The Trauma Research Center is a multi-institutional, multidisciplinary research unit supported by the National Institute of General Medical Sciences (NIGMS) of the United States' National Institutes of Health (NIH). The Trauma Research Program is an extensive, collaborative effort that draws upon several related sources all located within the Texas Medical Center in an effort to improve trauma medicine through translational research efforts. The Center's research focus is to study traumatic brain injury, resuscitation, hemorrhagic shock and organ injury/dysfunction.
| LITES Task Order 7: Type O Whole Blood and Assessment of Age During Prehospital Resuscitation Trial (TOWAR) |
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| Site PI – Bryan Cotton, MD |
| Co-Investigators – Charles Wade, PhD; David Meyer, MD; Erin Fox, PhD |
| Supporting Agency – University of Pittsburgh |
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Due to the time sensitive nature of the treatment of hemorrhage, the ideal resuscitation intervention would entail use of blood products containing all essential hemostatic components, administration closest to time of injury, and mitigation of the devastating downstream consequences of shock and coagulopathy. Whole blood transfusion following traumatic injury represents the ‘essential next step’ for the management of hemorrhagic shock post-injury. Prehospital whole blood is significant in that it brings this lifesaving hospital intervention to those patients who need it most, at a time before hemorrhagic shock and coagulopathy begin to have their detrimental consequences. We hypothesize that the initiation of whole blood resuscitation in the prehospital setting will significantly reduce the morbidity and mortality attributable to hemorrhagic shock post-injury as compared to standard prehospital resuscitation practice. Whole blood is a precious resource. The shelf life of the whole blood product depends on separation procedures and ranges from 21 to 35 days. The storage of whole blood leads to platelet dysfunction, cell lysis, and release of potassium and free heme which may reduce the resuscitative capacity of whole blood or contribute to end organ injury. The safety and efficacy of whole blood as a resuscitation fluid as it approaches its shelf life remains poorly characterized. The aims of the current Type O Whole blood and assessment of Age during prehospital Resuscitation (TOWAR) trial are to determine the efficacy and safety of whole blood resuscitation as compared to standard care resuscitation in patients at risk of hemorrhagic shock and to appropriately characterize the hemostatic competency of whole blood relative to its age. |
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| Postdoctoral Training Program in Trauma and Hemorrhagic Shock |
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| PI – Charles Cox, MD |
| Supporting Agency – National Institute of General Medical Sciences |
| Ruth L. Kirschstein National Research Service Award (NSRA) Institutional Research Training Grant - 2T32GM008792 |
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The long-term objective of this trauma research training program is to provide multidisciplinary research training for post doctorates in trauma to develop future independent investigators who will use these skills in research-intensive and research-related careers that increase understanding of the mechanisms of traumatic injury and inform clinical practice. To accomplish these objectives, our program selects fellows each calendar year for 2-year positions within the structured program. The program recruits postdoctoral candidates who are interested in pursuing an academic career in trauma-related research. At the end of the 2 years of training, the goal is that each fellow is able to 1) critically analyze available published data; 2) formulate a focused hypothesis; 3) design and perform necessary experiments to test the hypothesis; 4) analyze and interpret results to draw appropriate conclusions and potentially modify experimental strategies; 5) effectively present the results of their research both orally and in writing; and 6) prepare a competitive research proposal. |
| Stem Cells for the Prevention of Inflammatory Complications of Severely Injured Trauma Patients |
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| PI – Charles Cox, MD |
| Co-Investigators – Erin Fox, PhD; Laura Moore, MD; Charles Wade, PhD |
| Supporting Agency –Medical Technology Enterprise Consortium (MTEC) |
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The objective of this trial is to evaluate the safety and efficacy of MultiStem for the treatment of severely injured trauma patients suffering hemorrhagic shock for the prevention and early treatment of inflammatory complications. This trial will improve knowledge and techniques to treat ischemia-reperfusion injury. The investigational intervention is feasible early after injury, potentially even in remote operating environment scenarios. If the MultiStem cells decrease the incidence of inflammatory complications, transport of treated casualties from remote locations will be logistically simpler and safer, and mortality of these patients would be expected to decrease. |
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| Microvascular Barrier Biomarkers to Predict ICP Therapeutic Intensity After Severe TBI |
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| PI - Charles Cox, MD |
| Co-Investigators – Erin Fox, PhD; Charles Wade, PhD |
| Supporting Agency – US Army Medical Research & Material Command (W81XWH18SBAA1) |
