Maximizing transfusion efficacy through nitric oxide enhancement strategies

通过一氧化氮增强策略最大化输血功效

• 批准号: 10009828
• 负责人: JOEL M FRIEDMAN
• 金额: $ 40.07万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10009828
• 关键词: Acute; Albumins; Anemia; Animal Model; Animals; Biological Availability; Blood; Blood Circulation; Blood Pressure; Blood Transfusion; Blood Vessels; Blood Viscosity; Blood capillaries; Blood flow; Cardiac Output; Cardiovascular system; Carrying Capacities; Chronic; Clinical; Clinical Data; Complete Blood Count; Data; Dextrans; Effectiveness; Endothelium; Erythrocytes; Experimental Animal Model; Financial compensation; Generations; Hamsters; Hematocrit procedure; Hemodilution; Hemorrhagic Shock; Human; Hypoxia; Intervention; Intravenous; Low Cardiac Output; Measurement; Measures; Mediating; Methods; Modeling; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitrites; Normal Range; Operative Surgical Procedures; Oral; Oral Administration; Outcome; Oxygen; Partial Pressure; Patients; Perfusion; Peripheral; Pharmacologic Substance; Pharmacology; Physiological; Plasma; Preparation; Production; Resistance; Retreatment; Role; SKIL gene; Serum Albumin; Silanes; Starch; Testing; Time; Tissues; Transfusion; Vascular Endothelium; Vascular resistance; Vasodilation; Vasodilator Agents; Viscosity; awake; base; biomaterial compatibility; blood pressure reduction; clinical application; cost; density; dosage; endothelial dysfunction; experimental study; falls; improved; in vivo; nanoparticle; restoration; shear stress; side effect

Project Summary The project seeks to improve the efficacy of blood transfusions (BTs), and thereby reduce the use of blood in BTs, by counteracting the increase in blood flow resistance caused by adding red blood cells (RBCs) to the circulation which increases blood viscosity thereby reducing oxygen delivery (DO2). Feasibility has been established from preliminary studies and BT studies, that show increased blood viscosity increases shear stress on the vascular endothelium which in turn causes vasodilation by stimulating the production of nitric oxide (NO). Our analytical studies of limited existing clinical BT data, and our more extensive studies on experimental animal models, show that beneficial effects due to BTs can be significantly improved by increased blood flow causing an increase of DO2 which is proportional to the product cardiac output (CO) times oxygen carrying capacity (CaO2): DO2 = CO x CaO2. Our studies also show that flow increases during BTs are due to vasodilation related to increased bioavailability of circulating NO. Most significantly, an analysis of existing clinical data indicates that O2 delivery by BTs falls short of being directly proportional to the increase of hematocrit (Hct), revealing that as much as 1/3 of the transfused RBCs do not contribute to increasing O2 delivery. We propose to circumvent the hindrance to blood flow due to increased blood viscosity by BTs by increasing blood flow via NO mediated vasodilation by three different approaches: 1) Increasing plasma viscosity after BT by means of the viscogenic starch-based plasma expander Hextend®, approved for clinical use but not for treating anemia. Our macro and microvascular experimental studies show that this is a highly effective approach for increasing flow that could become clinically applicable in the very short term; 2) Intravenous introduction of well tested biocompatible NO carrying and releasing silane nanoparticles (NO-nps) with tunable NO type (NO, SNO, nitrite) and rates of release, particularly suitable for the immediate treatment of anemia in conditions of endothelial dysfunction that limit bioavailability; and, 3) A pharmacological approach where existing NO based vasodilators, already approved for use for other treatments are re-purposed for increasing flow in anemia via either intravenous nanoparticle or oral administration. We propose validating our hypothesis by: 1) Analyzing in vivo microvascular effects of replacing O2 delivery by increased flow vs. increased CaO2; 2) Determining whether an NO based support of BTs improves treating anemia by limiting the amount of needed transfused blood, and, 3) Determining the relative efficacy of oral versus intravenous NO enhancement strategies. A positive outcome for this project will make the treatment of acute anemia less costly, more effective, more practical, and safer.

项目摘要 该项目旨在提高输血效率（BTS），从而减少血液的使用 在BTS中，通过抵消通过将红细胞（RBC）添加到 循环增加了血液粘度，从而减少了氧递送（DO2）。可行性已经存在 根据初步研究和BT研究建立的，表明血液粘度增加会增加剪切应力 在血管内皮上，这又通过刺激一氧化氮的产生（NO）而导致血管舒张。 我们对有限现有临床BT数据的分析研究以及我们对实验的更广泛研究 动物模型表明，由于血流增加，由于BTS引起的有益作用可以显着改善 引起DO2的增加，与产品心输出量成正比（CO）乘以氧气的氧气 容量（CAO2）：do2 = co x cao2。我们的研究还表明，BT期间的流量增加是由于血管舒张引起的 与循环号码的生物利用度增加有关。最重要的是，对现有临床数据的分析 表明BTS的O2递送与血细胞比容的增加成正比（HCT）， 揭示了多达1/3的输血的RBC不会促进O2递送的增加。 我们建议通过增加BT的血液粘度增加血液的障碍 通过三种不同方法通过无介导的血管舒张的血液流动：1）BT后增加血浆粘度 通过基于Viscogenic淀粉的等离子体扩张器Hextend®，批准用于临床使用，但未用于 治疗贫血。我们的宏观和微血管实验研究表明，这是一种高效的方法 对于可能在短期内临床上适用的流量增加； 2）静脉引入 经过良好测试的生物相容性无携带和释放的硅烷纳米颗粒（NONP），无类型（否， SNO，亚硝酸盐）和释放速率，特别适合在情况下立即治疗贫血 限制生物利用度的内皮功能障碍； 3）一种药物方法，现有的无基于 血管扩张剂，已经批准用于其他治疗的血管扩张剂，以通过 静脉注射纳米颗粒或口服给药。 我们建议通过以下方式验证我们的假设：1）分析替换O2递送的体内微血管效应 通过增加的流量与增加CAO2； 2）确定对BTS的不基于基于BTS的支持是否改善了治疗 贫血通过限制所需的输血的量，以及3）确定口服的相对效率 静脉注射没有增强策略。 该项目的积极结果将使急性贫血的治疗降低成本降低，更有效，更多 实用，更安全。