Abstract Sudden cardiac arrest (SCA) is a leading cause of death in the USA, with only 3-20% neurologically intact survival for >350,000 out-of-hospital SCA patients each year. Even after patients are initially resuscitated, many die within a week from severe brain injury. The goal of this application is to improve neurologically-intact survival rates after pre-hospital and in-hospital SCA. The Phase I pre-clinical studies showed 1) elevation of the head and thorax during active compression decompression (ACD) CPR with an impedance threshold device (ITD) doubled brain blood flow versus ACD+ITD CPR in the flat position and, 2) controlled and sequential head and thorax elevation with ACD+ITD CPR resulted in a 6-fold increase in neurologically-intact survival versus conventional CPR in the flat position. This novel method of CPR is called Head Up Position (HUP) CPR. It works by harnessing gravity to enhance venous blood flow from the brain to the heart, lower intracranial pressure, and enhance cardiac output. The first human HUP CPR device, the EleGARDTM, was designed, built, and tested with Phase I funding support. The EleGARD subsequently received FDA 510k clearance and has been used to help treat >400 SCA patients to date. Based upon these positive outcomes, the Phase II objectives are to 1) Design, develop, and build an improved EleGARD-2 to accelerate time to device application and increase adoption rates through a) a reduction in size and weight and an improved user interface, b) addition of regional cerebral oximetry (rSO2) and, c) incorporation of automated positive pressure breath delivery to increase crew safety in the age of Covid-19; 2) Demonstrate neurologically-intact survival is superior with ACD+ITD HUP CPR versus ACD+ITD CPR flat in a pig model that includes salvage with extra-corporeal membrane oxygenation (ECMO) to evaluate the potential benefit of HUP CPR with the rapidly evolving use of ECMO for SCA; and 3) Demonstrate HUP CPR utilizing EleGARD-2 reduces brain injury in a pig model of SCA utilizing advanced imaging techniques. The next generation HUP CPR device will be easier to store, carry, and deploy, will provide rSO2 to better guide care, and provide automated breath delivery to increase crew safety and reduce the number of rescuers needed to perform CPR. The animal studies will help determine the potential for HUP CPR to extend physiologic viability during resuscitation in refractory ventricular fibrillation until better hemodynamic support in the form of ECMO is available, and help determine if HUP CPR reduces brain injury, as determined by MRI and measurement of biochemical markers. Collectively, Phase II funding will support the development of the next generation HUP CPR platform and accelerate adoption of this innovative technology to improve neurologically-intact survival rates after SCA.