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.

项目摘要/摘要 需要连续的氧气供应以维持细胞结构和功能。甚至短暂的赤字 如肺损伤或气道问题患者中发生的氧合可能导致心脏停止跳动， 被称为心脏骤停的疾病。美国每年每年有超过20万名患者在心脏骤停 医院环境（即医院心脏骤停，IHCA）。其中，人们认为大约约40-60％ 由缺氧（即窒息心脏骤停或ACA）沉淀，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，氧气递送到 大脑，心脏和其他重要器官对于完整的生存至关重要。延迟几分钟可以是 恢复健康和永久神经系统障碍之间的区别。在最重心的病中 患者，潜在的肺部疾病（例如）使恢复正常氧气水平的恢复困难。解决 这个问题，我们已经开发了一种静脉注射氧气的方法。关键 技术是将氧气封装在足够小的气体填充微粒中 循环不会引起阻塞。颗粒壳由生物相容性材料组成， 修饰的乙酸葡萄糖琥珀酸酯（DAS），在存储中稳定，但立即释放气体 与血液接触后。在低氧血症（即ACA）引起心脏骤停的啮齿动物中， 静脉注射DAS（DAS-OX）微粒立即将氧气恢复到 近正常。恢复正常通气时，所有处理的动物均表现出自发的回归 循环（ROSC）；所有控制动物都死了。我们假设正常氧的早期恢复 使用静脉氧气注射的张力将维持心肌和脑能量产生 沥青心脏骤停，将实现早期ROSC并改善神经系统完整的生存。 该项目具有3个具体目标。在AIM I中，我们将优化DAS-OX MP的氧气承载能力 为了最大程度地减少有意义补充所需的DAS聚合物的给药量和质量 大型动物的氧气消耗。我们将改变制造参数和化学成分 在实验构造的设计中的壳，检查壳厚度，粒度，分散性和 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壳。在AIM III中，我们将测试是否 在杀伤性心脏骤停的猪模型中，静脉氧的给药可改善 神经学完整的生存。如果成功，这项工作将创造一种改变范式的技术 实现低氧血症的快速逆转，并代表了一种强大的新疗法，用于治疗 窒息心脏骤停。

项目成果

Hyperbaric polymer microcapsules for tunable oxygen delivery.

• DOI: 10.1016/j.jconrel.2020.08.003
• 发表时间: 2020-08
• 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

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

• DOI: 10.1073/pnas.2115276119
• 发表时间: 2022-03-29
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 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.