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Combat Casualty Care Research Program (CCCRP)CCCRP Web Site

Mission | Background and Environment | Goals and Objectives | Key Themes and MessagesQuestions and Answers

MissionThe mission of the Combat Casualty Care Research Program is to reduce the mortality and morbidity resulting frominjuries 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.

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Background and EnvironmentSoldiers 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 healthcare can be provided. Furthermore, initial treatment and subsequent evacuation occur in austere environmentscharacterized by limited supplies and limited diagnostic and life-support equipment; and provision of acute andcritical care is labor intensive and must frequently be provided by non-physician medical personnel. The primarychallenge 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 closeto the geographic location and time of injury as possible.

Combat casualty care is constrained by logistics, manpower, and the hostile operational environment. Sincemid-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 injuriesare also major causes of death where proper treatments and training could significantly reduce mortality andmorbidity. The treatment of battlefield casualties is exacerbated by the long evacuation times often found inmilitary operations. This requires battlefield medics and physician's assistants to stabilize patients for extendedperiods and makes battlefield trauma care markedly different from civilian trauma care. Because approximately 86percent 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 battlefieldinjuries. The need to provide such care with a reduced logistics footprint is the cornerstone around which thefuture of combat casualty care research is built.

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Goals and ObjectivesThe CCCRP is focused on leveraging cutting-edge research and knowledge from government and civilian researchprograms to fill existing and emerging gaps in combat casualty care. This focus provides requirements-drivencombat 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 servicemembers injured in combat with other organizations in the MRMC and thus focus our efforts in ten major areas ofemphasis.

These are:

Damage Control Resuscitation

Extremity Trauma and Regenerative Medicine

Pain Control

Advanced Capabilities for Emergency Medical Monitoring

Critical Care Engineering (including Medical Knowledge Engineering)

Clinical Trials

Craniomaxillofacial Injury

Blood Products

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Medical R&D Overview Research Areas Congressional Programs Support Functions

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Last Modified Date: 13-Nov-2012

Neuroprotection

Neurological Effects of Blast

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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 atthe point of injury. As a result of improved initial care, as well as rapid evacuation and positioning of surgicalcapabilities close to the point of injury, service members with severe injuries survive to reach field hospitals. Thisresults in lower overall mortality by reducing the Killed in Action rate, but paradoxically, yields an increase in theDied of Wounds rate. Reducing this rate is the current focus of much of the research in Damage ControlResuscitation. It is known that severely injured casualties may develop metabolic disorders characterized byacidosis, hypothermia and coagulopathy, which are often termed "the lethal triad." This set of disorders isaddressed 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 circulatingvolume to restore tissue perfusion and correct metabolism. The U.S. military has implemented a change from earlyresuscitation using crystalloid and packed red cells to early resuscitation using equal ratios of packed red cells,plasma, and platelets.

Extremity Trauma

The majority of battlefield wounds occur to the extremities (55%) and head/neck region (30%). In theextremities, 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 andRegenerative Medicine team is addressing these problems several different ways with the goal of returning theinjured Warrior to full function.

First, injuries and their clinical outcomes are being defined. Until recently, there was not a good understanding ofthe injuries sustained by our Soldiers in ongoing conflicts. To help direct research efforts, retrospective studies areconducted to determine the incidence, rate, and qualitative outcomes of extremity injuries in the Iraq andAfghanistan 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 andsoft tissue and bone injury. We strive to evaluate the most advanced and promising technologies using the mostclinically 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 Control

Pain, both acute and chronic, is recognized as a leading problem among US soldiers injured on active duty orduring deployments. Pain is experienced throughout the continuum of trauma care and within all ranks of themilitary. 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 3facilities, 71% experience pain of 5 or greater on a scale of 0 to 10. Accepted clinical guidelines classify pain of 5or greater as severe pain and recommend treating pain rated as 4 or greater. Treatment of acute pain isparticularly important because recent evidence suggests that uncontrolled acute pain leads to neuronal remodelingand increased incidence of chronic pain.

The over-arching focus of this research area is the study of pain from the battlefield through recovery. Particularattention is paid to identifying novel pain control techniques (including novel pain control targets) and molecularmechanisms in the pain pathway. While the recognition of pain as a disease process rather than a symptom hasshed 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 withinherently limited access and availability, and the lack of a consensus concerning the best tools to use forvalidating pain research.

