Combat Casualty Care Research Program (CCCRP)
The mission of the Combat Casualty Care Research Program is to reduce the mortality and morbidity resulting from injuries on the battlefield through the development of new life-saving strategies, new surgical techniques, biological and mechanical products, and the timely use of remote physiological monitoring.
Background and Environment
Soldiers face many threats in hostile fire arenas, whether conducting large-scale mechanized warfare, low-intensity conflicts, or operations other than war. Military casualties may wait for hours before definitive health care can be provided. Furthermore, initial treatment and subsequent evacuation occur in austere environments characterized by limited supplies and limited diagnostic and life-support equipment; and provision of acute and critical care is labor intensive and must frequently be provided by non-physician medical personnel. The primary challenge for combat casualty care research is to overcome these limitations by providing biologics, pharmaceuticals, and devices that enhance the capability of first responders to effectively treat casualties as close to the geographic location and time of injury as possible.
Combat casualty care is constrained by logistics, manpower, and the hostile operational environment. Since mid-World War II, nearly 50 percent of combat deaths have been due to exsanguinating hemorrhage. Of those, about half could have been saved if timely, appropriate care had been available. Head injuries and lung injuries are also major causes of death where proper treatments and training could significantly reduce mortality and morbidity. The treatment of battlefield casualties is exacerbated by the long evacuation times often found in military operations. This requires battlefield medics and physician's assistants to stabilize patients for extended periods and makes battlefield trauma care markedly different from civilian trauma care. Because approximately 86 percent of all battlefield deaths occur within the first 30 minutes after wounding, the ability to rapidly locate, diagnose, and render appropriate initial treatments are vital to reversing the historical outcomes of battlefield injuries. The need to provide such care with a reduced logistics footprint is the cornerstone around which the future of combat casualty care research is built.
Goals and Objectives
The CCCRP is focused on leveraging cutting-edge research and knowledge from government and civilian research programs to fill existing and emerging gaps in combat casualty care. This focus provides requirements-driven combat casualty care medical solutions and products for injured soldiers from self-aid through definitive care, across the full spectrum of military operations. We share this mission of developing improved treatment for service members injured in combat with other organizations in the MRDC and thus focus our efforts in ten major areas of emphasis.
Key Themes and Messages
Damage Control Resuscitation (DCR)
Hemorrhage remains the major cause of potentially preventable death on the battlefield in conventional warfare. This fact has led to significant efforts to improve the ability of soldiers to limit blood loss and treat hemorrhage at the point of injury. As a result of improved initial care, as well as rapid evacuation and positioning of surgical capabilities close to the point of injury, service members with severe injuries survive to reach field hospitals. This results in lower overall mortality by reducing the Killed in Action rate, but paradoxically, yields an increase in the Died of Wounds rate. Reducing this rate is the current focus of much of the research in Damage Control Resuscitation. It is known that severely injured casualties may develop metabolic disorders characterized by acidosis, hypothermia and coagulopathy, which are often termed "the lethal triad." This set of disorders is addressed by avoiding dilution of coagulation factors via replacement of appropriate blood products (e.g., plasma) to provide these factors, providing oxygen carrying capability (Red Blood Cells), and restoring sufficient circulating volume to restore tissue perfusion and correct metabolism. The U.S. military has implemented a change from early resuscitation using crystalloid and packed red cells to early resuscitation using equal ratios of packed red cells, plasma, and platelets.
The majority of battlefield wounds occur to the extremities (55%) and head/neck region (30%). In the extremities, the wounds are predominantly penetrating soft tissue wounds and open fractures. Infection, delayed/nonunion of bone, and impaired/loss of muscle function are common outcomes. The Extremity Trauma and Regenerative Medicine team is addressing these problems several different ways with the goal of returning the injured Warrior to full function.
First, injuries and their clinical outcomes are being defined. Until recently, there was not a good understanding of the injuries sustained by our Soldiers in ongoing conflicts. To help direct research efforts, retrospective studies are conducted to determine the incidence, rate, and qualitative outcomes of extremity injuries in the Iraq and Afghanistan conflicts.
