Abstract The overall goal of this application is to improve neurologically-intact survival rates after sudden cardiac arrest (SCA), the leading cause of death in adults in the US. Despite conventional (C) CPR, <10% of 300,000 pre- hospital and <30% of 300,000 in-hospital SCA patients in the US each year survive with favorable neurological function. We propose to develop and evaluate a novel comprehensive Head Up Position (HUP) cardiopulmonary resuscitation (CPR) System designed primarily to allow Basic Life Services (BLS) providers (a fire crew without paramedics) to rapidly deliver fully automated CPR, including for the first time, automated breath delivery and automated and optimized full lift active compression decompression, to increase the likelihood of neurologically intact survival after SCA and increase crew safety. The proposal focuses on further developing and delivering an innovative all-in-one HUP resuscitation system (HRS) for BLS teams based on our most recent breakthroughs in optimizing brain perfusion during SCA using controlled sequential elevation of the head and thorax combined with Active Compression Decompression (ACD) CPR and an impedance threshold device (ITD). As demonstrated in a well-accepted porcine SCA model, HUP CPR combined with full lift ACD CPR and an ITD uniquely harnesses gravity to enhance drainage of venous blood from the head and neck, lower intracranial pressure, and markedly increase systemic and cerebral blood flow and likelihood for neurologically-intact survival. The overall objectives of this application are also supported by new clinical data from a HUP CPR Registry demonstrating this neuroprotective approach provides a striking benefit when deployed rapidly by Emergency Medical Services (EMS) first responders. Moreover, in resource-strapped EMS systems countrywide there is a growing need to develop technology that minimizes the number of resources required to deliver high quality CPR that is best for patient outcomes and safer for rescue personnel. We propose to achieve these collective objectives by demonstrating that incorporation of 1) automated and integrated ACD CPR and 2) automated breath delivery into an easy to deploy and fully automated HUP CPR system, is feasible and safe for BLS providers, will reduce CPR personnel resource requirements, and most importantly, will optimize chances for neurologically intact survival after SCA. As such, the Specific Aims are: 1) Determine the optimal waveform during HUP with full ACD CPR to optimize brain and heart blood flow and compare the optimized waveform with a LUCAS 3.1 waveform in a porcine survival study and 2) Design and prototype a functional HRS, an all-in-one device with integrated, optimized, and automated full ACD CPR and automated breath delivery.