Plasma treatment is associated with decreased brain lesion and resuscitation requirements after traumatic brain injury in a swine model of prolonged damage-control resuscitation.

Background: Hemorrhage and traumatic brain injury (TBI) are the leading causes of death in trauma. Future military conflicts are likely to be in austere environments, where prolonged damage-control resuscitation (p-DCR) may be required for 72 hours before evacuation. Previous studies showed that early administration of fresh frozen plasma (FFP) during p-DCR can significantly decrease the volume of resuscitation required in models of hemorrhagic shock and also provide neuroprotection after TBI.

Testing Neuroprotective Strategies in Prolonged Field Care Model of Traumatic Brain Injury and Hemorrhagic Shock.

Background: Prolonged field care is a military adaptation of tactical combat casualty care providing extended prehospital management during delayed extrication. Effects of addition of valproic acid (VPA) to fresh-frozen plasma (FFP) in a prolonged field care model of hemorrhagic shock and traumatic brain injury are not known. We hypothesized that VPA is associated with decreased neurological impairment, and its protective changes are detected at the transcriptomic level.

Finding the Right Balance: Partial REBOA in a Swine Model of Uncontrolled Vascular Injury.

Background: We have previously shown that partial REBOA (pREBOA) deployment in the thoracic aorta is safe for 2 to 4 hours, but it is unclear whether the distal blood flow after partial aortic occlusion would lead to ongoing hemorrhage. The objective of this study was to evaluate the hemostatic efficacy of pREBOA in a model of uncontrolled vascular injury.

Study Design: Female Yorkshire swine (n = 10, 40 to 45 kg) were anesthetized and instrumented.

Prolonging the zone 1 aortic occlusion time to 4 hours using a partial resuscitative endovascular balloon in a swine model.

Background: The clinical usage of the resuscitative endovascular balloon occlusion of the aorta (REBOA) is limited by distal ischemia resulting from complete aortic occlusion. We hypothesized that animals would physiologically tolerate the prolonged partial occlusion using the novel partially occluding REBOA (pREBOA) with survivable downstream injuries.

Methods: This study used the pREBOA-PRO catheter in a previously established swine model.

Recombinant human MG53 protein attenuates brain lesion size in a large animal model of traumatic brain injury.

Background: MG53, a member of the tripartite motif (TRIM) protein family, plays an essential role in cell membrane repair and promotes cell survival. Recent studies show that systemic delivery of recombinant human MG53 (rhMG53) protein markedly attenuates tissue injury/inflammation, and facilitates healing. This study was performed to test whether intravenous administration of rhMG53 protein would decrease the lesion size in a clinically relevant large animal model of traumatic brain injury (TBI).

A single dose of valproic acid improves neurologic recovery and decreases brain lesion size in swine subjected to an isolated traumatic brain injury.

Background: We lack specific treatments for traumatic brain injury (TBI), which remains the leading cause of trauma-related morbidity and mortality. Treatment with valproic acid (VPA) improves outcomes in models of severe TBI with concurrent hemorrhage. However, it is unknown if VPA will have similar benefits after isolated nonlethal TBI, which is the more common clinical scenario.

Development of a large animal model of lethal polytrauma and intra-abdominal sepsis with bacteremia.

Background: Trauma and sepsis are individually two of the leading causes of death worldwide. When combined, the mortality is greater than 50%. Thus, it is imperative to have a reproducible and reliable animal model to study the effects of polytrauma and sepsis and test novel treatment options.

A novel partial resuscitative endovascular balloon aortic occlusion device that can be deployed in zone 1 for more than 2 hours with minimal provider titration.

Background: Hemorrhage is a leading cause of mortality in trauma. Resuscitative endovascular balloon occlusion of the aorta (REBOA) can control hemorrhage, but distal ischemia, subsequent reperfusion injury, and the need for frequent balloon titration remain problems. Improved device design can allow for partial REBOA (pREBOA) that may provide hemorrhage control while also perfusing distally without need for significant provider titration.

Administration of valproic acid in clinically approved dose improves neurologic recovery and decreases brain lesion size in swine subjected to hemorrhagic shock and traumatic brain injury.

Background: Traumatic brain injury (TBI) and hemorrhage remain the leading causes of death after trauma. We have previously shown that a dose of valproic acid (VPA) at (150 mg/kg) can decrease brain lesion size and hasten neurologic recovery. The current Food and Drug Administration-approved dose of VPA is 60 mg/kg.

Valproic acid decreases resuscitation requirements after hemorrhage in a prolonged damage-control resuscitation model.

Background: Hemorrhage is the leading cause of preventable death in trauma. Future military conflicts are likely to be in austere environments, where prolonged damage-control resuscitation (p-DCR) may be required for 72 hours before evacuation. There is a need to demonstrate that p-DCR is feasible and to optimize its logistics.

Early single-dose exosome treatment improves neurologic outcomes in a 7-day swine model of traumatic brain injury and hemorrhagic shock.

Background: Early single-dose treatment with human mesenchymal stem cell-derived exosomes promotes neuroprotection and promotes blood-brain barrier integrity in models of traumatic brain injury (TBI) and hemorrhagic shock (HS) in swine. The impact of an early single dose of exosomes on late survival (7 days), however, remains unknown. We sought to evaluate the impact of early single-dose exosome treatment on neurologic outcomes, brain lesion size, inflammatory cytokines, apoptotic markers, and mediators of neural plasticity in a 7-day survival model.

