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.

项目摘要 创伤是全球死亡的主要原因，45岁以下的人和出血性冲击 仍然是创伤后早期死亡的主要原因。以后的创伤死亡经常归因于 创伤的内皮病（EOT），这是对受损特征的激​​活内皮细胞的全身反应 血流，屏障完整性和凝结。在临床上，EOT表现为促炎的状态 微循环泄漏和组织水肿，导致急性呼吸窘迫综合征（ARDS），多 器官功能障碍，最终死亡。纤维蛋白原替代恢复体外内皮性糖囊肿 在小鼠中通过稳定syndecan-1，一种基于糖蛋白的蛋白聚糖。纤维蛋白原的稳定 Syndecan-1然后减轻EOT并恢复微循环屏障完整性。但是，目前尚不清楚是否 基于纤维蛋白原的内皮完整性的恢复可以改善人类的临床结果。 此外，当前创伤中的输血方案提供的纤维蛋白原太少或太晚。这是一个问题 因为发育EOT的创伤患者死亡的可能性是那些没有死亡的患者。所以， 恢复内皮屏障完整性对于缓解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对内皮和内皮的影响 重症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 在医院到达后6小时内更换纤维蛋白原时的结果。但是，我们不知道是否 内皮恢复是主要机制。为了解决这一差距，我们将测试我们的总体 假设可以通过早期纤维蛋白原替代来保存内皮功能将防止ARD和多种 创伤后器官功能障碍。我们将以以下特定目的检验该假设：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）确定早期的效果 内皮功能上的纤维蛋白原替代； 3）确定内皮病的累积作用对 补充无氧的日子。为了实现这些目标，候选人David Douin，医学博士将利用他的 临床研究和急诊医学中现有研究基础设施的背景 手术和麻醉学部门。作为麻醉师和外科医师，杜恩博士是独特的 实现拟议的K23研究和职业发展目标的定位。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 重症创伤患者。 Douin博士通过广泛的临床组合了一个多学科的导师团队 以及转化研究经验和创伤性损伤，重症监护，临床试验方面的专业知识， 内皮功能和肺部受伤，以确保他在实现既定目标和职业方面的成功 目标。该建议将使杜因博士能够过渡到独立的医师科学家，并为他做好准备 未来的NIH R61/R33资金，最终是NIH UG3/UH3或R01资金。