Despite the significant clinical benefit of therapeutic hypothermia, this emerging therapy has not yet achieved its full potential due to the lack of a rapid pre-hospital cooling technology coupled with our uncertainty regarding the optimal timing of cooling after cardiac arrest. The long term goal of our project is to improve neurologically favorable survival rates for victims of prolonged cardiac arrest. The overall objective of this application is to further develop the engineering to create microparticulate ice-slurry coolants for rapid cooling and determine the critical timing for cooling following prolonged arrest; we also intend to determine whether the first priority for resuscitation should be to cool first or to prioritize a return of spontaneous circulation (ROSC) first. We hypothesize that intra-arrest cooling prior to reperfusion avoids the deleterious effects of warm reperfusion that are seen upon ROSC without cooling. We present strong preliminary data on the advantage for cooling first over ROSC first and also on microparticulate ice-saline slurry and nasopharyngeal cooling technology to accomplish rapid intra-arrest cooling. During the first award period, the BRP established novel biocompatible microparticulate ice-saline slurries, pioneered the concept of intra-arrest cooling, and generated 10 US patents and 22 publications. This renewal Award will provide answers to questions on the optimal timing of cooling, test ice-saline slurries and nasopharyngeal cooling, and develop heterogeneous ice nucleation of supercooled saline, a new method for making slurry-on-demand. Aim #1 will develop new slurry generation prototypes, using supercooled saline, that will be transportable to the experimental labs and capable of producing ice-slurries with >45% ice percentage at a rate of >250ml per minute. Aim #2 will map the temperature changes in the body and brain using the two novel cooling methods and relate these to standard cooling techniques under differing conditions of blood flow to understand the compartmentalized thermo-kinetics of differing cooling methods. Aims #3 and #4 will provide important scientific data on the optimal timing for cooling. Specifically we will determine whether, following a prolonged period of ischemia, it is better to first prioritize cooling or ROSC. The proposed research is significant because >250,000 US citizens die each year from cardiac arrest and our current cooling practices allows <6% of these near-death patients to receive any form of cooling. Experimental data clearly indicate that many more victims would survive under a new paradigm of intra-arrest cooling. If we develop a rapid intra-arrest cooling method for ambulance use and disseminate the knowledge that early cooling is most beneficial prior to ROSC, this would shift the treatment paradigm for cardiac arrest patients. We foresee a future wherein many more patients would survive cardiac arrest, having been cooled with ongoing CPR being performed, before ROSC, rather than hours after ROSC, as is the current practice.