DESCRIPTION (provided by applicant): Out-of-hospital cardiac arrest (OHCA) remains one of the leading causes of death in the United States. Even with the best clinically documented methods of cardiopulmonary resuscitation (CPR) and post-resuscitation care, more than 85-90% of the 350,000 Americans with OHCA die or have severe neurological deficits. Despite intensive research, little or no improvement in outcomes has been observed for over half a century. This application is focused on treating cardiac arrest patients that have been successfully defibrillated during the post-resuscitation phase. There remains a tremendous opportunity to optimize and improve the care of these patients, during the period of time when there is maximal hemodynamic instability and when the processes the result in neurologic damage begin to impact the ultimately outcome. In this application we propose to test the hypothesis that neurological recovery during the post-resuscitation phase will improve by non-invasively modulating cerebral perfusion and brain electrical activity with brain-specific intrathoracic pressure regulation (IPR) therapy in the first 12 hours after cardiac arrest. IPR therapy was developed by our research group and relies on active withdrawal of air from the lungs to create a small sub-atmospheric pressure during the expiratory phase of the typical positive pressure ventilation cycle. It has been demonstrated to increase hemodynamics, cerebral perfusion and blood flow in shock and brain injured states, and neurologically intact survival when used during CPR. Our intent is to demonstrate proof of preclinical concept that non-invasive brain-specific-IPR modulation of intracranial pressure and cerebral blood flow will improve processed EEG signals and neurological functional outcomes after cardiac arrest and return of spontaneous circulation (ROSC). As such, the specific aim of this proposal is to determine the safety and efficacy of two different levels of IPR therapy compared to no IPR therapy on hemodynamics, cerebral blood flow, ICP and EEG signals during the interval between ROSC and 12 hours post-ROSC and to correlate findings with brain histopathology and neurologically intact survival at 48 hours in a porcine model. If successful, IPR therapy will result in a novel post- resuscitation treatment and will effectively bridge the link between ROSC and long-term neurological function, significantly improving neurological survival and quality of life post cardiac arrest.

PUBLIC HEALTH RELEVANCE: Utilization of intrathoracic pressure regulation (IPR) therapy after the return of spontaneous circulation (ROSC) is a novel application of a technology developed with previous SBIR funding. Based on the significant improvements during CPR previously demonstrated with the use of IPR therapy and its newly discovered effect on cerebral blood flow, post-ROSC treatment with IPR has the potential to further improve neurological and survival outcomes. This technology is needed because achieving ROSC is only the first stage in the process of complete resuscitation from cardiac arrest. Effective post-ROSC strategies play a critical link between ROSC and long-term neurological function. Even in the most efficient emergency medical systems, less than 20% of all patients with an out-of-hospital cardiac arrest are discharged from the hospital with intact neurological function. Strikingly, the average national survival to hospital discharge after out-of-hospital cardiac arrest has remained less than 5% for decades. This complex disease state remains the nation's #1 killer, claiming more than 1000 lives outside the hospital and 1000 lives inside the hospital each day in the United States alone. Improved circulation to the brain and other vital organs during CPR, and most importantly during post- resuscitation care, has the potential to significantly reduce morbidity and mortality from cardiac arrest.