at a dose of 50 mg/kg, and the other at a dose of 75 mg/kg.

A single dose of intravenous 0.9% sodium chloride given over 20 minutes through a peripheral intravenous line as the placebo arm of the study.

The primary outcome in this pilot trial is demonstration of the ability to enroll severely ill children with asthma in a randomized trial requiring timely delivery of IVMg or placebo. The investigators anticipate that the primary outcome of the future large trial will be the proportion of children hospitalized at the index visit in each arm.

Hospitalization will be recorded through two definitions; the treating clinician's stated disposition two hours after the start of study infusion, and the actual patient disposition from medical record review after completion of ED treatment. Hospitalization will be defined as any outcome other than discharge from the ED, including hospitalization in an ICU, hospital unit, or observation area. This pilot study is not powered to detect a difference in hospitalization between arms, but will contribute to sample size estimates for the future trial.

Adverse events will be defined at 2 hours after IVMg infusion and include hypotension, diarrhea, nausea, stomach cramping, or facial flushing. Decrease in blood pressure will be categorized based on degree of associated symptoms (see Data and Safety Monitoring Plan). Hypotension will be defined by age-based Pediatric Advanced Life Support guidelines. More serious but rare side effects including urinary retention, lethargy, apnea, and irregular heartbeat will be monitored and graded based on severity. Counts and percentages of adverse effects will be summarized overall and by study arm.

At IV placement before infusion of study drug, 20-40 minutes after the start of study drug infusion, and 2 hours after the start of study drug infusion.

Study staff will record these and other outcomes that could be influenced by IVMg including intubation, positive pressure ventilation, high flow nasal cannula, hospitalization 24 hours after intervention, and use of rescue therapies including epinephrine, systemic beta agonists, and heliox.

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 PRAM score of 8 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, 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)