Second, pre-clinical studies are conducted to determine which therapies have the greatest clinical potential. Various animal models that mimic traumatic injury are utilized to evaluate potential therapies for infection and soft tissue and bone injury. We strive to evaluate the most advanced and promising technologies using the most clinically relevant and stringent animal models possible.
Third, we conduct prospective clinical trials aimed at improving outcomes of extremity wounds.
Finally, we are actively involved in extramural research programs focused on repair of extremity injuries.
Pain, both acute and chronic, is recognized as a leading problem among US soldiers injured on active duty or during deployments. Pain is experienced throughout the continuum of trauma care and within all ranks of the military. Recent initiatives track pain scores from as early as time of admission to the Emergency Department (ED) at Level 2 and Level 3 facilities. Preliminary results indicate that, of soldiers admitted to Level 2 and Level 3 facilities, 71% experience pain of 5 or greater on a scale of 0 to 10. Accepted clinical guidelines classify pain of 5 or greater as severe pain and recommend treating pain rated as 4 or greater. Treatment of acute pain is particularly important because recent evidence suggests that uncontrolled acute pain leads to neuronal remodeling and increased incidence of chronic pain.
The over-arching focus of this research area is the study of pain from the battlefield through recovery. Particular attention is paid to identifying novel pain control techniques (including novel pain control targets) and molecular mechanisms in the pain pathway. While the recognition of pain as a disease process rather than a symptom has shed light onto the important role of pain, a more comprehensive understanding of pain has yet to be achieved. Major hurdles include the unreliability of medical records when collected from austere environments with inherently limited access and availability, and the lack of a consensus concerning the best tools to use for validating pain research.
Although significant advancements have been made in the care of acute pain, we are just beginning to realize the far-reaching impacts of suboptimal pain management on health processes; these include inflammation, immunosuppression, longer hospital stays with slower recovery times, less effective physical rehabilitation, neuropsychological pathology, and poor quality of life. As leaders in the management and research into pain control, military pain specialists have established themselves as indispensable members of the combat casualty team and the soldier's primary advocate in the treatment of pain.
Advanced Capabilities for Emergency Medical Monitoring
The objective of the Advanced Capabilities for Emergency Medical Monitoring program is to conduct basic and applied research that leads to the identification and integration of physiological measures that reflect the complexity of compensatory responses by the body during the early dynamic phase(s) of hemorrhage. The goal is to apply this knowledge to the development of new technologies and devices that advance the medical monitoring capabilities of combat medical personnel for triage, diagnosis and decision-making to improve the management of combat casualties. An important research tool is a research effort focused on investigating the time course of central hemodynamics, autonomic functions, and peripheral tissue metabolism during progressive reductions in central blood volume induced by lower body negative pressure in healthy human subjects. Basic research efforts are also used to investigate and describe the physiological signals that distinguish patients with low tolerance (non-responders) to reductions in blood volume from those with high tolerance. Evolving technologies are applied to assess physiological performance to reduction in blood volume. These include measures of early and continuous alterations in central hemodynamics, autonomic functions and tissue perfusion including bioimpedance, real time measures of cardiac beat-to-beat (R-R interval) performance and waveform analysis of arterial blood pressure for stroke volume estimates and pressure oscillations, direct measurement of sympathetic nerve activity, linear and non-linear frequency analysis of R-R interval captured from a standard ECG (heart rate variability indices to assess autonomic oscillations; heart rate complexity indices), and near infrared spectroscopy (muscle oxygenation, pH, lactate). Loss of the normal relationship between the circulatory system and nervous system sympathetic activity is investigated as a potential mechanism of the poor blood pressure/tissue perfusion that occurs during progressive reductions in central blood volume. The impact of other combat-related stressors such as heat, cold, exercise and anxiety on physiological measures associated with monitoring patients with hemorrhage are investigated.
