Cardiac arrest remains one of the leading causes of death and disability in the United States. Over 400,000 patients per year are treated for cardiac arrest and less than 10% survive after out-of-hospital cardiac arrest. Irreversible brain damage caused by ischemia/reperfusion injury is a significant contributor to the high mortality of resuscitated patents. Evidence from pre-clinical models, including from our research group, suggests novel therapeutic strategies and early delivery methodologies are needed to optimize patient outcomes. We propose a rigorous translational approach to evaluate and optimize early delivery of two candidate therapies during CPR by bystanders or first responders during the initial minutes of CPR. Research has demonstrated that insulin and magnesium sulfate can be used as neuroprotective strategies following global cerebral ischemia. Insulin has the advantage that it can be administered intranasally (IN). Magnesium sulfate delivery through intramuscular (IM) injectors has been established as safe in the setting of preeclampsia. There are three critical steps to translation: 1) validation and optimization in the setting of cardiac arrest, 2) evaluating time to treatment in a large animal model, and 3) developing a novel clinical trial design to test interventions by lay providers (Clinical and Population Projects). Our goal is to overcome these barriers and develop IN insulin and IM magnesium sulfate as simple and effective therapies to limit brain injury in resuscitated patients. Our hypothesis is that the positive neuroprotective effects of intra-arrest therapy with IN insulin and IM magnesium sulfate during CPR is dependent on early intervention during or immediately following CPR. The objective of this project is to evaluate and translate IN insulin and IM magnesium sulfate as promising neuroprotective therapies that can be delivered by bystanders or first responders during the initial minutes of CPR. We will identify the optimal dosing regimen and the therapeutic window for IN insulin and IM magnesium sulfate during CPR in a rat cardiac arrest model. With IN insulin as our lead candidate, we will then elucidate the impact of time to therapy initiation on the neuroprotective effect in a clinically-relevant swine cardiac arrest model. Overall, the results will provide important translational insights to inform clinical trial design and drive the development and implementation of these neuroprotective strategies.
|Program type||Strategically Focused Research Network|
|Effective start/end date||07/01/2019 → 06/30/2023|