Intravenous oxygen microparticles for treatment of cardiac arrest

静脉注射氧气微粒治疗心脏骤停

• 批准号: 10223923
• 负责人: John Nagi Kheir
• 金额: $ 61.2万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2024-08-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223923
• 关键词: Acetates; Address; Adverse effects; Animals; Arrhythmia; Back; Biocompatible Materials; Biodistribution; Blood; Blood Circulation; Blood Pressure; Blood Vessels; Brain; Brain Hypoxia-Ischemia; Caliber; Cardiac Output; Carrying Capacities; Cell physiology; Cellular Structures; Cerebrum; Chemicals; Chemistry; Coagulation Process; Consumption; Control Animal; Critical Illness; Dextrans; Disease; Dose; Emulsions; Encapsulated; Endothelium; Ensure; Excipients; Exhibits; Family suidae; Fluorocarbons; Formulation; Gases; Goals; Grant; Health; Heart; Heart Arrest; Hematology; Heme; Hospitals; Human; Hypoxemia; Hypoxia; Impairment; Injections; Injury; Intravenous; Ischemia; Lead; Liquid substance; Lung; Lung diseases; Modeling; Myocardial; Nervous System Trauma; Neurologic; Obstruction; Organ; Oxygen; Oxygen Consumption; Oxygen Therapy Care; Particle Size; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Polymers; Process; Production; Property; Pulmonary Pathology; Pulmonary Vascular Resistance; Pulmonary artery structure; Resuscitation; Rheology; Risk; Rodent; Rodent Model; Safety; Speed; Succinates; Surface; Survivors; System; Technology; Testing; Thick; Thinness; Tissues; Work; blood rheology; clinically relevant; deprivation; design; experimental study; functional outcomes; hemodynamics; improved; indexing; interfacial; intravenous administration; intravenous injection; lung injury; mortality; nanoparticle; novel therapeutics; organ injury; particle; porcine model; preservation; pressure; restoration; supplemental oxygen; ventilation

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.

项目概要/摘要 需要持续供应氧气来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发生的氧合可能会导致心脏停止跳动， 称为心脏骤停的疾病。美国每年有超过 200,000 名患者出现心脏骤停 医院环境（即院内心脏骤停，IHCA）。其中，大约 40-60% 被认为 由缺氧引发（即窒息性心脏骤停，或 ACA），死亡率在 70% 至 95% 之间， 神经损伤在幸存者中很常见。在这些患者中，氧气输送迅速恢复 大脑、心脏和其他重要器官对于完整的生存至关重要。几分钟的延迟可能是 恢复健康与永久性神经功能障碍之间的区别。在病情最危重的时候 对于患者来说，潜在的肺部疾病（例如）使得恢复正常的氧气水平变得困难。致地址 针对这个问题，我们开发了一种静脉注射氧气的方法。这其中的关键 技术是将氧气封装在足够小的充气微粒中以通过 循环，不造成阻塞。颗粒壳由生物相容性材料组成， 改性右旋糖酐乙酸琥珀酸酯 (DAS)，可在储存数月内保持稳定，但会立即释放气体 与血液的 pH 值接触后。在因低氧血症（即 ACA）引起心脏骤停的啮齿类动物中， 静脉注射含氧 DAS (DAS-Ox) 微粒立即将氧气水平恢复到 接近正常。当恢复正常通气时，所有接受治疗的动物均表现出自发恢复 循环（ROSC）；所有对照动物均死亡。我们假设早期恢复正常氧气 使用静脉注射氧气来维持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 并提高神经系统完整的生存率。 该项目有 3 个具体目标。在目标 I 中，我们将优化 DAS-Ox MP 的携氧能力 为了最大限度地减少有效补充所需的 DAS 聚合物的给药量和质量 大型动物的耗氧量。我们将改变制造参数和化学成分 实验结构设计中的壳的结构，检查壳厚度、粒径、分散性和 流变学作为终点。在目标 II 中，我们将向猪体内注入优化的微粒以筛查肺部疾病 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壳。在目标 III 中，我们将测试是否 静脉输氧可改善猪窒息心脏骤停模型 神经系统完好无损的存活。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，并代表一种强大的治疗低氧血症的新疗法 窒息性心脏骤停。

项目成果

Hyperbaric polymer microcapsules for tunable oxygen delivery.

用于可调氧气输送的高压聚合物微胶囊。

• DOI: 10.1016/j.jconrel.2020.08.003
• 发表时间: 2020-08-13
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Tien Nguyen;Yifeng Peng;Raymond P. Seekell;J. Kheir;B. Polizzotti
• 通讯作者: B. Polizzotti

A microfluidic device for real-time on-demand intravenous oxygen delivery.

一种用于实时按需静脉输氧的微流体装置。

• 发表时间: 2022-03-29
• 影响因子: 11.1
• 作者: Vutha, Ashwin Kumar;Patenaude, Ryan;Cole, Alexis;Kumar, Rajesh;Kheir, John N;Polizzotti, Brian D
• 通讯作者: Polizzotti, Brian D