Combat Casualty Care Engineering
Combat Casualty Care Engineering (C3E) is directed at improving care by responding to a gap in critical care technology on the current battlefield, particularly at echelons 2 and higher and en route. In general, as a casualty moves to higher echelons of care, the resources available increase and care approaches, but doesn't reach, the standards of a civilian or military hospital in the continental U.S. This gap between the highest standard of care and that available at earlier echelons (and the even larger gap that exists as casualties are moved between facilities) is the target of research and development efforts in C3E.
The potential impact of improvements in critical care capabilities on mortality and on resource utilization was suggested by a study that showed both Intensive Care Unit (ICU) length of stay and mortality progressively decreased at the Combat Support Hospital in Baghdad as the resources for care improved from No Intensivist, to Intensivist Consult, to Intensivist-Directed Team. However, appropriately trained personnel are often not available. The goal of C3E is to develop new systems-based technology which includes hardware and software systems which incorporate sensors, processors, and effectors to help close this care gap. Because of the heavy emphasis on trauma patient validation and rapid product delivery to the battlefield, the focus of C3E is on clinical trials in trauma and burn patients, and on product testing in clinically relevant models of severe injury where appropriate.
C3E works at the interface between knowledge and devices. Examples include:
- Current vital signs used to diagnose and treat trauma patients do not provide an accurate assessment of the true injury severity and are only useful after patient has physiologically unstable. Advanced vital signs will be developed through research into new approaches for processing current vital signs, research on data fusion and multivariate analysis approaches for processing combinations or groups of different vital signs simultaneously, and the use of artificial intelligence technologies for learning vital sign patterns that can be used for prediction and diagnosis of the physiologic state of a casualty.
- The development of new approaches that use information technology to help the care provider port large volumes of data generated by the patient care environment into decision support systems, open-loop systems, and, eventually, fully automated control of critical care processes.
- Research into better effectors focused on ventilator systems for support of patients in austere environments. In particular, development of simplified ventilators that can be used in patients with severe traumatic brain injury, acute respiratory distress syndrome, smoke inhalation injury, pulmonary contusions, and/or massive transfusion.
The CCCRP Clinical Trials program is centered at the US Army Institute of Surgical Research (USAISR). The USAISR is unique within the Medical Research and Development Command because both patients and research scientists are present within the same Institute. This collaborative, integrated environment provides an opportunity to translate science into improvements in combat casualty care and deliver these improvements to the battlefield. The clinical trials program has two primary objectives. The first is to observe current combat casualties to identify emergent challenges and opportunities for improved care. The USAISR serves as the only American Burn Association verified burn center in the Department of Defense. Consequently, the USAISR receives all significant burn injured service members evacuated from the wars in Iraq and Afghanistan. As a result, we have the opportunity to observe patterns of injury and implement programs in order to prevent and better treat these burns. Examples of our findings include identification of significant numbers of waste burning accidents and implementation of an awareness program, identification of large numbers of debilitating hand burns and implementation of a rapid equipping program for fire resistant gloves, identification of thermal injury to the portions of the torso not covered by body armor and development of improved protective clothing, and identification of over resuscitation injury and implementation of a burn resuscitation flow sheet to ensure appropriate care. The second objective is to translate pre-clinical research from the other research areas at the Institute into a clinical environment for validation. Examples of this type of translational effort include testing of wound care dressings in donor sites, and assessment of damage control resuscitation strategies in the burn operating room.
The USAISR Clinical Research program prides itself on being responsive to clinical problems and striving for excellence in burn care, critical care medicine, and the care of the multiply injured casualty. Critical advances in burn care and trauma care developed and tested at the USAISR have significantly improved patient survival and outcomes in combat casualties.
