Skip Navigation and Go To Content

Active Research

Trauma Research Center

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 4: Cold-Stored Platelet Early Intervention in Hemorrhagic Shock Trial (CriSP-HS)
Site PI – Bryan Cotton, MD
Co-Investigator – Erin Fox, PhD
Supporting Agency – University of Pittsburgh

Resuscitation strategies for the acutely injured patient in hemorrhagic shock have evolved with patients benefitting from receiving less crystalloid and early red blood cell use with balanced ratios of plasma and platelets. These resuscitation practices have been termed Damage Control Resuscitation and have been incorporated into massive transfusion protocols in level 1 trauma centers across the country. Despite these changes, deaths from traumatic hemorrhage continue to occur in the first hours following arrival at the trauma center, underscoring the importance of early interventions which provide benefit. Platelet transfusions are a vital component of damage control resuscitation and are essential to early hemostasis. Currently, platelets are not available in the prehospital or early resuscitation setting and are typically provided only after massive transfusion protocols are initiated, beyond the early phase of care for hemorrhagic shock patients.

Platelet use in far forward environments are not available due to logistical storage and shelf-life requirements. Cold-stored platelets can be refrigerated similar to red blood cells and plasma units and may be less prone to bacterial contamination. Growing evidence suggests that cold-stored platelets have superior hemostatic capabilities. For patients in hemorrhagic shock, cold stored platelets may be beneficial in an urgent release fashion soon after arrival to the trauma center as compared to current standard care. The aims of the Cold Stored Platelet early intervention (CriSP) pilot trial are to determine the feasibility, efficacy and safety of urgent release cold stored platelets in patients in hemorrhagic shock.

  • AIM 1: Determine the feasibility, most appropriate study population and primary outcome that will lead to a large multicenter clinical trial designed to evaluate the effectiveness of cold stored platelet early intervention in patients with injury and hemorrhagic shock.
  • AIM 2: Determine whether early cold stored platelet infusion compared to standard care results in improved clinical outcomes and hemostatic function in injured patients with hemorrhagic shock.
  • AIM 3: Determine if early cold stored platelet hemostatic function is similar at 1 through 7 days as compared to 8 through 14 days in patients with hemorrhagic shock.
LITES Task Order 7: Type O Whole Blood and Assessment of Age During Prehospital Resuscitation Trial (TOWAR)
Site PI – Bryan Cotton, MD
Co-Investigators – Charles Wade, PhD; David Meyer, MD; Erin Fox, PhD
Supporting Agency – University of Pittsburgh

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.

  • AIM 1: Determine whether prehospital low titer whole blood as compared to standard prehospital resuscitation results in lower 30-day mortality in patients at risk of hemorrhagic shock.
  • AIM 2: Determine whether old prehospital whole blood (age > 14 days) as compared to young prehospital whole blood (age ≤ 14 days) is associated with equivalent clinical outcomes, hemostasis, prevention of coagulopathy, and platelet function in patients at risk of hemorrhagic shock.
  • AIM 3: Determine whether prehospital low titer whole blood as compared to standard prehospital resuscitation results in lower early mortality endpoints, blood and blood component transfusion requirements, lower incidence of coagulopathy, and improved hemostatic and platelet function in patients at risk of hemorrhagic shock.
A Multi-Center, Randomized, Controlled Trial Evaluating the Effects of Early High-Dose Cryoprecipitate in Adult Patients with Major Trauma Hemorrhage Protocol Activation (Cryostat2 Study)
Site PI – Bryan Cotton, MD
Co-Investigators – Erin Fox, PhD; Charles Wade, PhD
Supporting Agency – Queen Mary University of London

Bleeding is a major cause of death in severely injured patients. Many of these patients rapidly develop an abnormality of the clotting system, known as ‘acute traumatic coagulopathy’ (ATC). The two most important abnormalities in ATC are a low fibrinogen and increased clot breakdown. It has been hypothesized, and there are some non-randomized studies that show, that treatment of trauma patients who are bleeding with fibrinogen therapy stops bleeding more effectively than standard care, reduces transfusion needs and may reduce death rates. This study will look at the effects of transfusing early high dose cryoprecipitate (which is a concentrated source of fibrinogen), to adult trauma patients with severe bleeding within 90 minutes of admission to hospital. This study will evaluate whether early cryoprecipitate reduces death rates when major bleeding occurs after injury.

