PET Evalutaion of Hemorrhagic Shock and Resuscitation

描述（由申请人提供）：在美国，每年大约有15万人死于创伤。尽管对医疗保健有这样的影响，但创伤中的液体复苏仍然是一个有争议的问题。通常使用晶体或胶体，这些流体仅通过增加预负荷来增加氧气的输送。唯一能同时增加携氧能力和预负荷的液体是血红蛋白产品。因此，本研究的长期目标是开发包膜血红蛋白作为一种完整和通用的复苏液体，以解决失血性休克的多方面病理生理问题。脂质体包裹血红蛋白（LEH），以及其他基于血红蛋白的氧载体（hboc），已经进行了广泛的评估。但是，一个有效的氧气载体并不一定是一个有效的氧气输送载体。PET能够直观、定量和无创地评估复苏时的氧气输送和代谢。假设1)LEH以与红细胞相同的方式向大脑输送氧气，2)LEH比未包封的HBOCs持续更长的时间，3)在严重失血时，包封高亲和血红蛋白的LEH比含低亲和血红蛋白的LEH向大脑输送更多的氧气。具体目标是：1)；建立并验证图像衍生的心脏时间-活动曲线作为动脉输入函数在MicroPET研究大鼠脑氧代谢（CMRO2）中的应用。2）. 探讨大鼠失血性休克模型复苏后LEH中血红蛋白氧亲和力对脑氧代谢的影响。3）.在失血性休克大鼠模型中评价LEH复苏后cro2和能量代谢的改善。我们将使用O-15放射性示踪剂（O2气体、CO气体和H2O）进行微pet成像，以测定cmo_2和CBF。用LEH、全血、乳酸林格氏液和5%白蛋白对失血性休克大鼠模型进行复苏。脑能量代谢将通过有氧代谢的组织标志物来建立。这是一个创新的提议，利用最先进的成像技术在一个小动物模型。该研究不仅将解决与休克和复苏中的氧代谢有关的重要问题，也可能对正在进行临床前和临床试验的其他人工氧载体的评估有用。

DESCRIPTION (provided by applicant): In the USA, trauma kills approximately 150,000 people each year. Despite such an impact on health care, fluid resuscitation in trauma continues to be a debatable issue. Crystalloids or colloids are commonly used and these fluids augment O2 delivery only by increasing preload. The only fluids that can increase both O2- carrying capacity and preload are hemoglobin based products. Thus, the long-term goal of this research is to develop encapsulated hemoglobin as a complete and universal resuscitative fluid to address multifaceted pathophysiology of hemorrhagic shock. Liposome encapsulated hemoglobin (LEH), as well as other hemoglobin-based O2 carriers (HBOCs), have undergone extensive evaluation. But, an efficient O2 carrier is not necessarily an efficient O2 delivery vehicle. PET has the capability to visually, quantitatively and non- invasively assess O2 delivery and metabolism in response to resuscitation. HYPOTHESES 1) LEH delivers O2 to the brain in the same fashion as RBCs, 2) cerebral O2 delivery from LEH is sustained for a longer period of time than the unencapsulated HBOCs, and 3) LEH encapsulating high-affinity hemoglobin delivers more O2 to the brain than LEH containing low-affinity hemoglobin in severe blood loss. SPECIFIC AIMS are: 1). Develop and validate image-derived cardiac time-activity curve as an arterial input function in MicroPET investigation of rat cerebral oxygen metabolism (CMRO2). 2). Investigate the effect of oxygen affinity of hemoglobin in LEH on cerebral oxygen metabolism after resuscitation in a rat model of hemorrhagic shock. 3).Evaluate the improvement in CMRO2 and energy metabolism after LEH resuscitation against standard resuscitative fluids in a rat model of hemorrhagic shock. We will perform microPET imaging with O-15 radiotracers (O2 gas, CO gas and H2O) to determine CMRO2 and CBF. A rat model of hemorrhagic shock will be resuscitated with LEH, whole blood, Ringer's lactate solution and 5% albumin. Cerebral energy metabolism will be established by tissue markers of aerobic metabolism. This is an innovative proposal that utilizes state-of-the-art imaging technology in a small animal model. The study will not only address important issues pertaining to oxygen metabolism in shock and resuscitation, it may also be useful in evaluation of other artificial oxygen carriers undergoing preclinical and clinical trials.