The United States Army Dental and Trauma Research Detachment (USADTRD) is the largest military dental research organization in the Department of Defense and it is the only military research facility dedicated to the study of injuries to the craniomaxillofacial (CMF) complex. Use of improvised explosive devices in Iraq and Afghanistan and the capability of body armor to decrease fatal torso injuries have resulted in new wounding patterns among survivors that includes ruinously destructive CMF trauma and burns. Wounds to the CMF are usually associated with a poor prognosis because restoration of the specialized structures and cosmetics are significantly challenging and impact functional outcomes, sense of self and social re-integration. The USADTRD's research foci is established around three research areas; a) development of composite tissues for grafting and implantation, b) ameliorating the effects of host healing processes and infection on trauma and burn wound repair, and c) restoration of damaged or replacement of missing CMF tissues and structures.
Craniomaxillofacial Research at the USADTRD at USAISR will emphasize 3 challenges:
Recent efforts in blood products research have centered on finding suitable replacement compounds for use in blood component therapy. That is, when fresh whole blood is not available, various components of blood (plasma, platelets, red blood cells, etc.) are administered. Various methods to prepare such components including drying and freezing components are being investigated. However, a requirement to identify and treat the underlying causes of the lack of effective coagulation in severely injured patients has become apparent. Current efforts to address the "coagulopathy of trauma" are largely focused on attempting to improve outcomes using treatment regimens that incorporate available products in different ways, for example, more aggressive use of plasma transfusion, earlier correction of pH, etc. These efforts provide incremental advances in care but are necessarily limited by the existing products and knowledge. Major advances in patient care will require new products and knowledge. Development of new diagnostics, therapeutic targets and drug candidates requires a more in-depth knowledge of underlying mechanisms. This work is closely coordinated with the studies undertaken in the Damage Control Resuscitation area. Research encompasses in vitro systems, animal models, and clinical studies to:
- elucidate mechanisms relevant to coagulopathy,
- to relate changes observed in blood with patient outcomes, and
- to investigate potential diagnostic and therapeutic approaches.
An emphasis is that data collected is suitable for data integration and modeling efforts, such as systems biology or other modeling approaches. Modeling efforts are incorporated into the research program to augment the coordinated bench, animal and clinical research efforts.
Traumatic Brain Injury
Traumatic Brain Injury (TBI) is a collective term used for multiple different physiological states that are consequences of physical damage to the brain. Within the Combat Casualty Care Research Program, there are two major subdivisions which study very different forms of TBI. One group (Neuroprotection) focuses on penetrating brain injury, damage to the brain caused by shrapnel, bullets, or other projectiles passing through the skull and physically lodging in or passing through the brain matter. The other (Neurological Effects of Blast) studies the effects of acute exposure to blast waves, or "blast overpressure," on the brain. The goal of each is to increase understanding of the etiology of TBIs, in order to develop new treatments and to arrive at evidence-based solutions. Both of these areas have benefitted from substantial amounts of supplemental funding in the recent past.
- The Neuroprotection subdivision seeks solutions for penetrating ballistic-type TBI and is focused on the discovery/development of novel therapeutics (drugs, stem cells, and brain hypothermia), diagnostics, and doctrine to mitigate the morbidity caused by TBI.
- The aim of the Neurological Effects of Blast effort is the development and utilization of pre-clinical animal models of blast-induced TBI that recreate the hallmarks of this injury as sustained by the warfighter. The knowledge from this effort will be used to establish mitigation strategies (preventive and post-injury therapeutics and treatment guidelines) to decrease the incidence of significant functional impairment and increase the rate of return to duty after blast exposure. The focus is on battlefield interventions because it is predicted that pre-injury or early post-injury therapies will have the greatest impact on outcome.
Questions and Answers
What is Damage Control Resuscitation?
It was developed as a structured intervention aimed to treat the approximately 8-10% of casualties who are the most severely injured, are coagulopathic, and are at the greatest risk of dying. DCR combines research efforts in hemostasis and resuscitation to evaluate hemostatic dressings and to investigate optimal resuscitation strategies.
What are some examples of Damage Control Resuscitation research?
Accomplishments of this program include the fielding of safe and effective tourniquets and two generations of improved hemostatic dressings. All three of these efforts were designated "Army Greatest Inventions" as was the concept of DCR.