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Severe traumatic brain injury (TBI) is a leading cause of death and disability, and often occurs at the same time as multiple other injuries and with and without bleeding. Current care of the patient with a brain injury is designed to avoid factors that cause the initial injury to become worse (low blood pressure and lack of oxygen). This project seeks to identify early laboratory measures that can predict whether a patient is likely to get worse, then treat the causes of the condition. The ultimate goal is to be able to use a simple blood test that identifies the degraded components in the brain to rapidly identify the subset of severe TBI patients that require high-intensity neurocritical care. |
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| Comparison of Surgery and Medicine on the Impact of Diverticulitis (COSMID Trial) |
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| Site PI – Lillian Kao, MD |
| Supporting Agency – University of Washington |
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The Comparison of Surgery and Medicine on the Impact of Diverticulitis (COSMID) study aims to test if, from a patient’s perspective, partial colectomy is better than medical management for the treatment of quality of life (QoL)-limiting diverticulitis. We hypothesize that partial colectomy will be better than medical management with respect to patient-reported and patient-centered outcomes. A large-scale pragmatic, randomized trial is expected to result in better understanding of the best management of a common gastrointestinal, QoL-limiting condition in patients nationwide. Understanding which patient subgroups benefit from partial colectomy and which patient subgroups benefit from best medical management will improve patient choice and support a shift from practice variations dependent on provider preferences or precedent to clinical care that corresponds to selecting the right treatment for the right patient at the right time. |
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| Treatment Individualized Appendicitis Decision Making Implementation Program – TRIAD |
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| PI – Lillian Kao, MD |
| Supporting Agency – University of Washington |
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Accumulating evidence for the safety and efficacy of non-operative management of appendicitis with antibiotics means that patients now have a preference-sensitive decision for how to treat appendicitis. The goal of this study is to understand how patients are making this treatment decision and their opinions and satisfaction with the type of information and support they are receiving in making this decision. This information will be used to inform the design of decision-support interventions to help patients improve their ability to make an informed decision in line with their preferences and values. |
| Impact of Health Literacy on Infections (Health LIT) Study |
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| PI – Krislynn Mueck, MD |
| Supporting Agency – Surgical Infection Society |
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The proposed study aims to study HL in patients undergoing emergency surgery at two high-volume centers in order to evaluate its impact on the development, timing of diagnosis, and severity of postoperative infectious complications. The goal is to develop an intervention to address HL to reduce the prevalence and impact of infectious complications.
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| Antithrombin to Improve Thromboprophylaxis and Reduce the Incidence of Trauma-Related Venous Thromboembolism (TRAIT) RCT |
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| PI – Bryan Cotton, MD |
| Co-Investigator – Erin Fox, PhD; Charles Wade, PhD; David Meyer, MD |
| Supporting Agency – Grifols Shared Services North American, Inc. |
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Thromboembolic complications are a serious threat to recovery in surviving trauma patients, affecting 2-20% of this population. Despite prophylactic treatment with enoxaparin, these rates of venous thromboembolism (VTE) have persisted and are associated with aggressive interventions, increased lengths of hospital and ICU stay, and recurrent thrombotic disease. The data from this trial could redefine VTE prophylaxis protocols for trauma patients and have a significant impact of the burden of VTE in this population. The overall goal of this project is to perform a multicenter, randomized trial to determine if early administration of antithrombin will improve responsiveness to low molecular weight heparin prophylaxis and reduce the incidence of venous thromboembolism in hospitalized and recovering trauma patients.
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| Prothrombin Complex Concentrate (Human) for Treatment of Traumatic Injury and Acute Major Bleeding: TAP Trial |
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| PI – David Meyer, MD |
| Supporting Agency – CSL Behring |
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There is good preliminary clinical evidence for a potential therapeutic role of 4F-PCC in trauma patients to improve survival. Therefore, this phase 3, randomized, double-blind, placebo-controlled study has been designed to evaluate the efficacy and safety of BE1116 when administered early in patients who have traumatic injury and confirmed or suspected acute major bleeding predicted to receive a large volume blood product transfusion (i.e., a massive transfusion protocol setting). In addition to the study site’s standard resuscitation methods and protocol, a single IV infusion of investigational product (IP) (BE1116 or placebo) will be administered, starting within 90 minutes of arrival at the emergency department (ED). Efficacy and safety data will be collected for the primary hospitalization period, up to the time of death/hospital discharge / Day 30, whichever occurs first. The primary endpoint is all-cause mortality within 6 hours after the start of the IP infusion.
