Resuscitating Blood-Substituted Hypothermic Dogs

描述(由申请人提供)： 目前，由于发病率和死亡率较高，低温停循环(HCA)仅限于最困难的外科病例。在HCA期间，身体不接受任何灌流、氧气或能量供应。我们的目标是开发技术，实现数小时而不是数分钟的HCA，在此期间可以修复广泛的创伤和目前无法切除的心血管和大脑损伤。我们的方法将提高HCA程序的安全性，并至少将安全时限增加一倍。目前HCA的时间限制(1小时)源于目前使用的低温水平对新陈代谢和氧气需求的有限抑制，以及当使用更深低温时温度降低对血液的有害影响。血液在微血管系统中的淤泥(低温增加血液粘度)会在循环停止期间导致主要器官的微血管系统堵塞。我们的技术通过将极低的温度与全失血和血液替代与BioTime的FDA批准的血浆容量扩张器HExend(R)相结合，最大限度地发挥了低温的保护作用，同时避免了基于血液的系统的并发症。用重碳酸盐HEXTEND(R)进行血液置换可以最大限度地减少微血管淤泥，当与超深低温(4摄氏度)相结合时，甚至可以安全地实现2小时的循环骤停。这种时限的延长将允许进行以前不可行的“不流血手术”，并导致一种重要的新产品HetaCoolTM，该产品将适合各种新的利基市场。我们建议将麻醉的狗连接到心肺机上，以循环氧气并为狗降温，同时血液[完全]被HEXTEND(R)取代。在4摄氏度时，停止灌流，使狗进入休眠状态[2小时]，然后恢复循环，复温，输血，然后恢复心脏和肺的活动。[第二组]将使用常规方法(15摄氏度和适度稀释的血液)接受2小时的HCA。将使用生化和神经行为[评分]来评估康复情况，然后进行[大脑和其他器官]的组织学检查，以量化病理变化。]这些研究将扩展我们的数据，证明我们方法与当前方法相比的有效性，并支持未来医院允许[在精心挑选的患者中]进行临床试验的请求。

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.]