Studies of severely injured patients have identified a population that appears to become hypocoagulable in response to trauma (as opposed to iatrogenic injury). This phenomenon, termed the Acute Coagulopathy of Trauma (ACOT) is under investigation to determine its incidence, causes and potential treatments. Current research efforts attempt to refine this practice, optimize the use of blood products, and avoid delivering blood products to those that do not require this type of intervention. Other research efforts focus on identifying better means to treat non-compressible hemorrhage as well as investigate genetic, genomic, and immunological responses to trauma/hemorrhage and finding improved means to reduce hypothermia. Using relevant animal models and studies in human trauma patients, the ultimate goal is to develop products for resuscitation and hemorrhage control that can be used at all echelons of care to improve survival and reduce morbidity in injured Soldiers.
How large a problem are extremity injuries?
A published study shows that 1,566 soldiers sustained 6,609 combat wounds with 3,575 of the wounds to the extremities (82% of the soldiers had at least one extremity wound). Based on the conclusion that for every injured soldiers there are 2.3 extremity wounds, the total number of extremity wounds in OIF/OEF to date exceeds 33,000.
What are some examples of extremity trauma research?
Currently, we are studying and evaluating a database of over 200 type 3 open tibia fractures to determine what causes poor clinical outcomes (e.g., concomitant soft tissue loss, nerve defects, infection, type of fixation, etc.). We have also determined that skeletal muscle injury is the main reason for limited functional recovery and are now directing resources to solve this problem. Perhaps most importantly, the Military Orthopaedic Trauma Registry (MOTR) was created. Currently, the Joint Theater Trauma Registry does not collect the information that is needed to understand the severity of the extremity wounds, how they are treated, or their outcomes. MOTR will have these needed data elements.
Clinical practice guidelines for irrigation of contaminated wounds have been created from studies that we conducted in animals. Other notable efforts include developing animal models for compartment syndrome, massive contaminated defects, and large segmental muscle loss. The concept of a dual-purpose bone implant (promotes regeneration and prevents infection) was developed and is being evaluated. The Brooke Army Medical Center Department of Orthopedics has initiated several clinical trials in the areas of combat casualty care and several more are planned in the near future.
The Combat Casualty Care Research Program (CCCRP) oversees a multi-center clinical trials consortium known as the Orthopaedic Extremity Trauma Research Program (OETRP). The OETRP focuses on improving outcomes of extremity injuries within the next 5 years. This is accomplished by funding translational research projects that evaluate new and emerging therapies and by conducting clinical trials to evaluate current standards of care and available treatments. In addition, the CCCRP provides technical oversight to more than 20 large research contracts with universities and companies engaged in extremity trauma research. These relationships are used to advance scientific inquiry in the areas of soft tissue and bone injury, infection, and tissue regeneration.
What are some examples of pain research?
Current research projects include studies which examine the effects of anesthetic agents on short-term outcomes such as resuscitation requirements and optimal transfusion ratios. Long-term outcomes such as Post Traumatic Stress Disorder (PTSD), patient satisfaction (health care related quality of life), opioid addiction/tolerance, and chronic pain are also being studied. In a retrospective study, anesthetic ketamine was not associated with an increased prevalence of PTSD and was correlated with decreased PTSD development in burned soldiers. Later work showed that the beta-adrenergic receptor blocking agent propranolol was not associated with a decrease in PTSD development in burned soldiers despite its effects on memory and occasional off-label use as a PTSD prophylactic.
What are some examples of emergency monitoring research?
Research includes studies designed to test and develop new 'wear-and-forget' Physiological Status Monitors (PSM) that enhance far forward capabilities for remote triage, diagnosis, and decision-making relative to casualty management. We are investigating the applicability of information that from the electrocardiogram and other sensor signals of the PSM to specifically track reduction in central blood volume resulting from hemorrhage, and further define the practical requirements (i.e., computing power, heart beats required, etc.) for their potential use on the battlefield. We also investigate technologies using light sources for the development of standoff triage. Emphasis is placed on developing a machine-learning algorithm that will provide early indication of severity of hemorrhage and subsequent need for prioritization of treatment or evacuation.
