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

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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.