Transfusion Trigger Extension by Plasma Expanders

通过血浆扩张器进行输血触发延长

• 批准号: 7285205
• 负责人: Marcos Intaglietta
• 金额: $ 34.86万
• 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/7285205
• 关键词: Abbreviations; Acute; Albumins; Alginates; Anemia; Animals; Apoptosis; Autologous; Binding; Blood; Blood Pressure; Blood Transfusion; Blood Vessels; Blood Viscosity; Blood capillaries; Blood flow; Cardiac; Cardiac Output; Cardiovascular system; Carrying Capacities; Cell Death; Clinical; Clinical Trials; Condition; Critiques; Drug Formulations; Electrocardiogram; Emergency Situation; Endothelium; Erythrocytes; Glycocalyx; Hamsters; Health Systems Agencies; Heart; Hematocrit procedure; Hemodilution; Hemorrhage; Hemorrhagic Shock; Hypotension; Hypovolemia; Iodine-131 Human Serum Albumin; Knowledge; Liquid substance; Maintenance; Materials Testing; Measurement; Measures; Mechanics; Mediating; Microcirculation; Microspheres; Mitochondria; Modeling; Monitor; Myocardial Ischemia; Myocardium; Necrosis; Nitric Oxide; Numbers; Optics; Organ; Organism; Outcome; Oxygen Consumption; Peer Review; Perfusion; Plasma; Polyethylene Glycols; Publications; Rate; Rattus; Reactive Oxygen Species; Recovery; Regulation; Relative (related person); Reporting; Research; Research Personnel; Resuscitation; Shock; Signal Transduction; Simulate; Solutions; Staging; Standards of Weights and Measures; Study Section; Surrogate Endpoint; System; Techniques; Testing; Therapeutic; Tissue Viability; Tissues; Toxic effect; Tracer; Transfusion; Translating; Trauma; Vasodilation; Viscosity; Whole Blood; anesthesia complication; capillary; clinically relevant; concept; density; design; exhaust; falls; follow-up; heart function; improved; in vivo; indexing; novel; pressure; programs; research study; response; restoration; shear stress; transmission process; 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PE的应用，从而降低输血触发器，这将最大程度地减少或延迟输血的使用。常规血浆扩张子（PES）较低的血液粘度及其在输血之外的用途触发原因：1）动脉血管收缩和血液流量减少； 2）减少了红细胞转运的毛细血管数量（即功能性毛细管密度，FCD）； 3）降低血压。这些影响也发生在心脏的微循环中，导致心脏功能和心脏输出减少。在正常条件下，血流产生的内皮上的剪切应力会产生足够的一氧化氮（NO），导致正常的血管张力和血液流动，从而限制了线粒体组织氧气的消耗。相反，当目前使用的PES获得的血液粘度降低和心脏功能降低不会产生血管壁剪应力，而当超出输血触发之外的使用时，使用了足够的心血管调节。我们鉴定出高粘度PE和聚乙烯乙二醇共轭白蛋白（一种中等粘度PE）为恢复FCD，心脏功能和平均动脉血压的流体。我们建议通过维持心肌的微血管灌注以及通过与糖蛋白的相互作用来限制对内皮功能和容器壁完整性的损害来改善心脏功能。我们的研究将检验以下假设：微血管恢复与心脏功能的改善之间存在直接关系。研究将通过微血管分析，通过直接在体内测量微PO2，微-NO，毛细管压力，微血管流动，FCD，组织pH，活性氧（ROS）形成以及细胞坏死和凋亡。这些研究将与旨在记录心肌缺血的心电图测量结果相关。心脏功能还将通过测量收缩力（DP/DT）和心脏输出来评估。将使用荧光示踪剂测量到主要器官的血流分布。平行研究将在分离的微血管中进行，以确定所提出的材料通过与糖蛋白的相互作用来确定所提出的材料对微血管反应性的影响。糖脂研究也将在仓鼠窗室模型中进行。血液将用仓鼠窗室模型中的PE代替，该模型可以研究而无需麻醉并发症。极端的血液稀释和出血性休克模型随后出血，将用于模拟现实的临床状况。将研究以血浆复苏和输血交换的最佳随访策略。