Transfusion Trigger Extension by Plasma Expanders

描述(申请人提供)：我们的目标是确定新的PES的应用，这种PES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推迟输血的使用。传统的血浆扩张器(PES)可降低血液粘度，其使用超出输血触发范围会导致：1)小动脉血管收缩和血流减少；2)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)；以及3)血压降低。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下降。在正常情况下，血流对内皮细胞产生的剪应力会产生足够的一氧化氮(NO)，导致正常的血管张力和血流，限制线粒体组织的氧气消耗。相反，用目前使用的PES获得的较低的血液粘度和心功能下降不会产生必要的血管壁剪应力，当超过输液触发时，产生足够的NO用于心血管调节。我们确定藻酸盐(一种高粘度PE)和聚乙二醇偶联白蛋白(一种中等粘度PE)是在极端血液稀释中恢复FCD、心功能和平均动脉压的液体。我们认为，这些效应是通过维持心肌的微血管灌流来改善心功能，并通过与糖基化反应限制对内皮功能和管壁完整性的损害而产生的。我们的研究将验证这一假设，即在极端血液稀释和休克复苏中，微血管的恢复与心功能的改善有直接关系。研究将使用微血管分析，通过直接在体内测量微氧分压、微一氧化氮、毛细血管压、微血管流量、FCD、组织pH、活性氧物种(ROS)的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能力(dp/dt)和心输出量来评估。将使用荧光示踪剂测量流向主要器官的血流分布。将在分离的微血管中进行平行研究，以确定所建议的材料通过与糖基化反应对微血管反应性的影响。还将在仓鼠窗房模型中进行糖萼研究。在仓鼠窗房模型中，血液将被PES替代，该模型可以在没有麻醉并发症的情况下进行长时间的研究。将使用极端血液稀释和失血性休克模型，然后继续出血，以模拟真实的临床条件。将研究血浆复苏和输血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.