Postdoctoral Training Program in Trauma and Hemorrhagic Shock
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

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
PI – Charles Cox, MD
Co-Investigators – Erin Fox, PhD; Laura Moore, MD; Charles Wade, PhD
Supporting Agency –Medical Technology Enterprise Consortium (MTEC)

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.

  • Aim 1: Compare the incidence, severity and duration of acute kidney injury (AKI) in multiply injured, post-hemorrhage patients administered MultiStem with patients administered placebo.
  • Aim 2: Compare the incidence of inflammatory complications in multiply injured, post-hemorrhage patients administered MultiStem with patients administered placebo.
  • Aim 3: Compare all-cause mortality at 30 days in multiply injured, post-hemorrhage patients administered MultiStem with patients administered placebo.
  • Aim 4: Determine the inflammatory profiles associated with incidence of AKI, other inflammatory complications and mortality.
Microvascular Barrier Biomarkers to Predict ICP Therapeutic Intensity After Severe TBI
PI - Charles Cox, MD
Co-Investigators – Erin Fox, PhD; Charles Wade, PhD
Supporting Agency – US Army Medical Research & Material Command (W81XWH18SBAA1)

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.

  • Aim 1: Determine the time course of syndecan-1 release and colloid osmotic pressure (COP) in patients with severe TBI, and correlate this with pressure-time intracranial hypertension (ICH) exposure.
  • Aim 2: Test whether the degree of microvascular barrier disruption as quantified by initial or 24-hour peak endotheliopathy of trauma (EoT) results predicts the malignant intracranial pressure (ICP) phenotype.
Mesenchymal Stem Cells for Treatment of ARDS Following Trauma
Site PI – Laura Moore, MD
Co-Investigators – Charles Cox, MD; Erin Fox, PhD; Lillian Kao, MD; Charles Wade, PhD
Supporting Agency – Regents of the University of California-San Francisco
W81XWH-16-PRMRP-CTA – US Army Medical Research Acquisition Activity

Acute respiratory distress syndrome (ARDS) is a life-threatening medical condition in which the lung is injured or inflamed to the degree that it cannot properly exchange gases and oxygenate the body. ARDS can be caused by a variety of conditions including infections, trauma, severe blood loss, multiple or large volume blood transfusions, burns, and the inhalation of chemical poisons or smoke. According to the National Heart Lung and Blood Institute, approximately 190,000 people in the U.S. develop ARDS each year. Even with state-of-the-art supportive care with optimal, lung protective mechanical ventilation, the death rate from ARDS ranges from 25–40%, with higher rates seen in less technologically developed areas. Recent studies from the Department of Defense Iraq Trauma Registry (DoDTR) reported that ARDS developed in a large number of severely wounded warfighters and was associated with higher death rates. To date, there have been few advances in the treatment of major trauma related conditions such as ARDS. The development of new therapeutics that can limit the severity and/or progression of lung injuries that lead to ARDS and death is an immediate clinical need in both military and civilian sectors. The overall objective of this project is to carry out a randomized, double-blinded, placebo-controlled, multicenter phase 2b trial to test the therapeutic potential of allogeneic bone-marrow derived mesenchymal stromal cells (MSC) for treating ARDS in trauma patients.