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| Vitamin C in Thermal injury: The VICToRY Trial |
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| PI – John Harvin, MD |
| Supporting Agency – Queen’s University at Kingston |
| The objective of this pilot trial is to demonstrate feasibility and safety of a high-dose intravenous vitamin C administration in 180 severely burned patients. Furthermore, this study´s purpose is a) to gain first information about the safety and pharmacokinetics of high dose intravenous vitamin C in this patient population, b) determine possible endpoints for a definitive study, and c) to evaluate the oxidation-reduction potential as a new biomarker for oxidative stress. If feasibility is demonstrated in the pilot, a larger phase II/III component will be conducted and aimed at lowering morbidity and mortality and reducing health care costs in an otherwise very devastating and disabling injury worldwide. However, before proceeding to such a large trial, we propose to conduct a smaller pilot trial aimed at assessing the feasibility and fidelity of implementation of the larger trial protocol. We hypothesize that the inexpensive therapeutic strategy tested in this randomized controlled trial will be feasible to conduct with high fidelity of implementation. This trial will be conducted in compliance with the protocol, GCP and the applicable regulatory requirements. |
| Trauma-induced coagulopathy and the blood-brain barrier: Impact of resuscitation |
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| PI – Charles Cox, MD |
| Co-Investigators – Erin Fox, PhD; Charles Wade, PhD; Brijesh Gill, MD |
| Supporting Agency – Department of Defense |
| Hemorrhagic shock (HS) amplifies and exacerbates bleeding and barrier dysfunction after traumatic brain injury (TBI). Endothelial failure, more broadly, failure of the neurovascular unit that comprises the blood-brain barrier (BBB), has severe physiological consequences. Further, trauma-induced fibrinolysis that develops in 25% of HS patients is linked to endotheliopathy through the release of coagulation enzymes and byproducts into systemic circulation (via crosstalk mechanisms) that can disrupt homeostasis in distant organs/vascular beds. |
| We seek to understand these interactions with a multi-platform strategy using patient samples from trauma-induced fibrinolysis phenotypes (delayed clot initiation/polymerization; reduced clot strength; platelet dysfunction [PD]; hyperfibrinolysis) and unique in vitro assays: (1) a novel platelet contractility assay; (2) a neurovascular unit, circulating-microfluidic BBB model capable of measuring physiological pressures/flows; (3) an HS/TBI animal model; and (4) advanced magnetic resonance imaging (MRI) protocols of patients to quantitate cytotoxic and vasogenic edema. We further seek to identify transfusion practices that not only reverse fibrinolysis but also attenuate pathological mechanisms that subsequently promote hemorrhagic expansion and edema in the neurovasculature |
| The following 4 projects comprise our Focused Program Award addressing Focus Area 2 (Prevent and Assess) and subarea 2a, "Identification and validation of biomarkers or other objective markers for diagnosis, prognosis, or monitoring of …TBI" and Focus Area 3 (Treat) and subarea 3a, "Interventions that promote sustained functional recovery, including interventions administered acutely, during the post-acute phase, or during the chronic phase of injury." |
| Project 1: The goals are to define the role of fibrin(ogen) degradation products (FDPs) in mediating disruption of the BBB through their interaction with vascular and circulating blood cells and identify therapeutic targets for inhibiting FDP release and cellular interactions. We hypothesize that FDPs drive disruption of the BBB and that attenuation of FDP release and blocking of FDP-endothelial cell (EC) interactions will mitigate BBB disruption and cerebral edema following TBI+HS. The overall approach is to quantify FDPs in polytrauma patient plasma and correlate with clinical BBB metrics; identify novel EC receptors for FDPs; and determine the effects of inhibiting FDP release and blocking FDP-EC interactions on BBB disruption. |
| Project 2: The goal is to define the mechanism by which HS and/or fibrinolysis exacerbate cerebral edema after severe TBI using our novel, high-throughput, physiologically relevant BBB model to test variables that can only be inferred in vivo or are impractical to test in a multimodal manner. We propose to determine the influence of increasing injury severity/complexity on BBB permeability; characterize the fibrinolytic phenotype that worsens TBI via the PAR1-MMP9-SUR1-TRPM4 signaling axis; and determine the contribution of upregulation and/or SUR1-TRPM4 channel activation mechanisms to HS amplification of BBB permeability. Our approach will allow us to optimize therapeutic approaches for TBI patients using data derived from the proposed experiments. |
| Project 3: The goal is to define platelet dysfunction in the setting of TBI +/- HS. Four potential contributory mechanisms will be explored: activation, aggregation, and contraction phenotypes in each patient cohort; metabolic crisis and/or RNA degradation as etiology of dysfunction; and impact of FDPs on platelet dysfunction. Understanding platelet dysfunction in the setting of TBI +/- HS +/- hyperfibrinolysis will provide insight into resuscitation strategies, potential druggable targets, and early clinical risk stratification by comparison of samples taken on patient arrival and after resuscitation is completed. |
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Project 4: The goal is to longitudinally quantify and compare acute/subacute vasogenic cerebral edema due to BBB disruption across TBI patients with and without HS and relate these metrics back to corresponding fibrinolytic and phenotypes ascertained in Projects 1 and 2. The impact will be to quantify BBB permeability 4 and cerebral edema and correlate this with blood-based biomarkers. These data will provide a translational link to the pathophysiology of how HS amplifies cerebral edema after TBI. This Project implements a multimodal, transdisciplinary approach to investigate longitudinal relationships between blood-based markers of fibrinolysis, blood-based markers of cerebral edema (CE), and physiologic measures of CE. This Project will provide clinically relevant imaging data that link to mechanisms and biomarkers that are measurable with standard techniques.
