PET Evalutaion of Hemorrhagic Shock and Resuscitation

描述(申请人提供)：在美国，创伤每年导致大约15万人死亡。尽管对医疗保健有这样的影响，但创伤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，这些液体只有通过增加预负荷才能增加氧气的输送。唯一可以增加载氧量和预负荷的液体是基于血红蛋白的产品。因此，这项研究的长期目标是开发一种完全和通用的复苏液来解决失血性休克的多方面病理生理问题。脂质体包裹的血红蛋白(LEH)以及其他以血红蛋白为基础的氧气载体(HBOC)已经经历了广泛的评估。但是，高效的氧气载体并不一定是高效的氧气输送载体。PET具有直观、定量和非侵入性地评估复苏后氧气输送和代谢的能力。假设1)LEH以与红细胞相同的方式将氧气输送到大脑，2)LEH向大脑输送氧气的时间比未包裹的HBOC更长，以及3)包裹高亲和力血红蛋白的LEH向大脑输送的氧气比含有低亲和力血红蛋白的LEH更多。具体目标有：1)。开发并验证图像导出的心脏时间-活动曲线作为动脉输入函数用于microPET研究大鼠脑氧代谢(CMRO2)。2)。在失血性休克大鼠模型上，探讨LEH中血红蛋白的氧亲和力对复苏后脑氧代谢的影响。3)比较标准复苏液对失血性休克大鼠复苏后CMRO2和能量代谢的影响。我们将使用O-15放射性示踪剂(O2气体、CO气体和H2O)进行microPET成像，以确定CMRO2和CBF。失血性休克的大鼠模型将用LEH、全血、林格氏乳酸盐溶液和5%白蛋白复苏。大脑能量代谢将通过有氧代谢的组织标志物来建立。这是一项创新的提议，它利用了最先进的成像技术在小动物模型中进行成像。这项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，还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.