Although significant advancements have been made in the care of acute pain, we are just beginning to realize thefar-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 paincontrol, military pain specialists have established themselves as indispensable members of the combat casualtyteam 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 andapplied research that leads to the identification and integration of physiological measures that reflect thecomplexity of compensatory responses by the body during the early dynamic phase(s) of hemorrhage. The goal is


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to apply this knowledge to the development of new technologies and devices that advance the medical monitoringcapabilities of combat medical personnel for triage, diagnosis and decision-making to improve the management ofcombat casualties. An important research tool is a research effort focused on investigating the time course ofcentral hemodynamics, autonomic functions, and peripheral tissue metabolism during progressive reductions incentral blood volume induced by lower body negative pressure in healthy human subjects. Basic research effortsare 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 appliedto assess physiological performance to reduction in blood volume. These include measures of early and continuousalterations in central hemodynamics, autonomic functions and tissue perfusion including bioimpedance, real timemeasures of cardiac beat-to-beat (R-R interval) performance and waveform analysis of arterial blood pressure forstroke volume estimates and pressure oscillations, direct measurement of sympathetic nerve activity, linear andnon-linear frequency analysis of R-R interval captured from a standard ECG (heart rate variability indices to assessautonomic 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 activityis investigated as a potential mechanism of the poor blood pressure/tissue perfusion that occurs during progressivereductions in central blood volume. The impact of other combat-related stressors such as heat, cold, exercise andanxiety on physiological measures associated with monitoring patients with hemorrhage are investigated.

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Combat Casualty Care Engineering

Combat Casualty Care Engineering (C3E) is directed at improving care by responding to a gap in critical caretechnology on the current battlefield, particularly at echelons 2 and higher and en route. In general, as a casualtymoves to higher echelons of care, the resources available increase and care approaches, but doesn't reach, thestandards of a civilian or military hospital in the continental U.S. This gap between the highest standard of careand that available at earlier echelons (and the even larger gap that exists as casualties are moved betweenfacilities) 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 wassuggested by a study that showed both Intensive Care Unit (ICU) length of stay and mortality progressivelydecreased at the Combat Support Hospital in Baghdad as the resources for care improved from No Intensivist, toIntensivist 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 whichincorporate sensors, processors, and effectors to help close this care gap. Because of the heavy emphasis ontrauma patient validation and rapid product delivery to the battlefield, the focus of C3E is on clinical trials intrauma 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.

a.

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.

b.

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.

c.

Clinical Trials

The CCCRP Clinical Trials program is centered at the US Army Institute of Surgical Research (USAISR). TheUSAISR is unique within the Medical Research and Materiel Command because both patients and researchscientists are present within the same Institute. This collaborative, integrated environment provides anopportunity to translate science into improvements in combat casualty care and deliver these improvements to thebattlefield. The clinical trials program has two primary objectives. The first is to observe current combat casualtiesto identify emergent challenges and opportunities for improved care. The USAISR serves as the only AmericanBurn Association verified burn center in the Department of Defense. Consequently, the USAISR receives allsignificant burn injured service members evacuated from the wars in Iraq and Afghanistan. As a result, we havethe opportunity to observe patterns of injury and implement programs in order to prevent and better treat theseburns. Examples of our findings include identification of significant numbers of waste burning accidents andimplementation of an awareness program, identification of large numbers of debilitating hand burns andimplementation of a rapid equipping program for fire resistant gloves, identification of thermal injury to theportions of the torso not covered by body armor and development of improved protective clothing, andidentification of over resuscitation injury and implementation of a burn resuscitation flow sheet to ensureappropriate care. The second objective is to translate pre-clinical research from the other research areas at theInstitute into a clinical environment for validation. Examples of this type of translational effort include testing ofwound care dressings in donor sites, and assessment of damage control resuscitation strategies in the burn


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operating room.

The USAISR Clinical Research program prides itself on being responsive to clinical problems and striving forexcellence in burn care, critical care medicine, and the care of the multiply injured casualty. Critical advances inburn care and trauma care developed and tested at the USAISR have significantly improved patient survival andoutcomes in combat casualties.