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| Dronabinol on the Pain Experience (DOPE): a pragmatic, randomized clinical trial |
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| PI – Krislynn Mueck, MD |
| Co-Investigator – John Harvin, MD |
| Supporting Agency – Eastern Association for the Surgery of Trauma (EAST) |
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The opioid epidemic is an ongoing public health crisis that has only intensified during the COVID-19 pandemic. Due to the nature of multisystem injuries, need for multiple painful procedures, and lengthy hospitalization, injured patients’ acute pain control needs differ from those in other surgical specialties. In an effort to reduce opioid exposure while maintaining optimal pain control, surgeons are increasingly using multi-modal pain regimens (MMPR). Our current institutional MMPR is derived from the Multi-Modal Analgesic Strategy for Trauma (MAST) trial which demonstrated a reduction in opioid exposure while maintaining pain control. However, adjunct medications are commonly added to improve pain control. One such adjunct is dronabinol, a synthetic delta-9-tetrahydrocannabinol (delta-9-THC), that is commonly used for its analgesic properties but the data supporting its use for acute pain after traumatic injury is limited.
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| Freeze Dried Mechanotransduced MSC Derived Exosomes for Neurological Injury |
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| PI – Charles Cox, MD |
| Supporting Agency – TRC4 – Trauma Research & Combat Casualty Care Collaborative |
| We propose to manufacture and validate EVs derived from MSCs that have undergone shear stress mechanotransduction in a novel bioreactor to down regulate the inflammatory response to TBI. Further, these will be freeze-dried for use in rural and military environments. |
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| Identifying SUR1/TRPM4 Polymorphisms to Reduce Contusion Expansion after Traumatic Brain Injury: Clinical Trial Planning Grant |
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| PI – Charles Cox, MD |
| Supporting Agency – TRC4 – Trauma Research & Combat Casualty Care Collaborative |
| A critical mode of failure in clinical trials for TBI is related to heterogeneity of the population in terms of type of injury, and now we have insight into genetic variation that is impactful. To design an impactful clinical trial, both must be considered to be important. We propose using BOTH a contusion endophenotype AND developing the infrastructure for rapid SNP genotyping to allow determination of the population most likely to respond to SUR1/TRPM4 inhibition. Genetic determination of therapeutic responders for personalized TBI treatment is not currently available and would alter the treatment paradigm for TBI, preferentially benefiting populations with historically worse outcomes after trauma. The failure mode of the previous trials utilizing this strategy is due to a relatively small number of patients with the genetic variants most responsive to treatment. Identifying those SNPs will then allow a rapid determination strategy to allow personalized medicine approaches to treating severe TBI. Further, we will utilize advanced imaging to confirm the biologic activity of the treatment after TBI in reducing cerebral edema using quantitative DT-MRI. |
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| Hemodynamic Management Following Acute Traumatic Spinal Cord Injury: A Pilot Randomized, Controlled Trial |
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| PI – David Meyer, MD |
| Supporting Agency – TRC4 – Trauma Research & Combat Casualty Care Collaborative |
| We propose to perform a randomized, controlled trial comparing the effectiveness of goal-directed therapy targeting MAP ≥85 mmHg or SCPP ≥65 mmHg compared to usual care (MAP ≥65 mmHg) with strict avoidance of hypotension for the first 5 days following SCI. The primary outcome is degree of neurologic impairment at 12 months as measured by the American Spinal Injury Association (ASIA) motor score and the Spinal Cord Independence Measure (SCIM). |
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| Pediatric Prospective Observational Vascular Injury Trial (Pedi PROOVIT) |
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| PI – Natalie Drucker, MD |
| Supporting Agency – TRC4 – Trauma Research & Combat Casualty Care Collaborative |
| The objective of this proposal is to improve understanding of pediatric major vascular injuries by establishing a prospective pediatric multicenter vascular injury registry. We will then review the database to compare management and outcomes in pediatric major vascular injuries to provide evidence-based interventions to improve outcomes and standard of care for children with vascular injuries. |
