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.

Site PI – Bryan Cotton, MD

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.

Site PI – Bryan Cotton, MD

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.

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.

PI – Charles Cox, MD

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.

PI - Charles Cox, MD

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.

Site PI – Laura Moore, MD

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.

Site PI – David Meyer, MD

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.

PI – Charles Wade, PhD

Supporting Agency – Athersys, Inc.

In the study, we propose to use a fixed pressure hemorrhage rat model to determine if human MultiStem cells from Athersys, will attenuate acute kidney injury. We hypothesize administration of MultiStem cells, after reperfusion following severe hypotensive hemorrhage, will improve kidney function, decrease renal stress, attenuate the systemic inflammatory response, and decrease kidney damage as determined by histological, immunohistology and immunohistochemistry. This project will utilize the well-described rat model of pressure driven hemorrhagic shock (HS).

Site PI – Jessica Cardenas, PhD

Supporting Agency – US Army Medical Research Acquisition Activity

FY20 PRMRP/Investigator-Initiated Research Award-Partnering PI Option (W81XWH-20-PRMRP-IIRA)

Early administration of platelets is highly efficacious for promoting hemostasis and improving survival in severely injured patients. Unfortunately, limitations to shelf stability, shelf-life, and storage lesions preclude the widespread use of platelets for hemorrhage control in austere environments. Our work strongly suggests platelet-derived extracellular vesicles (PEVs) could be used as an alternative to platelets, as they can withstand freeze-thawing and lyophilization for rapid reconstitution and administration to a bleeding soldier. Importantly, our published data show that PEVs are highly pro-hemostatic and when given early, can prevent the development of hemorrhagic shock (HS). Further, we found that PEVs improve endothelial function and could therefore reduce the likelihood that a patient develops multiple organ dysfunction (MOD). Thus, PEVs are an ideal product for prolonged field care scenarios to stabilize patients until a medical treatment facility is reached and definitive hemorrhage control is achieved.

• Aim 1: Determine the efficacy of PEVs in supporting hemostasis and improving short-term outcomes following trauma and hemorrhage.
• Aim 2: Determine the effects of PEVs on endothelial function.
• Aim 3: Evaluate the efficacy of PEVs on long-term survival and hemorrhagic shock induced multiple organ dysfunction.

PI – Jessica Cardenas, PhD

Supporting Agency – National Institute of General Medical Sciences

R35 Maximizing Investigators’ Research Award (MIRA) for Early-Stage Investigators

Complications that arise secondary to an exaggerated innate immune response, such as multiple organ failure, are a major cause of late-stage mortality in trauma patients. The overall goal is to initiate an innovative and translational research program focused on elucidating mechanisms through which the vascular endothelium regulates the host inflammatory response to severe trauma. In particular, the research is focused on the immunomodulatory functions of the antithrombin (AT)-heparan sulfate system. AT elicits anti-inflammatory signaling upon binding to specific heparan sulfate proteoglycan (HSPG) receptors on the endothelial surface that contain a 3-O-sulfate (3-OS) modification. Our ongoing experiments demonstrate that dysregulation of the AT-HSPG system is a novel mechanism driving inflammation and organ injury following severe trauma and hemorrhagic shock. However, the mechanisms that govern 3-OS HSPG expression and AT binding following trauma is a major knowledge gap in the field. Understanding these mechanisms will enable us to develop novel clinical tools to attenuate aberrant inflammation following trauma and treat or prevent subsequent organ failure. The next 5 years of the research program will focus on 3 developing programmatic areas that seek to elucidate 1) mechanisms that mediate 3-OS HSPG degradation; 2) mechanisms that regulate 3-OS HSPG biosynthesis; and 3) the biological role and therapeutic potential of unique AT variants capable of regulating inflammation when 3-OS HSPG expression is reduced. Results of these investigations have broad-reaching implications for many conditions in which inflammation contributes to the pathogenesis, such as sepsis, transplantation, and COVID-19.

• Goal 1: Increase our basic understanding of how endothelial cells regulate inflammation.
• Goal 2: Define mechanisms occurring during endothelial dysfunction that drive organ injury.
• Goal 3: Identify novel therapeutic tools that limit post-injury organ damage and improve trauma patient survival.

PI – Jessica Cardenas, PhD & Bryan Cotton, 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 re-define VTE prophylaxis protocols for trauma patients and have a significant impact of the burden of VTE in this population.

• 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.

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.