  • Aim 1: Test the clinical efficacy of intravenously delivered allogenic human MSCs in trauma patients with ARDS.
  • Aim 2: Test the mechanisms by which MSCs reduce acute lung injury in trauma patients with ARDS.
A Prospective, Randomized, Controlled Trial on Pre-Hospital Use of Kcentra® in Trauma Patients with Hemorrhagic Shock
Site PI – David Meyer, MD
Co-Investigators – Erin Fox, PhD; Charles Wade, PhD
Supporting Agency – Oregon Health and Science University, funding provided by CSL Behring

Severe tissue trauma and shock results in the acute coagulopathy of trauma (ACT), a hypo coagulable state that exacerbates bleeding and increases the risk of death in trauma patients. ACT has been detected in the field prior to fluid resuscitation and it has been associated with a mortality approaching 50%. Aggressive fluid resuscitation with high chloride containing crystalloid solutions exacerbates ACT by inducing hypothermia, acidosis, fibrinogen dysfunction, and platelet dysfunction. These effects worsen bleeding increasing the risk of exsanguination, which is the leading cause of preventable death after trauma. However, alternative methods to resuscitate patients and correct coagulopathy early after trauma may improve outcomes. Recent work from the PROPPR trial showed that balanced resuscitation with transfusion of high ratios of plasma to RBCs results in improved early survival after trauma in patients requiring blood transfusions. In addition to its effects on correcting coagulopathy, plasma transfusion also reduces endothelial permeability to theoretically reduce the need for resuscitation, and the development of edema and organ failure.

While balanced blood product resuscitation is ideal, blood component therapy is not typically available in the prehospital setting on ground ambulances. Therefore, there is no current effective method to treat ACT in the field. What is needed is a low volume, readily available resuscitative adjunct that can be safely stored on all ambulances, and rapidly administered to correct coagulopathy and endothelial leak in severely hemorrhaging trauma patients. Stabilization of endothelial leak in trauma patients would theoretically reduce the need for resuscitation by decreasing third spacing and reduce the incidence of multiple organ failure.

Comparison of Surgery and Medicine on the Impact of Diverticulitis (COSMID Trial)
Site PI – Lillian Kao, MD
Supporting Agency – University of Washington

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.

  • Aim 1: Compare patient-reported outcomes (e.g., quality of life, work productivity, decisional regret) in patients with QoL-limiting diverticulitis randomized to elective colectomy vs. best medical management.
  • Aim 2: Compare clinical outcomes (e.g., rates of serious adverse events, number of subsequent episodes of diverticulitis) between patients with QoL-limiting diverticulitis randomized to elective colectomy vs. best medical management.
  • Aim 3: Compare healthcare utilization between patients with QoL-limiting diverticulitis randomized to elective colectomy vs. best medical management.
Treatment Individualized Appendicitis Decision Making Implementation Program – TRIAD
PI – Lillian Kao, MD
Supporting Agency – University of Washington

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
PI – Krislynn Mueck, MD
Supporting Agency – Surgical Infection Society

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.

  • Aim 1: To determine if there is an association between patient HL and prevalence, time to diagnosis, and severity of infectious complications.
  • Aim 2: To explore how HL affects infectious outcomes after surgery.
  • Aim 3: To design and pilot an intervention tailored to low HL patients to improve their post-operative surveillance for and prevention of infectious complications.
Antithrombin to Improve Thromboprophylaxis and Reduce the Incidence of Trauma-Related Venous Thromboembolism (TRAIT) RCT
PI – Bryan Cotton, MD
Co-Investigator – Erin Fox, PhD; Charles Wade, PhD; David Meyer, MD
Supporting Agency – Grifols Shared Services North American, Inc.

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.

  • Aim 1: Determine the efficacy of Thrombate administration for reducing the 14-day VTE incidence among severely injured trauma patients.
  • Aim 2: Determine the efficacy of Thrombate administration for improving responsiveness to enoxaparin and reducing time to achieve a target anti-FXa among severely injured trauma patients.
  • Aim 3: Assess the incidence of other thrombotic complications, bleeding events and evaluate lengths of hospital stay, antithrombin activity levels, endothelial markers and inflammatory markers between randomization arms.
Prothrombin Complex Concentrate (Human) for Treatment of Traumatic Injury and Acute Major Bleeding: TAP Trial
PI – David Meyer, MD
Supporting Agency – CSL Behring

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. 

