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Peritoneal Oxygen Delivery For The Treatment Of Acute Respiratory Distress Syndrome

腹膜供氧治疗急性呼吸窘迫综合征

基本信息

批准号：
10556430
负责人：
Mark Andrew Borden
金额：
$ 65.2万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-09 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10556430
关键词：
Acute Respiratory Distress Syndrome Affect Animal Model Animals Anticoagulants Anticoagulation Beds Blood Vessels Brain Bypass Chemistry Circulation Data Diffusion Dose Drug Kinetics Electrodes Endotoxins Engineering Esters Extracorporeal Membrane Oxygenation Formulation Gases Goals Greater sac of peritoneum Hemorrhage In Vitro Inhalation Injury Intensive Care Units Intraperitoneal Injections Journals Lipids Lipopolysaccharides Lung Measures Mechanical ventilation Medicine Membrane Methods Microbubbles Modeling Molecular Structure Multicenter Studies Muscle New England Organ Oxygen Patients Peripheral Peritoneal Phospholipids Property Proteins Publishing Pulmonary Surfactants Rattus Research Research Project Grants Rest Risk Rodent Model Safety Serum Albumin Smoke Inhalation Injury Source Structure of parenchyma of lung Sucrose System Techniques Technology Testing Therapeutic Tissues Trauma Traumatic injury Ventilator Work body cavity design healing improved in vivo innovation intraperitoneal lung health mortality novel phosphorescence porcine model rational design response safety testing smoke inhalation sugar supplemental oxygen surfactant trauma care ventilation

项目摘要

Severe acute respiratory distress syndrome (ARDS) occurs in approximately 10% of patients entering the intensive care unit, affecting nearly 190,000 patients per year in the US alone. The initiation of ARDS is multifactorial but often results in an inability to oxygenate the patient using conventional ventilation methods. Despite the use of different ventilator modes and various inhalational agents, patient proning etc., approximately 30-50% of ARDS cases end in mortality. The ultimate aim of pulmonary support is to cause the least damage to the lung parenchyma while it heals; with this in mind, extracorporeal membrane oxygenation (ECMO) has been used in the most severe cases, when other means have failed. Unfortunately, ECMO also has a substantial contraindication list and risk profile, which in part is driven by the need for full anticoagulation while the patient is on the circuit. For a large portion of patients – traumatically injured patients, in particular – full anticoagulation carries the risk of uncontrolled hemorrhage in the brain or other organs affected by trauma. We therefore continue to search for effective means of resting the lungs while supporting the oxygenation and ventilation needs of the patient. Oxygen microbubbles (OMBs) have shown promise as a method of extra-pulmonary oxygenation that is safe, versatile and does not require use of anticoagulants. Our work is innovative as it explores a novel method for extra-pulmonary oxygenation using body cavities, such as the peritoneal cavity. This could have a significant impact on the field of trauma care in situations where anticoagulants cannot be used, as well as in settings where ECMO technology is not readily accessible or practical. We have shown in small-animal models of ARDS induced by lipopolysaccharide (LPS) and smoke inhalation (SI) that an intraperitoneal injection of OMBs improves peripheral oxygenation saturation by 10-15% to normoxic levels, as well as survival and lung health. While our preliminary studies have shown favorable improvements in oxygenation and survival in a preliminary lipid-based formulation, it is unclear that this chemistry is the optimal formulation for intraperitoneal delivery. The goal of this research project is to develop, characterize and test alternative OMB formulations based on different lipids, lung surfactant, protein and sugar shells. The first aim will determine pharmacokinetic parameters for novel OMB formulations. We will perform a “deep dive” design analysis of four different shell types: characterizing mass transfer properties, gas-exchange phenomena and in vivo persistence in the peritoneal cavity. The second aim will use a novel electrode-phosphorescence method to measure OMB dose response and effects on muscle microvascular O2 supply in local tissue. The third aim will test the new OMB formulations in rodent and pig models of LPS-ARDS. Finally, the fourth aim will Test new OMB formulations in rodent and pig models of SI-ARDS. Overall, this research will test safety and efficacy of peritoneal microbubble oxygenation in small and large animal models of ARDS, as well as establish key engineering principles for rational design of oxygen microbubbles for peritoneal oxygenation.

大约 10% 的入院患者出现严重急性呼吸窘迫综合征 (ARDS) 仅在美国，重症监护病房每年就影响近 190,000 名患者。 ARDS 的起始是其原因是多因素的，但通常会导致无法使用传统通气方法为患者供氧。尽管使用不同的呼吸机模式和各种吸入剂、患者俯卧等，大约 30-50% 的 ARDS 病例最终死亡。肺支持的最终目的是对患者造成最小的伤害愈合时的肺实质；考虑到这一点，体外膜肺氧合（ECMO）已被当其他方法都失败时，在最严重的情况下使用。不幸的是，ECMO 也有大量的禁忌症清单和风险状况，部分原因是患者在治疗期间需要全面抗凝是在电路上。对于大部分患者——尤其是外伤患者——全面抗凝存在大脑或受创伤影响的其他器官失控出血的风险。因此我们继续寻找让肺部休息的有效方法，同时支持肺部的氧合和通气需求病人。氧气微泡 (OMB) 作为一种肺外氧合方法已显示出前景安全、通用且不需要使用抗凝剂。我们的工作具有创新性，因为它探索了一种新颖的方法使用体腔（例如腹膜腔）进行肺外氧合。这可能会产生重大影响在无法使用抗凝剂的情况下以及在无法使用抗凝剂的情况下对创伤护理领域的影响 ECMO 技术并不容易获得或实用。我们已经在 ARDS 诱导的小动物模型中表明通过脂多糖 (LPS) 和烟雾吸入 (SI) 腹腔注射 OMB 可以改善外周氧合饱和度提高 10-15% 至含氧量正常水平，以及生存和肺部健康。虽然我们的初步研究表明，基于脂质的初步研究可显着改善氧合和存活率。制剂中，尚不清楚该化学物质是否是腹膜内递送的最佳制剂。该研究项目的目标是开发、表征和测试基于 OMB 的替代配方不同的脂质、肺表面活性物质、蛋白质和糖壳。第一个目标将确定药代动力学新型 OMB 配方的参数。我们将对四种不同的外壳进行“深入”设计分析类型：表征传质特性、气体交换现象和体内持久性腹膜腔。第二个目标将使用新型电极磷光方法来测量 OMB 剂量对局部组织肌肉微血管 O2 供应的反应和影响。第三个目标将测试新的 OMB LPS-ARDS 啮齿动物和猪模型中的制剂。最后，第四个目标将测试新的 OMB 配方 SI-ARDS 的啮齿动物和猪模型。总的来说，这项研究将测试腹膜微泡的安全性和有效性 ARDS 的小型和大型动物模型中的氧合，以及建立关键的工程原理合理设计用于腹膜氧合的氧气微泡。