Transfusion Trigger Extension by Plasma Expanders

描述（由申请人提供）：我们的目标是确定新pe的应用，该pe专门维持微血管和心脏功能，允许降低输血触发，这将最大限度地减少或延迟输血的使用。常规血浆扩张器（PEs）降低血液黏稠度及其使用超出输血触发原因：1)小动脉血管收缩和血流量减少；2)红细胞过境毛细血管数量减少（即功能性毛细血管密度，FCD）；3)降低血压。这些影响也发生在心脏的微循环中，导致心脏功能和心输出量减少。正常情况下，血流对内皮产生的剪切应力产生足够的一氧化氮（NO），使血管张力和血流正常，限制线粒体组织耗氧量。相反，目前使用的PEs获得的血液粘度降低和心功能下降，在输血触发之外使用时，不会产生血管壁剪切应力，以产生足够的NO来调节心血管。我们确定海藻酸盐，一种高粘度PE和聚乙二醇偶联白蛋白，一种中等粘度PE，作为液体恢复FCD，心脏功能和平均动脉血压在极端血液稀释。我们认为，这些作用是通过维持心肌微血管灌注和限制与糖萼相互作用对内皮功能和血管壁完整性的损害来改善心脏功能的。我们的研究将验证在极度血液稀释和休克复苏中微血管恢复与心功能改善之间存在直接关系的假设。研究将使用微血管分析，通过直接在体内测量微po2、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。这些研究将与旨在记录心肌缺血的心电图测量相关联。心功能也将通过测量收缩力（dP/dt）和心输出量来评估。使用荧光示踪剂测量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萼相互作用对微血管反应性的影响。糖萼研究也将在仓鼠窗室模型中进行。在仓鼠窗室模型中，将血液替换为PEs，可以在没有麻醉并发症的情况下进行长时间的研究。极端血液稀释和失血性休克模型随后持续出血将被用来模拟现实的临床条件。探讨血浆复苏和换血的最佳随访策略。

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.