Craniomaxillofacial Injury

The United States Army Dental and Trauma Research Detachment (USADTRD) is the largest military dentalresearch organization in the Department of Defense and it is the only military research facility dedicated to thestudy of injuries to the craniomaxillofacial (CMF) complex. Use of improvised explosive devices in Iraq andAfghanistan and the capability of body armor to decrease fatal torso injuries have resulted in new woundingpatterns among survivors that includes ruinously destructive CMF trauma and burns. Wounds to the CMF areusually associated with a poor prognosis because restoration of the specialized structures and cosmetics aresignificantly challenging and impact functional outcomes, sense of self and social re-integration. The USADTRD'sresearch foci is established around three research areas; a) development of composite tissues for grafting andimplantation, 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:

Craniomaxillofacial (CMF) Regenerative Medicine

Battle Injuries cause devastating deformities to the CMF area at a higher rate than previous wars. Current

treatment procedures for serious craniomaxillofacial battle injuries were developed during World War I. Using

the injured persons own tissue, a surgeon attempts to lessen one deformity while creating another. The end

point of these treatments is usually patient frustration, not successful outcome. The three research areas will

be fundamental in providing technologies to improve outcome in CMF battle injuries.

Biofilm-Impaired Wound Healing

The ultimate goal of this research is to mitigate the influence of infection on healing and regeneration.

Infections of the teeth (decay) and tooth-supporting tissues (periodontitis) are caused by plaque which is a

biofilm found in every mouth. Plaque, besides causing an enormous burden of disease on Soldiers and the

Military Healthcare System, is a perfect disease model to study and to develop therapeutic strategies to

prevent/treat biofilms of different bacterial species found in combat wounds.

Amelioration of Scar Formation in Injured Skin and Soft Tissues

Scar formation is currently the inevitable consequence of postnatal wound repair and is the means by which

the body expeditiously restores cutaneous barrier function following traumatic or burn injuries. Normal and

pathologic scarring (excessive collagen deposition beyond the borders of injury) of skin which includes

hypertrophic scars and keloids significantly reduce the function of injured skin and the underlying tissues.

Severe cases of hypertrophic scars can result in disfigurement, restriction of motion, and disabling pain in skin

and soft tissue wounds. The effects of pathologic scars on quality of life are significant and often

underappreciated. The impact is particularly magnified in oro-facial injuries where scarring can lead to

significant anatomical, functional and aesthetic facial degradation. This places a huge burden on the injured

warfighter for their re-integration into society. The pathophysiology underlying hypertrophic scar formation is

not well understood and is a subject for research.

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Blood Products

Recent efforts in blood products research have centered on finding suitable replacement compounds for use inblood 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 dryingand freezing components are being investigated. However, a requirement to identify and treat the underlyingcauses of the lack of effective coagulation in severely injured patients has become apparent. Current efforts toaddress the "coagulopathy of trauma" are largely focused on attempting to improve outcomes using treatmentregimens that incorporate available products in different ways, for example, more aggressive use of plasmatransfusion, earlier correction of pH, etc. These efforts provide incremental advances in care but are necessarilylimited by the existing products and knowledge. Major advances in patient care will require new products andknowledge. Development of new diagnostics, therapeutic targets and drug candidates requires a more in-depthknowledge of underlying mechanisms. This work is closely coordinated with the studies undertaken in the DamageControl Resuscitation area. Research encompasses in vitro systems, animal models, and clinical studies to:

elucidate mechanisms relevant to coagulopathy,a.

to relate changes observed in blood with patient outcomes, andb.

to investigate potential diagnostic and therapeutic approaches.c.

An emphasis is that data collected is suitable for data integration and modeling efforts, such as systems biology orother modeling approaches. Modeling efforts are incorporated into the research program to augment the


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coordinated bench, animal and clinical research efforts.

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Traumatic Brain Injury

Traumatic Brain Injury (TBI) is a collective term used for multiple different physiological states that areconsequences of physical damage to the brain. Within the Combat Casualty Care Research Program, there are twomajor subdivisions which study very different forms of TBI. One group (Neuroprotection) focuses on penetratingbrain injury, damage to the brain caused by shrapnel, bullets, or other projectiles passing through the skull andphysically lodging in or passing through the brain matter. The other (Neurological Effects of Blast) studies theeffects of acute exposure to blast waves, or "blast overpressure," on the brain. The goal of each is to increaseunderstanding of the etiology of TBIs, in order to develop new treatments and to arrive at evidence-basedsolutions. Both of these areas have benefitted from substantial amounts of supplemental funding in the recentpast.