  • Aim 1: To assess all-cause in-hospital mortality at hospital discharge or up to 24 hours after the start of the IP infusion
  • Aim 2: To assess all-cause in-hospital mortality at hospital discharge or up to 30 days after the start of the IP infusion
  • Aim 3: To assess the requirement for surgical or interventional radiological procedures to stop hemorrhage
  • Aim 4: To assess the safety of BE1116
Vitamin C in Thermal injury: The VICToRY Trial
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
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.

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.

  • Aim 1a. Quantify release of FDPs in patients with TBI+/-HS and correlate with transfusions and clinical outcomes
  • Aim 1b. Define the impact and critical dose thresholds of FDPs for inducing hyperpermeability using an in vitro BBB model
  • Aim 1c. Examine EC signaling events induced by FDP exposure that result in endothelial activation and hyperpermeability
  • Aim 1d. Identify novel therapeutic targets to limit FDP-endothelial interactions
  • Aim 1e. Determine the effectiveness of inhibiting FDP release and/or FDP-EC interactions on BBB disruption
  • Aim 2a. Determine the influence of increasing injury severity/complexity on BBB permeability
  • Aim 2b. Characterize the fibrinolytic phenotype that worsens TBI via the PAR1-MMP-9-SUR1-TRPM4 signaling axis
  • Aim 2c. Determine the contribution of upregulation and/or SUR1-TRPM4 channel activation mechanisms to HS amplification of BBB permeability
  • Aim 3b. Determine the relative contribution of metabolic crisis vs. mRNA degradation as the etiology of platelet contractile dysfunction
  • Aim 3c. Investigation of GPVI-fibrin interface in platelet dysfunction and hyperfibrinolysis
  • Aim 4a. Determine the relationship between changes in extent and subtype of CE (acutely with CT and subacutely with MRI) with quantitative assays of blood-based concentrations of FDPs and potential biomarkers of CE
  • Aim 4b. Determine the relationship between quantitative measures of BBB permeability (Ktrans; 3T DCE-MRI) with blood-based concentrations of SUR1, TRPM4, AQP4, and FDPs
  • Aim 4c. Determine the relationship between quantitative BBB permeability measures and volume of vasogenic CE
Dronabinol on the Pain Experience (DOPE): a pragmatic, randomized clinical trial
PI – Krislynn Mueck, MD
Co-Investigator – John Harvin, MD
Supporting Agency – Eastern Association for the Surgery of Trauma (EAST)

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.

