Resuscitating Blood-Substituted Hypothermic Dogs

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DESCRIPTION (provided by applicant): Currently, due to high morbidity and mortality, the use of hypothermic circulatory arrest (HCA) is limited to only the most difficult surgical cases. During HCA, the body receives no perfusion, oxygen, or energy supply. Our goal is to develop technology to achieve hours rather than minutes of HCA during which extensive traumatic injuries and currently "unresectable" cardiovascular and brain lesions could be repaired. Our method will improve the safety of HCA procedures and at least double the safe time limit. The present time limit (<1 hour) for HCA stems from the limited suppression of both metabolism and oxygen demand provided by currently used levels of hypothermia and deleterious effects of reduced temperatures on the blood when deeper hypothermia is used. Sludging of blood in the microvasculature (hypothermia increases blood viscosity) causes blockage of the microvasculature of the major organs during the period of circulatory arrest. Our technique maximizes the protective effects of hypothermia while avoiding the complications of a blood-based system by combining very low temperatures with total exsanguination and blood substitution with BioTime's FDA-approved plasma volume expander Hextend(r). Blood replacement with bicarbonated Hextend(r) minimizes microvascular sludging and when combined with ultraprofound hypothermia (4 degrees C) will allow even a 2-hour period of circulatory arrest to be safely achieved. Such an extension of the time limit would permit previously unfeasible "bloodless surgeries" and lead to an important new product, HetaCoolTM that would fit into a variety of new market niches. We propose to attach anesthetized dogs to a heart-lung machine to circulate oxygen and cool the dog while the blood is [entirely] replaced with Hextend(r). At 4 degrees C perfusion is stopped putting the dog into suspended animation for [2 hours] after which circulation is resumed, rewarming occurs, blood is transfused followed by restoration of heart and lung activity. [A second group] will be submitted to 2 hours of HCA using conventional methods (15 degrees C and moderately diluted blood). Recovery will be [evaluated for 28 days] using biochemical and neurobehavioral [scores] followed by histological examination of [the brain and other organs to quantify pathological changes.] These studies will extend our data, demonstrate the effectiveness of our approach as compared to current methods, and support a future request for hospital permission to perform clinical trials [in carefully selected patients.]