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.

a.

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.

b.

Learn more

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Questions and Answers

Q1. What is Damage Control Resuscitation?

A1. It was developed as a structured intervention aimed to treat the approximately 8-10% of casualties who arethe most severely injured, are coagulopathic, and are at the greatest risk of dying. DCR combines research effortsin hemostasis and resuscitation to evaluate hemostatic dressings and to investigate optimal resuscitationstrategies.

Q2. What are some examples of Damage Control Resuscitation research?

A2. Accomplishments of this program include the fielding of safe and effective tourniquets and two generations ofimproved hemostatic dressings. All three of these efforts were designated "Army Greatest Inventions" as was theconcept of DCR.

Studies of severely injured patients have identified a population that appears to become hypocoagulable inresponse to trauma (as opposed to iatrogenic injury). This phenomenon, termed the Acute Coagulopathy ofTrauma (ACOT) is under investigation to determine its incidence, causes and potential treatments. Currentresearch efforts attempt to refine this practice, optimize the use of blood products, and avoid delivering bloodproducts to those that do not require this type of intervention. Other research efforts focus on identifying bettermeans to treat non-compressible hemorrhage as well as investigate genetic, genomic, and immunologicalresponses to trauma/hemorrhage and finding improved means to reduce hypothermia. Using relevant animalmodels and studies in human trauma patients, the ultimate goal is to develop products for resuscitation andhemorrhage control that can be used at all echelons of care to improve survival and reduce morbidity in injuredSoldiers.

Q3. How large a problem are extremity injuries?

A3. A published study shows that 1,566 soldiers sustained 6,609 combat wounds with 3,575 of the wounds to theextremities (82% of the soldiers had at least one extremity wound). Based on the conclusion that for every injuredsoldiers there are 2.3 extremity wounds, the total number of extremity wounds in OIF/OEF to date exceeds33,000.

Q4. What are some examples of extremity trauma research?

A4. Currently, we are studying and evaluating a database of over 200 type 3 open tibia fractures to determinewhat 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 andare now directing resources to solve this problem. Perhaps most importantly, the Military Orthopaedic TraumaRegistry (MOTR) was created. Currently, the Joint Theater Trauma Registry does not collect the information that isneeded to understand the severity of the extremity wounds, how they are treated, or their outcomes. MOTR willhave these needed data elements.

Clinical practice guidelines for irrigation of contaminated wounds have been created from studies that we


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conducted in animals. Other notable efforts include developing animal models for compartment syndrome, massivecontaminated defects, and large segmental muscle loss. The concept of a dual-purpose bone implant (promotesregeneration and prevents infection) was developed and is being evaluated. The Brooke Army Medical CenterDepartment of Orthopedics has initiated several clinical trials in the areas of combat casualty care and severalmore are planned in the near future.

The Combat Casualty Care Research Program (CCCRP) oversees a multi-center clinical trials consortium known asthe Orthopaedic Extremity Trauma Research Program (OETRP). The OETRP focuses on improving outcomes ofextremity injuries within the next 5 years. This is accomplished by funding translational research projects thatevaluate new and emerging therapies and by conducting clinical trials to evaluate current standards of care andavailable treatments. In addition, the CCCRP provides technical oversight to more than 20 large research contractswith universities and companies engaged in extremity trauma research. These relationships are used to advancescientific inquiry in the areas of soft tissue and bone injury, infection, and tissue regeneration.

Q5. What are some examples of pain research?

A5. Current research projects include studies which examine the effects of anesthetic agents on short-termoutcomes such as resuscitation requirements and optimal transfusion ratios. Long-term outcomes such as PostTraumatic Stress Disorder (PTSD), patient satisfaction (health care related quality of life), opioidaddiction/tolerance, and chronic pain are also being studied. In a retrospective study, anesthetic ketamine was notassociated with an increased prevalence of PTSD and was correlated with decreased PTSD development in burnedsoldiers. Later work showed that the beta-adrenergic receptor blocking agent propranolol was not associated with adecrease in PTSD development in burned soldiers despite its effects on memory and occasional off-label use as aPTSD prophylactic.

