Development of Combat-Applicable Lower Extremity Trauma Models Incorporating the Effects of Ischemia Reperfusion Injury Relevant to Prolonged Field Care

Patients This Proposal Will Help: This proposal will develop translatable solutions for early management of combat-related and trauma-induced injury to minimize morbidity and improve recovery in prolonged field care (PFC) settings. Specifically, this proposal addresses the need to develop an animal model that replicates combat-applicable orthopaedic injuries and ischemia reperfusion injury (IRI), which are challenging in a PFC scenario.

Rationale: Experts imply that the future battlefield environments may be more widespread across remote multi-domain austere operating areas. This will require a major shift in current combat casualty transport and care paradigms to delayed evacuations of critical casualties (beyond the 'Golden Hour'), necessitating 'PFC-patient stabilization' for hours to days post-injury if military medical support is not readily accessible.

Major blood loss (hemorrhage) remains a major cause of potentially preventable combat trauma-related deaths on the battlefield. Perfusion of the body with oxygen-rich blood is necessary to keep organs/tissues functional and a person alive. The shutdown of blood supply to an area of tissue results in an immediate shortage of oxygenated blood (ischemia), leading to numerous detrimental cellular metabolic and ultrastructural changes. The length of time a tissue or organ can survive without adequate amount of oxygen varies.

Advances in pre-hospital care, through tourniquet usage to control massive bleeding, have led to improved survival on the battlefield. Timely return (restoration or reperfusion) of the blood supply to the ischemic tissue is critical to prevent irreversible tissue injury; however, often the reperfusion of oxygen-deprived tissues causes major secondary insults (IRI) that may worsen tissue injury in excess of that produced by ischemia alone. One problem of tourniquet application is the occlusion of blood flow to the extremity below the level it is applied. If left in place too long, permanent damage may occur. If muscle tissue is already damaged because of traumatic injury or blast wave exposure, it could lead to earlier or more exaggerated tissue damage and cell death. Dying cells release warning signals, known as 'Damage Associated Molecular Patterns' (DAMPs), which activate the body's immune system, leading to a whole-body inflammatory response, which if uncorrected, may lead to multiple organ failure (MOF) and death. Measurements of DAMPs and other blood biomarkers may help individualize and refine the triage and treatment of wounded Service personnel during PFC.

Research Strategy: Develop combat-applicable models to determine the effects of tourniquet-induced IRI on the development of organ dysfunction and heterotopic ossification in a blast-related model of combat-related lower-limb extremity injury and amputation. We hypothesis that tourniquet-IRI plays a critical role in exacerbating the early inflammatory response following blast-related lower-extremity injury/amputation by compounding pre-existing cellular damage and molecular-mediated injury, resulting in secondary end-organ injury and increased mortality. By combining biological data derived from these models and retrospective analysis of data repositories such as the SC2i, we will seek to identify the clinical predictors of IRI to develop clinical decision support tools (CDSTs) and identify future targets to mitigate its onset.

Potential Clinical Applications, Benefits, and Risks: PFC was designated in a Capabilities Needs Analysis as the number one gap across the U.S. Army. Strategies to mitigate the risk of delivering care in a challenging PFC environment are critical to the advancement of military medicine in future conflicts. The 10 PFC capabilities include monitoring, resuscitation, and gaining awareness of potential problems. Developing our understanding of IRI in combat-relevant injury patterns helps address all of these. Review of recent U.S. military PFC cases showed durations between 4-120 hours (median 10 hours), with active bleeding (43%), shock (29%), burns (17%), and fracture (11%) the most common injury patterns managed. Incorporating these injuries into models will improve the applicability of preclinical research to patient care.

Projected Timeline to Patient-Related Outcomes: Proven PFC models of combat orthopaedic injuries and initial field care will provide a platform to develop CDSTs to assist the combat medic to predict and monitor trauma-induced IRI in the PFC environment and act as a platform to trial potential therapeutics to prevent IRI-induced secondary injury. With follow-on funding, we plan to test candidate PFC credible treatment interventions.

Benefit to Service Members, Veterans, and/or Their Family Members: This proposed research will significantly improve current diagnostic and treatment strategies available to all patients who are at risk of developing trauma-induced IRI. Through this research, we w .......