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.

Public Health Relevance

Hundreds of thousands of Americans die prematurely from cardiac arrest each year, yet experimental evidence demonstrates that many of these victims could survive if we developed better cooling therapies. Our current cooling strategies are applied only to a small percentage of victims because we do not yet understand the optimal timing for cooling to be most protective, nor do we have a practical, rapid method for cooling that is realistic for pre-hospital use. Our bioengineering research partnership will advance the technology to achieve rapid intra-arrest cooling with novel human coolants, answer critical questions regarding the optimal timing of cooling after a cardiac arrest, and could have an immediate impact on the clinical practice of cooling thus saving lives in our communities.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067630-09
Application #
8460066
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Rao, Anupama
Project Start
2001-06-15
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
9
Fiscal Year
2013
Total Cost
$729,848
Indirect Cost
$273,693
Name
University of Pennsylvania
Department
Emergency Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Kim, Junhwan; Villarroel, José Paul Perales; Zhang, Wei et al. (2016) The Responses of Tissues from the Brain, Heart, Kidney, and Liver to Resuscitation following Prolonged Cardiac Arrest by Examining Mitochondrial Respiration in Rats. Oxid Med Cell Longev 2016:7463407
Shinozaki, Koichiro; Lampe, Joshua W; Kim, Junhwan et al. (2016) The effects of early high-volume hemofiltration on prolonged cardiac arrest in rats with reperfusion by cardiopulmonary bypass: a randomized controlled animal study. Intensive Care Med Exp 4:25
Lampe, Joshua W; Tai, Yin; Bratinov, George et al. (2015) Developing a kinematic understanding of chest compressions: the impact of depth and release time on blood flow during cardiopulmonary resuscitation. Biomed Eng Online 14:102
Kim, Junhwan; Lampe, Joshua W; Yin, Tai et al. (2015) Phospholipid alterations in the brain and heart in a rat model of asphyxia-induced cardiac arrest and cardiopulmonary bypass resuscitation. Mol Cell Biochem 408:273-81
Patil, Kaustubha D; Halperin, Henry R; Becker, Lance B (2015) Cardiac arrest: resuscitation and reperfusion. Circ Res 116:2041-9
Shinozaki, Koichiro; Lampe, Joshua W; Wang, Chih-Hsien et al. (2015) Developing dual hemofiltration plus cardiopulmonary bypass in rodents. J Surg Res 195:196-203
Lampe, Joshua W; Bratinov, George; Weiland 3rd, Theodore R et al. (2015) Volume infusion cooling increases end-tidal carbon dioxide and results in faster and deeper cooling during intra-cardiopulmonary resuscitation hypothermia induction. Intensive Care Med Exp 3:37
Kim, Junhwan; Yin, Tai; Yin, Ming et al. (2014) Examination of physiological function and biochemical disorders in a rat model of prolonged asphyxia-induced cardiac arrest followed by cardio pulmonary bypass resuscitation. PLoS One 9:e112012
Lampe, Joshua W; Becker, Lance B (2011) State of the art in therapeutic hypothermia. Annu Rev Med 62:79-93
Lampe, Joshua; Bull, Diana; Becker, Lance (2011) RAPID INDUCTION OF HETEROGENEOUS ICE NUCLEATION IN A BIOLOGICALLY COMPATIBLE COOLANT. Int J Transp Phenom 12:307-317

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