  • Aim 1: To perform a randomized comparative effectiveness trial to identify the effect dronabinol has on opioid exposure when used as an adjunct to our current institutional MMPR.
  • Aim 2: To examine the effect dronabinol has on opioid exposure when used as an adjunct to our current institutional MMPR in known high risks groups such as patients with a positive urine drug screen.
Freeze Dried Mechanotransduced MSC Derived Exosomes for Neurological Injury
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.
  • Aim 1: Determine dose response using a high-throughput blood-brain barrier (BBB) apparatus and correlate with an established activated splenocyte suppression assay, which has been predictive of in vivo potency in TBI.
    • Subaim 1a: Compare potency in BBB apparatus of reanimated freeze-dried EVs vs. fresh EVs.
  • Aim 2: Determine the therapeutic window of intravenously infused EVs in an established rodent model of controlled cortical impact of TBI. Three established read-outs will be examined: (a) BBB permeability, (b) microglial activation state, and (c) functional assessment of spatial-temporal memory using the Morris water maze.
Identifying SUR1/TRPM4 Polymorphisms to Reduce Contusion Expansion after Traumatic Brain Injury: Clinical Trial Planning Grant
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.
  • Aim 1: Technology transfer and validation of SNP assays (single rs8104571) and multiplexed assay (ABCC8: rs2237982, rs2283261, rs8192695, rs3819521; TRPM4: rs370666, rs1477363, rs10410857, rs909010).
  • Aim 2: Harmonize imaging protocols with site training and validation. Two main imaging modalities will require harmonization: (1) non-contrast Computed Tomography (NCCT) to assess lesion volume and cerebral edema scoring according to methods of Kothuri et al8 and Lietke et al 9 and (2) DT-MRI.
  • Aim 3: Finalize material transfer agreement (MTA) for intravenous (IV) glibenclamide (or develop oral protocol as performed in China [NCT05148403]) and investigative pharmacy planning for administration and monitoring.
  • Aim 4: Develop Manual of Operations/finalize Clinical Trial Protocol in conjunction with Remedy, Pharmaceuticals or alone if using oral dosing.
  • Aim 5: Hold pre-IND meeting with FDA early in process if using oral dosing or EOP2 meeting if using IV dosing in conjunction with Remedy.
Hemodynamic Management Following Acute Traumatic Spinal Cord Injury: A Pilot Randomized, Controlled Trial
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).
  • Aim 1: Prospectively determine functional neurologic outcomes in patients with acute SCI treated with MAP ≥85 mmHg or SCPP ≥65 mmHg compared to normal hemodynamics (MAP ≥65 mmHg).
  • Aim 2: Determine the effect of MAP or SCPP goal on non-neurologic adverse events following SCI.
  • Aim 3: Study the differences in structural and inflammatory CSF biomarkers between the three groups and correlate with functional outcomes.
Pediatric Prospective Observational Vascular Injury Trial (Pedi PROOVIT)
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.
  • Aim 1: Identify practice patterns in diagnosis, management, surveillance, and outcomes of pediatric vascular injuries.
  • Aim 2: Integrate the existing PROOVIT database with our pediatric database.
  • Aim 3: Using biomedical informatics and database integration, identify areas related to vascular injuries where improved training and education may be helpful, especially in underequipped environments, such as rural environments and combat zones.
An Assessment of Green Plasma: The Potential Hemostatic Superiority of a Currently Discarded Blood Product
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.
  • Aim 1: Identify the prevalence of green plasma in the current donor pool at a large, regional blood center, and quantify the “green-ness” of these units of plasma through spectrophotometry.
  • Aim 2: Determine hemostatic potential of green plasma compared to conventional plasma.
Assessment of the Relationship between Statins, Microvascular Dysregulation, and Venous Thromboembolism in Severely Injured Trauma Patients
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.
  • Aim 1: Evaluate the relationship between statin use and venous thromboembolism (VTE) after trauma in a prospective, observational study.
  • Aim 2: Investigate potential mechanisms for statin-mediated VTE attenuation in a prospective, observational biomarker analysis of injured patients.
  • Aim 3: Identify barriers to adoption of a multimodal VTE prevention strategy using a mixed-method approach at diverse Texas trauma centers.
Project TRUST – Trauma Recovery Using Support from Trauma-Informed-Care Approach
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
PI – John Harvin, MD
Supporting Agency – TRC4 – Trauma Research & Combat Casualty Care Collaborative
  • Aim 1: To demonstrate that our short-wave assessment tool (SWATT) with machine learning (ML) more accurately predicts tissue viability in human burn patients with greater accuracy than SWATT without machine learning.
  • Aim 2: To enhance multispectral SWATT for real-time mapping of different burn depths and a heat map of the depths’ classification for instant guidance.
A Video Conversation Aid to Improve Shared Decision-Making for Life-Sustaining Care after Injury in Older Adults
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.
  • Aim 1: Perform baseline assessment of discussions utilized to establish goals for life-sustaining care in older adults admitted after injury
  • Aim 2: Utilize a multidisciplinary team to create an educational code status primer video targeting injured older adults and their surrogates
  • Aim 3: Determine the factors that influence intervention-related healthcare preferences and the effect of a video-based conversation aid