Transfusion Trigger Extension by Plasma Expanders

通过血浆扩张器进行输血触发延长

• 批准号: 7146542
• 负责人: Marcos Intaglietta
• 金额: $ 37.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7146542
• 关键词: alginates; blood /plasma substitute; blood circulation; blood flow measurement; blood transfusion; blood viscosity; blood volume; cardiovascular function; electrocardiography; glycoproteins; hamsters; heart function; hemodynamics; hemorrhagic shock; laboratory rat; microcirculation; nitric oxide; oxygen consumption; polyethylene glycols; polysaccharides; respiratory oxygenation; vascular resistance; vasoconstriction

DESCRIPTION (provided by applicant): Our aim is to determine the application of new PEs that specifically maintain microvascular and heart function, allowing the lowering of the transfusion trigger, which would minimize or delay the use of blood transfusions. Conventional plasma expanders (PEs) lower blood viscosity and their use beyond the transfusion trigger causes: 1) Arteriolar vasoconstriction and decreased blood flow; 2) Reduced number of capillaries with red blood cell transit (i.e., functional capillary density, FCD); and, 3) Lowered blood pressure. These effects occur also in the microcirculation of the heart, causing heart function, and cardiac output to decrease. In normal conditions, shear stress on the endothelium generated by blood flow produces sufficient nitric oxide (NO) resulting in normal vascular tone and blood flow, restricting mitochondrial tissue oxygen consumption. Conversely, lowered blood viscosity and decreased heart function obtained with the presently used PEs do not generate the vessel wall shear stress necessary to produce sufficient NO for cardiovascular regulation when used beyond the transfusion trigger. We identified alginate, a high viscosity PE and polyethylene glycol conjugated albumin, a moderate viscosity PE, as fluids that restore FCD, heart function and mean arterial blood pressure in extreme hemodilution. We propose that these effects arise from improvement of heart function by maintaining microvascular perfusion of the myocardium and limiting damage to endothelial function and vessel wall integrity by interaction with the glycocalyx. Our research will test the hypothesis that there is a direct relationship between microvascular recovery and improvement of heart function in extreme hemodilution and shock resuscitation. Studies will use microvascular analysis by direct in vivo measurement of micro-pO2, micro-NO, capillary pressure, microvascular flow, FCD, tissue pH, reactive oxygen species (ROS) formation and cellular necrosis and apoptosis. These studies will be correlated with electrocardiographic measurements aimed at documenting myocardial ischemia. Heart function will also be assessed by measuring contractility (dP/dt) and cardiac output. Blood flow distribution to major organs will be measured using fluorescent tracers. Parallel studies will be made in isolated microvessels to determine the effects of the proposed materials on microvessel reactivity by interaction with the glycocalyx. Glycocalyx studies will also be made in the hamster window chamber model. Blood will be substituted with PEs in the hamster window chamber model which can be studied without complications of anesthesia and for long periods. An extreme hemodilution and a hemorrhagic shock model followed by continuous bleeding will be used to simulate realistic clinical conditions. Strategies for optimal follow up of plasma resuscitation and exchange with blood transfusion will be investigated.

描述（由申请人提供）：我们的目的是确定专门维持微血管和心脏功能的新型PE的应用，从而降低输血触发，这将最大限度地减少或延迟输血的使用。常规血浆膨胀剂（PE）降低血液粘度，并且它们在输血触发之外的使用导致：1）小动脉血管收缩和血流量减少; 2）具有红细胞转运的毛细血管数量减少（即，功能性毛细血管密度，FCD）;和，3）降低血压。这些影响也发生在心脏的微循环中，导致心脏功能和心输出量减少。在正常情况下，由血流产生的内皮上的剪切应力产生足够的一氧化氮（NO），导致正常的血管张力和血流，限制线粒体组织耗氧量。相反，当在输血触发之外使用时，用目前使用的PE获得的降低的血液粘度和降低的心脏功能不产生足够的NO用于心血管调节所必需的血管壁剪切应力。我们确定藻酸盐（一种高粘度PE）和聚乙二醇结合白蛋白（一种中等粘度PE）作为在极端血液稀释中恢复FCD、心脏功能和平均动脉血压的液体。我们认为，这些影响产生的心脏功能的改善，通过维持心肌的微血管灌注和限制损害内皮功能和血管壁的完整性与糖萼的相互作用。我们的研究将检验这样的假设：在极端血液稀释和休克复苏中，微血管恢复与心脏功能改善之间存在直接关系。研究将通过直接体内测量微pO 2、微NO、毛细血管压力、微血管流量、FCD、组织pH、活性氧（ROS）形成以及细胞坏死和凋亡来使用微血管分析。这些研究将与旨在记录心肌缺血的心电图测量相关。还将通过测量收缩力（dP/dt）和心输出量评估心脏功能。将使用荧光示踪剂测量主要器官的血流分布。将在分离的微血管中进行平行研究，以确定拟定材料通过与糖萼相互作用对微血管反应性的影响。还将在仓鼠窗室模型中进行糖萼研究。在仓鼠窗室模型中，将用PE代替血液，可以在没有麻醉并发症的情况下进行长期研究。将使用极端血液稀释和失血性休克模型，然后持续出血来模拟实际临床条件。将研究血浆复苏和输血交换的最佳随访策略。