Intravenous oxygen microparticles for treatment of cardiac arrest

项目总结/摘要 需要持续供应氧气以维持细胞结构和功能。即使是短暂的赤字， 肺损伤或气道问题患者的氧合可导致心脏停止跳动， 心脏骤停的症状在美国，每年有超过200，000名患者患有心脏骤停， 医院环境（即院内心脏骤停，IHCA）。其中，约40-60%被认为是 缺氧（即窒息性心脏骤停，或ACA），死亡率在70%至95%之间， 神经系统损伤在幸存者中很常见在这些患者中，快速恢复氧气输送到 大脑心脏和其他重要器官对完整的生存至关重要几分钟的延迟可能是 恢复健康和永久性神经损伤之间的区别。在病情最严重的 患者，潜在的肺部疾病（例如）使恢复正常的氧气水平变得困难。解决 这个问题，我们已经开发了一种方法，管理氧气静脉注射。这其中的关键 一种技术是将氧气封装在充气微粒中，微粒小到足以通过 不造成阻塞的循环。颗粒壳由生物相容性材料组成， 改性葡聚糖醋酸琥珀酸酯（DAS），储存数月稳定，但立即释放气体 与血液的pH值接触。在低氧血症（即ACA）引起心脏骤停的啮齿动物中， 静脉内施用含氧DAS（DAS-Ox）微粒立即恢复氧水平， 接近正常当恢复正常通气时，所有给药动物均表现出自发性呼吸恢复。 循环（ROSC）;所有对照动物死亡。我们假设早期恢复正常的氧气 使用静脉注射氧气的张力将维持心肌和大脑的能量产生， 窒息性心脏骤停，这将实现早期ROSC并改善神经系统完整的存活率。 该项目有三个具体目标。在目标I中，我们将优化DAS-Ox MP的携氧能力， 为了最小化有意义地补充所需的DAS聚合物的给药体积和质量， 大型动物的耗氧量。我们将改变制造参数和化学成分 在实验结构的设计内的壳，检查壳厚度，粒度，粒度， 流变学作为终点。在Aim II中，我们将在猪中注入优化的微粒以筛选肺 血管阻塞，严格检查内皮损伤，干扰血液成分，器官 损伤，并描述生物分布，根据需要重新设计颗粒外壳。在Aim III中，我们将测试 在窒息性心脏骤停猪模型中给予静脉内氧气改善了 神经系统完好的存活率如果成功，这项工作将创造一种改变范式的技术 能够快速逆转低氧血症，并代表了一种治疗 窒息性心脏骤停

Project Summary/Abstract A continuous supply of oxygen gas is required to maintain cellular structure and function. Even brief deficits in oxygenation, as occurs in patients with lung injury or airway problems, can cause the heart to stop beating, a disorder known as cardiac arrest. More than 200,000 patients per year in the US suffer from cardiac arrest in the hospital setting (i.e. in-hospital cardiac arrest, IHCA). Among those, approximately ~40-60% are thought to be precipitated by hypoxia (i.e. asphyxial cardiac arrest, or ACA), with a mortality rate between 70 and 95%, and neurologic injury is common in survivors. In these patients, the rapid restoration of oxygen delivery to the brain, heart, and other vital organs is paramount to intact survival. Delays of a few minutes can be the difference between recovering back to health and permanent neurologic impairment. In the most critically ill patients, underlying lung disease (for example) makes restoration of normal oxygen levels difficult. To address this problem, we have developed a way to administer oxygen gas intravenously. The key to this technology is that the oxygen gas is encapsulated within gas-filled microparticles small enough to pass through the circulation without causing obstruction. The particle shell is composed of a biocompatible material, modified dextran acetate succinate (DAS), which is stable for months in storage but releases gas immediately upon contact with the pH of blood. In rodents with cardiac arrest provoked by hypoxemia (i.e. ACA), the intravenous administration of oxygenated DAS (DAS-Ox) microparticles immediately restored oxygen levels to near-normal. When normal ventilation was restored, all treated animals exhibited return of spontaneous circulation (ROSC); all control animals died. We hypothesize that the early restoration of normal oxygen tension using injections of intravenous oxygen will sustain myocardial and cerebral energy production in asphyxial cardiac arrest, which will achieve early ROSC and improve neurologically intact survival. This project has 3 specific aims. In Aim I, we will optimize the oxygen carrying capacity of DAS-Ox MPs in order to minimize the volume of administration and mass of DAS polymer required to meaningfully supplement the oxygen consumption of large animals. We will vary manufacturing parameters and chemical composition of the shell within a design of experiments construct, examining shell thickness, particle size, dispersibility, and rheology as endpoints. In Aim II, we will infuse optimized microparticles in swine to screen for pulmonary vascular obstruction, rigorously examining for endothelial injury, interference with blood components, organ injury, and describing biodistribution, redesigning the particle shell as needed. In Aim III, we will test whether the administration of intravenous oxygen in a swine model of asphyxial cardiac arrest improves neurologically intact survival. If successful, this work would create a paradigm-changing technology enabling the rapid reversal of hypoxemia and representing a powerful new therapy for the treatment of asphyxial cardiac arrest.