Restoring Endothelial Function After Traumatic Injury to Reduce ARDS and Multi-Organ Dysfunction

创伤性损伤后恢复内皮功能以减少 ARDS 和多器官功能障碍

• 批准号: 10739123
• 负责人: David J. Douin
• 金额: $ 18.98万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-05 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739123
• 关键词: Accounting; Acute Respiratory Distress Syndrome; Address; Anesthesiology; Area Under Curve; Blood flow; Cardiovascular system; Cause of Death; Cessation of life; Clinical; Clinical Research; Clinical Trials; Coagulation Process; Critical Care; Critical Illness; Darkness; Data; Data Analyses; Dedications; Edema; Emergency Medicine; Endothelial Cells; Endothelium; Ensure; Exposure to; Fibrinogen; Functional disorder; Funding; Future; Glycocalyx; Goals; Grant; Hemorrhagic Shock; Heparitin Sulfate; Hospitals; Hour; Human; Impairment; In Vitro; Inflammatory; Injury Severity Score; Intervention; Kidney; Knowledge; Lung; Manuscripts; Measures; Mentors; Mentorship; Microcirculation; Microscopy; Modality; Morbidity - disease rate; Mus; National Heart, Lung, and Blood Institute; Operative Surgical Procedures; Organ; Organ Preservation; Outcome; Patient-Focused Outcomes; Patients; Persons; Physicians; Plasma; Positioning Attribute; Prospective, cohort study; Proteoglycan; Protocols documentation; Qualifying; Research; Research Infrastructure; Sampling; Scientist; Testing; Tissues; Training; Transfusion; Translating; Translational Research; Trauma; Trauma patient; Traumatic injury; United States National Institutes of Health; Ventilator; Whole Blood; Work; career; career development; experience; improved; improved outcome; innovation; lung injury; mortality; multidisciplinary; novel; preservation; prevent; prospective; research and development; respiratory; response; restoration; secondary outcome; success; supplemental oxygen; syndecan; trauma care; trauma centers; trauma surgery

PROJECT SUMMARY Trauma is the leading cause of death worldwide for people under 45 years old, and hemorrhagic shock remains the primary cause of early death after trauma. Later trauma deaths are frequently attributable to endotheliopathy of trauma (EOT), a systemic response to activated endothelial cells characterized by impaired blood flow, barrier integrity, and coagulation. Clinically, EOT manifests as a pro-inflammatory state of microcirculation leak and tissue edema, contributing to acute respiratory distress syndrome (ARDS), multi- organ dysfunction, and, eventually, death. Fibrinogen replacement restores the endothelial glycocalyx in vitro and in mice via stabilization of syndecan-1, a glycocalyx-based proteoglycan. Fibrinogen stabilization of syndecan-1 then mitigates EOT and restores microcirculation barrier integrity. However, it is unclear if fibrinogen-based restoration of endothelial integrity translates to improved clinical outcomes in humans. Further, current transfusion protocols in trauma provide fibrinogen too little or too late. This is a problem because trauma patients who develop EOT are twice as likely to die than those who do not. Therefore, restoring endothelial barrier integrity is essential to mitigating late morbidity and mortality in trauma. Accordingly, there is a critical need to determine the effect of early fibrinogen replacement on endothelial and organ dysfunction in critically ill trauma patients. Our preliminary data indicate improved patient-centered outcomes when fibrinogen is replaced within 6 hours of hospital arrival. However, we do not know whether endothelial restoration was the primary mechanism. To address this gap, we will test our overarching hypothesis that preserving endothelial function with early fibrinogen replacement will prevent ARDS and multi- organ dysfunction after trauma. We will test this hypothesis with the following specific aims: 1) determine the association between early fibrinogen replacement and multi-organ dysfunction; 2) determine the effect of early fibrinogen replacement on endothelial function; and 3) determine the cumulative effect of endotheliopathy on supplemental oxygen-free days. To achieve these aims, the candidate, David Douin, MD, will leverage his background in clinical research and the existing research infrastructure within the emergency medicine, trauma surgery, and anesthesiology departments. As an anesthesiologist and surgical intensivist, Dr. Douin is uniquely positioned to accomplish the proposed K23 research and career development aims. His long-term goal is to become an expert in novel interventions to prevent and treat multi-organ dysfunction and improve outcomes in critically ill trauma patients. Dr. Douin has assembled a multidisciplinary team of mentors with extensive clinical and translational research experience and topical expertise in traumatic injury, critical care, clinical trials, endothelial function, and lung injury to ensure his success in achieving the stated specific aims and career goals. This proposal will allow Dr. Douin to transition to an independent physician-scientist and prepare him for future NIH R61/R33 funding and, eventually, NIH UG3/UH3 or R01 funding.

项目概要 外伤是全球 45 岁以下人群死亡的主要原因，失血性休克 仍然是创伤后早期死亡的主要原因。后来的创伤死亡通常归因于 创伤性内皮病 (EOT)，一种对活化内皮细胞的全身反应，其特征是受损 血流、屏障完整性和凝血。临床上，EOT 表现为促炎状态 微循环渗漏和组织水肿，导致急性呼吸窘迫综合征（ARDS） 器官功能障碍，最终导致死亡。纤维蛋白原替代可在体外恢复内皮糖萼 在小鼠中，通过稳定 syndecan-1（一种基于糖萼的蛋白聚糖）。纤维蛋白原稳定化 syndecan-1 随后可减轻 EOT 并恢复微循环屏障的完整性。然而，尚不清楚是否 基于纤维蛋白原的内皮完整性恢复可改善人类的临床结果。 此外，当前的创伤输血方案提供的纤维蛋白原太少或太晚。这是一个问题 因为发生 EOT 的创伤患者死亡的可能性是没有发生 EOT 的患者的两倍。所以， 恢复内皮屏障完整性对于减轻创伤的晚期发病率和死亡率至关重要。 因此，迫切需要确定早期纤维蛋白原替代对内皮细胞和 危重创伤患者的器官功能障碍。我们的初步数据表明以患者为中心的改善 到达医院后 6 小时内更换纤维蛋白原的结果。然而，我们不知道是否 内皮修复是主要机制。为了解决这一差距，我们将测试我们的总体 假设通过早期纤维蛋白原替代来保留内皮功能将预防 ARDS 和多发性硬化症 创伤后器官功能障碍。我们将通过以下具体目标来检验这一假设：1）确定 早期纤维蛋白原替代与多器官功能障碍之间的关联； 2）确定早期效果 纤维蛋白原替代对内皮功能的影响； 3) 确定内皮病的累积效应 补充无氧天数。为了实现这些目标，候选人 David Douin 医学博士将利用他的 急诊医学、创伤领域的临床研究背景和现有研究基础设施 外科、麻醉科。作为一名麻醉师和外科重症医生，Douin 博士是独一无二的 旨在实现拟议的 K23 研究和职业发展目标。他的长期目标是 成为预防和治疗多器官功能障碍并改善预后的新型干预措施的专家 重症外伤患者。 Douin 博士组建了一支多学科导师团队，拥有广泛的临床经验 以及创伤性损伤、重症监护、临床试验方面的转化研究经验和主题专业知识， 内皮功能和肺损伤，以确保他成功实现既定的具体目标和职业生涯 目标。该提案将使 Douin 博士能够过渡为一名独立的医师科学家，并为他做好准备 未来的 NIH R61/R33 资金以及最终的 NIH UG3/UH3 或 R01 资金。