We are conducting research designed to develop and test new portable medical monitors that can be used by combat medical personnel during en route care and at higher echelons (e.g., Emergency Room). Current studies focus on identifying devices for vital sign monitoring, diagnostics and therapeutics for remote and on-scene assessment of the severity of hemorrhage and early prediction of onset of hemodynamic decompensation and progression toward the development of overt hemorrhagic shock . Technologies under consideration to meet these needs include infrared photoplethysmography, near-infrared spectroscopy, diffuse optical spectroscopy, and inspiratory resistance. The ultimate goal is to integrate these measurements using machine-learning techniques to develop a predictive, personalized algorithm for triage. In addition to the emphasis placed on personalized prediction of impending hemorrhagic shock, we will use our experimental human algorithm for predicting central blood volume changes to focus on the development of software algorithms and systems to provide a capability to track, and subsequently guide, resuscitation efforts.
What is combat critical care engineering?
Combat critical care engineering can best be described as the use of technology (hardware and software systems) to help those caring for critically injured casualties. This technology must be applied from prehospital thru ICU. The focus is on addressing the technology gap in critical care medicine between in-theater facilities and those in the US.
What are some examples of combat critical care engineering research?
New vital signs to provide personnel with more sensitive and specific indicators of the true extent of trauma injuries, in addition to providing more precise diagnosis at earlier stages of care. These new vital signs will allow for better and earlier diagnosis of impending cardiovascular collapse and will provide personnel with a more accurate indicator of the need for a life saving intervention. Part of this research involves the use of high performance computing approaches for the extraction of informative features from high frequency and high resolution waveform data digitized from different body sensors (i.e. EKG). Additionally, advanced information and computer processing approaches will be used to develop systems that can process and implement these new vital signs in smaller and lighter monitoring systems that can be carried by medics in the battlefield. To further automate critical care procedures, open loop systems will also be developed that will provider personnel with recommendations on treatment options in addition to providing the ability to execute the intervention automatically. Finally, closed loop control systems will be developed to fully automate the care of the patient with little or no intervention from the provider. Development of extracorporeal devices will be explored with capabilities to augment and/or replace mechanical ventilation requirements for patients with severe ARDS.
What are some examples of clinical trials research?
Clinical research in injured casualties is being conducted on a variety of combat-related medical issues. Research includes resuscitation protocols and stabilization in local and far forward care, clothing issues and protection from injury, continuous renal replacement therapy, antibiotic use, wound excision and closure techniques, diagnosis and treatment of head injury including blast injury, pharmacokinetics of antibiotics in the severely injured, topical wound treatments including silver products and vacuum assisted wound closure, wound healing of the skin donor site, hemorrhage control in the burn OR, nutrition during ICU stay and during outpatient recuperation, temperature control in the burned patient, hypotension control strategies, and heterotopic ossification in the severely burned.
What are some examples of craniomaxillofacial research?
Research to provide regenerated or genetically engineered tissue constructs to replace damaged or destroyed face features through accelerated pre-clinical and clinical trials, development of biological therapies combining tissue engineering and stem cell technologies to generate craniofacial structures at the USADTRD, and accelerated research in collaboration with other institutions to leverage their resources to build our research portfolio on craniomaxillofacial regenerative medicine. The deliverables will be a combination of a scientific process and products such as angiogenic and/or osteogenic scaffolds, tissue-specific stem (progenitor) cells capable of local repair and regeneration, vascularized soft tissue constructs conducive to the restoration of facial defects, and bioactive bone construct to repair and regenerate facial bones.