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| An Assessment of Green Plasma: The Potential Hemostatic Superiority of a Currently Discarded Blood Product |
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| PI – Bryan Cotton, MD |
| Supporting Agency – TRC4 – Trauma Research & Combat Casualty Care Collaborative |
| Our long-term goal is to determine whether green plasma should be actively re-introduced into the medical community for transfusion as a safe and functionally non-inferior (and potentially superior) product. |
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| Assessment of the Relationship between Statins, Microvascular Dysregulation, and Venous Thromboembolism in Severely Injured Trauma Patients |
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| PI – Gabrielle Hatton, MD |
| Supporting Agency – TRC4 – Trauma Research & Combat Casualty Care Collaborative |
| This study will evaluate the role of stains in treating trauma/combat casualty-induced injuries, specifically related to hemorrhage and vascular dysfunction, with the ultimate goal of including them in a multimodal VTE chemoprophylaxis strategy. |
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| Project TRUST – Trauma Recovery Using Support from Trauma-Informed-Care Approach |
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| PI – Stephanie Martinez-Ugarte, MD |
| Co-Investigator – Natalie Drucker, MD |
| Supporting Agency – TRC4 – Trauma Research & Combat Casualty Care Collaborative |
| Our project aims to provide a structured approach to implement TIC and screening for mental health illnesses after physical trauma in all Level I Trauma Centers (adult and pediatric) across the UT system. Our team of social worker and educator will travel to each participating site to ensure standardized implementation of the TIC curriculum and mental health screening. We plan to collect baseline mental health screening scores on patients and health care workers at each institution prior to full initiation of TIC and mental health screening. A validated PTSD / Depression checklist will be used for screening over the continuum of the project period of 18 months. Benefit to Cost Ratio will be calculated by reviewing readmission rates, compliance to scheduled follow-up after discharge, and post-injury quality of life scores before and after implementation at UT System affiliated ACS Verified Trauma Centers. |
| Novel ‘Short Wave Assessment Tool in Texas’ (SWATT) to Enhance Burn Tissue Viability Assessment |
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| PI – John Harvin, MD |
| Supporting Agency – TRC4 – Trauma Research & Combat Casualty Care Collaborative |
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| A Video Conversation Aid to Improve Shared Decision-Making for Life-Sustaining Care after Injury in Older Adults |
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| PI – Thaddeus Puzio, MD |
| UTHealth Houston Learning Healthcare Grant |
| The proposed study will evaluate the effectiveness and acceptability of a video conversation aid to enhance communication between trauma care providers and patient surrogate decision makers. We hypothesize that this tool will increase the concordance between care received and patient preferences. The results of this study will provide preliminary data for a larger multicenter trial. Guided by an experienced and knowledgeable mentoring and advisory team, this project will allow me to gain skills and expertise in implementing evidence-based practices, using mixed-methods, and conducting patient-centered geriatric research. |
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| Massive Transfusion in Children (MATIC-2) |
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| PI – Charles Cox, MD |
| Supporting Agency - Biomedical Advanced Research Development Authority (BARDA) |
| The Massive Transfusion in Children-2 (MATIC-2) trial will examine the effectiveness, safety and mechanisms between multiple resuscitation practices in children with life-threatening bleeding from traumatic injury. The interventions in the trial will include blood component therapy with red cells, plasma and platelet units compared to low titer group O whole blood, and tranexamic acid compared to placebo. These interventions have been chosen for this randomized controlled trial due to laboratory, animal, and human data that suggests the use of low titer group O whole blood and tranexamic acid have the potential to improve survival in children with life-threatening bleeding. The trial will also thoroughly explore the mechanisms of trauma induced blood failure and the biologic consequences of each of the interventions studied in this trial with the innovative use of a multi-omics platform (proteomics, lipidomics, and metabolomics). |
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