Another area of research is evaluation of the utility of Virtual Reality (VR) for acute pain control. Immersive VR isbeing studied as a means to decrease opioid requirements and improve pain control during painful medicalprocedures. Wounded Warriors enter the virtual world, known as SnowWorld, where icy landscapes of frigid tundraand frozen canyons are coupled with snowflakes, polar igloos and arctic animals designed to decrease the pain,anxiety and mental stress normally associated with daily burn wound dressing changes. The patients then interactwith the virtual world via high resolution optics, noise cancelling headphones and a computer mouse which allowsthem to target and expel native or hostile opposition forces. Patients endorse improved pain control and overallsatisfaction, and their families are also appreciative because of decreased sedation.

Other current projects include an evaluation of the utility of Ultra Rapid Opioid Detoxification under Anesthesia indecreasing narcotic consumption and opioid dependence in burned soldiers. Within our burn center, increased andimproved ketamine utilization was evident subsequent to development and implementation of a standardizedelectronic ketamine order set and guidelines. The research area also provided ongoing support for development ofthe intranasal ketamine product being fielded as a potential "silver-bullet" for battlefield pain control in the handsof combat medics. Current perioperative projects include using intravascular temperature management duringsevere burn surgery to minimize hypothermia and meet OSHA requirements for a safe workplace, evaluating highratios of plasma:PRBC interoperative transfusions to reduce postoperative transfusion requirements, and theevaluation of a supraglottic airway device for prone position rescue airway management.

Q6. What are some examples of emergency monitoring research?

A6. 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 casualtymanagement. We are investigating the applicability of information that from the electrocardiogram and othersensor signals of the PSM to specifically track reduction in central blood volume resulting from hemorrhage, andfurther define the practical requirements (i.e., computing power, heart beats required, etc.) for their potential useon 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 ofhemorrhage 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 bycombat medical personnel during en route care and at higher echelons (e.g., Emergency Room). Current studiesfocus on identifying devices for vital sign monitoring, diagnostics and therapeutics for remote and on-sceneassessment of the severity of hemorrhage and early prediction of onset of hemodynamic decompensation andprogression toward the development of overt hemorrhagic shock . Technologies under consideration to meet theseneeds include infrared photoplethysmography, near-infrared spectroscopy, diffuse optical spectroscopy, andinspiratory resistance. The ultimate goal is to integrate these measurements using machine-learning techniques todevelop a predictive, personalized algorithm for triage. In addition to the emphasis placed on personalizedprediction of impending hemorrhagic shock, we will use our experimental human algorithm for predicting centralblood volume changes to focus on the development of software algorithms and systems to provide a capability totrack, and subsequently guide, resuscitation efforts.

Q7. What is combat critical care engineering?

A7. Combat critical care engineering can best be described as the use of technology (hardware and softwaresystems) to help those caring for critically injured casualties. This technology must be applied from prehospitalthru ICU. The focus is on addressing the technology gap in critical care medicine between in-theater facilities andthose in the US.

Q8. What are some examples of combat critical care engineering research?


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A8. New vital signs to provide personnel with more sensitive and specific indicators of the true extent of traumainjuries, in addition to providing more precise diagnosis at earlier stages of care. These new vital signs will allowfor better and earlier diagnosis of impending cardiovascular collapse and will provide personnel with a moreaccurate indicator of the need for a life saving intervention. Part of this research involves the use of highperformance computing approaches for the extraction of informative features from high frequency and highresolution waveform data digitized from different body sensors (i.e. EKG). Additionally, advanced information andcomputer processing approaches will be used to develop systems that can process and implement these new vitalsigns in smaller and lighter monitoring systems that can be carried by medics in the battlefield. To furtherautomate critical care procedures, open loop systems will also be developed that will provider personnel withrecommendations on treatment options in addition to providing the ability to execute the interventionautomatically. Finally, closed loop control systems will be developed to fully automate the care of the patient withlittle or no intervention from the provider. Development of extracorporeal devices will be explored with capabilitiesto augment and/or replace mechanical ventilation requirements for patients with severe ARDS.

Q9. What are some examples of clinical trials research?

A9. 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 andprotection from injury, continuous renal replacement therapy, antibiotic use, wound excision and closuretechniques, diagnosis and treatment of head injury including blast injury, pharmacokinetics of antibiotics in theseverely injured, topical wound treatments including silver products and vacuum assisted wound closure, woundhealing of the skin donor site, hemorrhage control in the burn OR, nutrition during ICU stay and during outpatientrecuperation, temperature control in the burned patient, hypotension control strategies, and heterotopicossification in the severely burned.

