Resuscitating Blood-Substituted Hypothermic Dogs

复苏血液替代的低温犬

• 批准号: 6879209
• 负责人: Hal Sternberg
• 金额: $ 15万
• 依托单位: BIOTIME, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6879209
• 关键词: biological models; biomaterial development /preparation; blood /plasma substitute; blood chemistry; circulatory assist; dogs; heart /lung bypass; hematology; histology; induced hypothermia; neuropsychological tests; nonhuman therapy evaluation; resuscitation; sodium bicarbonate; therapy design /development

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.]

描述（由申请人提供）： 目前，由于高发病率和死亡率，低温停循环（HCA）的使用仅限于最困难的手术病例。在HCA期间，身体没有接受灌注，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，广泛的创伤性损伤和目前“不可切除”的心血管和大脑病变可以修复。我们的方法将提高HCA程序的安全性，并至少增加一倍的安全时间限制。目前HCA的时间限制（<1小时）源于目前使用的低温水平对代谢和需氧量的有限抑制，以及当使用更深的低温时降低的温度对血液的有害影响。血液在微脉管系统中的淤积（体温过低增加血液粘度）导致循环停止期间主要器官的微脉管系统的堵塞。我们的技术通过将极低温度与完全放血和血液替代与BioTime经FDA批准的血浆容量膨胀剂Hextend（r）相结合，最大限度地发挥低温的保护作用，同时避免血液系统的并发症。用碳酸氢盐Hextend（r）血液替代最大限度地减少了微血管淤积，当与超深低温（4摄氏度）相结合时，甚至可以安全地实现2小时的循环停止。这样延长时间限制将允许以前不可行的“无血手术”，并催生一种重要的新产品HetaCool TM，该产品将适应各种新市场利基。我们建议将麻醉的狗连接到心肺机上，以循环氧气并冷却狗，同时将血液[完全]替换为Hextend（r）。在4 ℃时停止灌注，使狗进入假死状态[2小时]，之后恢复循环，复温，输血，随后恢复心肺活动。[第二组]将使用常规方法（15 ℃和适度稀释的血液）进行2小时的HCA。将使用生化和神经行为[评分][评估28天]恢复情况，然后对[大脑和其他器官进行组织学检查，以量化病理变化]。这些研究将扩展我们的数据，证明我们的方法与当前方法相比的有效性，并支持未来要求医院允许[在精心挑选的患者中]进行临床试验。