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（BT）的效率，从而减少血液的使用。 在BT中，通过抵消由向血液中添加红细胞（RBC）引起的血流阻力的增加， 增加血液粘度从而减少氧气输送（DO 2）的循环。可行性已经 根据初步研究和BT研究建立，表明血液粘度增加会增加剪切应力 在血管内皮上，其又通过刺激一氧化氮（NO）的产生而引起血管舒张。 我们对有限的现有临床BT数据的分析研究，以及我们对实验性BT的更广泛研究， 动物模型表明，通过增加血流量， 导致DO 2的增加，DO 2与心输出量（CO）乘以携氧量的乘积成比例 容量（CaO 2）：DO 2 = CO x CaO 2。我们的研究还表明，在BT期间流量增加是由于血管舒张 与循环NO的生物利用度增加有关。最重要的是，现有临床数据的分析 表明BT的O2输送福尔斯未与血细胞比容（Hct）的增加成正比， 这揭示了多达1/3的输注的RBC对增加O2输送没有贡献。 我们建议通过增加血液粘度来避免由于BT增加血液粘度而导致的血流障碍。 通过三种不同途径通过NO介导的血管舒张的血流：1）BT后增加血浆粘度 通过增粘淀粉基血浆扩张剂Hextend®，批准用于临床，但不用于 治疗贫血我们的大血管和微血管实验研究表明，这是一种非常有效的方法 用于增加流量，在非常短的时间内可用于临床; 2）静脉内引入 经过充分测试的生物相容的携带和释放NO的硅烷纳米颗粒（NO-nps）具有可调的NO类型（NO， SNO，亚硝酸盐）和释放速率，特别适用于在以下条件下的贫血的立即治疗： 限制生物利用度的内皮功能障碍;和，3）药理学方法，其中现有的基于NO的 已经被批准用于其他治疗的血管扩张剂被重新用于增加贫血的血流量， 静脉内纳米颗粒或口服给药。 我们建议通过以下方法验证我们的假设：1）分析替代O2输送的体内微血管效应 2）确定BT的基于NO的载体是否改善了处理 通过限制所需输血量来治疗贫血，以及，3）确定口服与 静脉内NO增强策略。 该项目的积极成果将使急性贫血的治疗成本更低，更有效， 实用，更安全。