Additional research is ongoing into algorithms to understand biofilm pathophysiology and test therapeutic agents useful to treat not only dental plaque but biofilms which complicate healing of combat wounds. The deliverables will be FDA approved anti-biofilm agents in the form of a wound gel consisting of antimicrobials which exhibit low propensity to induce microbial resistance and biofilm dispersing agents. In addition, the research will produce evidence-based treatment modalities to improve the outcome of infected combat wounds. This treatment information will focus on being readily transferred into clinical testing.
Planned research includes development of a biological therapy comprised of cells (e.g., mixed-population of progenitor cell types), matrix, growth factors, and other small molecules (e.g., Transformation Growth Factor-β antagonist). The intent of this biotherapeutic is to accelerate healing and reduce scarring by attenuating the inflammatory response and by the recruitment of resident stem or progenitors cells and their secreted signaling molecules to the injured site. It is now well-known that mesenchymal stem or progenitor cells have the ability to modulate the inflammatory response. The deliverables include the identification of the most efficacious progenitor cell types, growth factors, and small molecules to improve healing and scarring using the rabbit scar model. These steps will provide information needed to achieve the next stage in the development of biological therapies to improve disabling scarring and tissue regeneration therapeutics in the oro-facial region.
What are some examples of potential replacement blood products?
Here is a list of a number of products being studied for use in humans provided they gain Food and Drug Administration approval:
- Freeze Dried Plasma
- Platelet Derived hemostatic Agents
- Cyropreserved Platelets
- Freeze dried Platelets
- Frozen platelets
- Freeze Dried RBCs
- Frozen RBCs
- Pharmed RBCs
- Pharmed platelets
- Extended Life Red Blood Cells
What are some examples of blood research?
It is vital that blood supplies not be contaminated. Methods of pathogen detection and, more importantly, inactivation are being studied. One promising study is trying to characterize the effects of a riboflavin-UV light pathogen inactivation process upon whole blood. Because whole blood is perishable, efforts to increase its "life span" research continues on extended storage solutions either to extend the storage or provide "fresher" quality cells at time of transfusion and to evaluate the quality of frozen/deglycerolized blood versus liquid stored red cells during storage (Days 0-42). Examples of blood research include determination of the underlying mechanisms and clinical consequences (outcomes) of the coagulopathy that frequently occurs after trauma, ultimately leading to development of diagnostics and therapeutics to effectively predict, diagnose, prevent, and treat trauma-induced coagulopathy.
This effort includes studies of trauma-related changes in:
- coagulation enzyme function
- anticoagulant mechanisms
- fibrinolytic enzyme function
- antifibrinolytic mechanisms
- platelet function
- endothelial function
- selected elements of inflammatory function involved in regulation of hemostatic mechanisms
What are some examples of TBI research?
Neuroprotection research includes work on preclinical biomarker discovery in the military relevant penetrating ballistic'like injury (PBBI) model, identification of cellular/molecular mechanisms of cell death, characterization of secondary cell death signals, and mechanisms of action of neuroprotection. It also includes discovery and early preclinical development of lead neuroprotection mono-therapies for the treatment of brain injury, including drugs, selective brain cooling, and stem cells; discovery and early preclinical development of lead anti-seizure mono-therapies for the treatment of silent seizures caused by brain injury, including FDA approved antiepileptic drugs as well as novel anti-seizure drugs (via Cooperative Research and Development Agreements); and initial preclinical development of combination therapies for the treatment of brain injury (neuroprotection and anti-seizure therapy combinations). These studies require the development of a rat model of PBBI and polytrauma and subsequent enhancement of the rat model in a larger species, i.e. pigs, also to include polytrauma.
Central to the neurological effects studies is the use of neuroimaging to provide a critical validation of the fidelity of preclinical models to reproduce the brain pathophysiology documented in injured warfighters, to rationally target neurobiologically-based therapeutic countermeasures, and to assess efficacy of these countermeasures. Once the imaging is possible, determination of the mechanisms underlying the appreciable contribution of the systemic effects of blast to brain injury which will lead to optimal blast mitigation countermeasures will be possible. Evaluation of time-dependent vulnerabilities to repeated blast overpressure provides essential insights to minimize injury to the warfighter.