Q10. What are some examples of craniomaxillofacial research?

A10. Research to provide regenerated or genetically engineered tissue constructs to replace damaged ordestroyed face features through accelerated pre-clinical and clinical trials, development of biological therapiescombining tissue engineering and stem cell technologies to generate craniofacial structures at the USADTRD, andaccelerated research in collaboration with other institutions to leverage their resources to build our researchportfolio on craniomaxillofacial regenerative medicine. The deliverables will be a combination of a scientific processand products such as angiogenic and/or osteogenic scaffolds, tissue-specific stem (progenitor) cells capable of localrepair and regeneration, vascularized soft tissue constructs conducive to the restoration of facial defects, andbioactive bone construct to repair and regenerate facial bones.

Additional research is ongoing into algorithms to understand biofilm pathophysiology and test therapeutic agentsuseful to treat not only dental plaque but biofilms which complicate healing of combat wounds. The deliverableswill be FDA approved anti-biofilm agents in the form of a wound gel consisting of antimicrobials which exhibit lowpropensity to induce microbial resistance and biofilm dispersing agents. In addition, the research will produceevidence-based treatment modalities to improve the outcome of infected combat wounds. This treatmentinformation will focus on being readily transferred into clinical testing.

Planned research includes development of a biological therapy comprised of cells (e.g., mixed-population ofprogenitor cell types), matrix, growth factors, and other small molecules (e.g., Transformation Growth Factor-946; antagonist). The intent of this biotherapeutic is to accelerate healing and reduce scarring by attenuating theinflammatory response and by the recruitment of resident stem or progenitors cells and their secreted signalingmolecules to the injured site. It is now well-known that mesenchymal stem or progenitor cells have the ability tomodulate the inflammatory response. The deliverables include the identification of the most efficacious progenitorcell types, growth factors, and small molecules to improve healing and scarring using the rabbit scar model. Thesesteps will provide information needed to achieve the next stage in the development of biological therapies toimprove disabling scarring and tissue regeneration therapeutics in the oro-facial region.

Q11. What are some examples of potential replacement blood products?

A11. Here is a list of a number of products being studied for use in humans provided they gain Food and DrugAdministration 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

Q12. What are some examples of blood research?

A12. It is vital that blood supplies not be contaminated. Methods of pathogen detection and, more importantly,


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inactivation are being studied. One promising study is trying to characterize the effects of a riboflavin-UV lightpathogen inactivation process upon whole blood. Because whole blood is perishable, efforts to increase its "lifespan" research continues on extended storage solutions either to extend the storage or provide "fresher" qualitycells at time of transfusion and to evaluate the quality of frozen/deglycerolized blood versus liquid stored red cellsduring storage (Days 0-42). Examples of blood research include determination of the underlying mechanisms andclinical consequences (outcomes) of the coagulopathy that frequently occurs after trauma, ultimately leading todevelopment of diagnostics and therapeutics to effectively predict, diagnose, prevent, and treat trauma-inducedcoagulopathy.

This effort includes studies of trauma-related changes in:

coagulation enzyme function1.

anticoagulant mechanisms2.

fibrinolytic enzyme function3.

antifibrinolytic mechanisms4.

platelet function5.

endothelial function6.

selected elements of inflammatory function involved in regulation of hemostatic mechanisms7.

Q13. What are some examples of TBI research?

A13. Neuroprotection research includes work on preclinical biomarker discovery in the military relevantpenetrating 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 includesdiscovery and early preclinical development of lead neuroprotection mono-therapies for the treatment of braininjury, including drugs, selective brain cooling, and stem cells; discovery and early preclinical development of leadanti-seizure mono-therapies for the treatment of silent seizures caused by brain injury, including FDA approvedantiepileptic 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 andanti-seizure therapy combinations). These studies require the development of a rat model of PBBI and polytraumaand 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 fidelityof preclinical models to reproduce the brain pathophysiology documented in injured warfighters, to rationallytarget 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 thesystemic 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 minimizeinjury to the warfighter.

Q14. Where can I find additional information about the combat casualty care research?

A14. Additional information about CCCRP can be found at https://ccc.amedd.army.mil .

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