Histone deacetylase 6 inhibition improves survival in a swine model of lethal hemorrhage, polytrauma, and bacteremia.

Background: Trauma is the leading cause of death for young Americans. Nonspecific histone deacetylase inhibitors, such as valproic acid, have been shown to improve survival in preclinical models of lethal trauma, hemorrhage, and sepsis. The doses needed to achieve a survival benefit are higher than Food and Drug Administration-approved doses, and the nonspecificity raises concerns about unintended adverse effects.

Early single-dose treatment with exosomes provides neuroprotection and improves blood-brain barrier integrity in swine model of traumatic brain injury and hemorrhagic shock.

Background: Administration of human mesenchymal stem cell (MSC)-derived exosomes can enhance neurorestoration in models of traumatic brain injury (TBI) and hemorrhagic shock (HS). The impact of early treatment with MSC-derived exosomes on brain injury in a large animal model remains unknown. We sought to evaluate the impact of early single-dose exosome treatment on brain swelling and lesion size, blood-based cerebral biomarkers, and blood-brain barrier (BBB) integrity.

Dose optimization of valproic acid in a lethal model of traumatic brain injury, hemorrhage, and multiple trauma in swine.

Background: Trauma is a leading cause of death, and traumatic brain injury is one of the hallmark injuries of current military conflicts. Valproic acid (VPA) administration in high doses (300-400 mg/kg) improves survival in lethal trauma models, but effectiveness of lower doses on survival is unknown. This information is essential for properly designing the upcoming clinical trials.

Valproic acid improves survival and decreases resuscitation requirements in a swine model of prolonged damage control resuscitation.

Background: Although damage control resuscitation (DCR) is routinely performed for short durations, prolonged DCR may be required in military conflicts as a component of prolonged field care. Valproic acid (VPA) has been shown to have beneficial properties in lethal hemorrhage/trauma models. We sought to investigate whether the addition of a single dose of VPA to a 72-hour prolonged DCR protocol would improve clinical outcomes.

Traumatic brain injury may worsen clinical outcomes after prolonged partial resuscitative endovascular balloon occlusion of the aorta in severe hemorrhagic shock model.

Background: The use of partial resuscitative endovascular balloon occlusion of the aorta (pREBOA) in combined hemorrhagic shock (HS) and traumatic brain injury (TBI) has not been well studied. We hypothesized that the use of pREBOA in the setting of TBI would be associated with worse clinical outcomes.

Methods: Female Yorkshire swine were randomized to the following groups: HS-TBI, HS-TBI-pREBOA, and HS-pREBOA (n = 5/cohort).

Isoform 6-selective histone deacetylase inhibition reduces lesion size and brain swelling following traumatic brain injury and hemorrhagic shock.

Background: Nonselective histone deacetylase (pan-HDAC) inhibitors, such as valproic acid (VPA), have demonstrated neuroprotective properties in trauma models. However, isoform-specific HDAC inhibitors may provide opportunity for more effective drug administration with fewer adverse effects. We investigated HDAC6 inhibition with ACY-1083 in an in vitro and an in vivo large animal model of injury.

Complete and Partial Aortic Occlusion for the Treatment of Hemorrhagic Shock in Swine.

Hemorrhage remains the leading cause of preventable deaths in trauma. Endovascular management of non-compressible torso hemorrhage has been at the forefront of trauma care in recent years. Since complete aortic occlusion presents serious concerns, the concept of partial aortic occlusion has gained a growing attention.

Mesenchymal Stem Cell-Derived Exosomes Provide Neuroprotection and Improve Long-Term Neurologic Outcomes in a Swine Model of Traumatic Brain Injury and Hemorrhagic Shock.

Combined traumatic brain injury (TBI) and hemorrhagic shock (HS) remains a leading cause of preventable death worldwide. Mesenchymal stem cell-derived exosomes have demonstrated promise in small animal models of neurologic injury. To investigate the effects of exosome treatment in a clinically realistic large animal model, Yorkshire swine underwent TBI and HS.

Valproic acid induces prosurvival transcriptomic changes in swine subjected to traumatic injury and hemorrhagic shock.

Background: Valproic acid (VPA) is a histone deacetylase inhibitor that improves outcomes in large animal models of trauma. However, its protective mechanism of action is not completely understood. We sought to characterize the genetic changes induced by VPA treatment following traumatic injuries.

Valproic acid decreases brain lesion size and improves neurologic recovery in swine subjected to traumatic brain injury, hemorrhagic shock, and polytrauma.

Background: We have previously shown that treatment with valproic acid (VPA) decreases brain lesion size in swine models of traumatic brain injury (TBI) and controlled hemorrhage. To translate this treatment into clinical practice, validation of drug efficacy and evaluation of pharmacologic properties in clinically realistic models of injury are necessary. In this study, we evaluate neurologic outcomes and perform pharmacokinetic analysis of a single dose of VPA in swine subjected to TBI, hemorrhagic shock, and visceral hemorrhage.

Resuscitation with Lyophilized Plasma Is Safe and Improves Neurological Recovery in a Long-Term Survival Model of Swine Subjected to Traumatic Brain Injury, Hemorrhagic Shock, and Polytrauma.

We have shown previously that fresh frozen plasma (FFP) and lyophilized plasma (LP) decrease brain lesion size and improve neurological recovery in a swine model of traumatic brain injury (TBI) and hemorrhagic shock (HS). In this study, we examine whether these findings can be validated in a clinically relevant model of severe TBI, HS, and polytrauma. Female Yorkshire swine were subjected to TBI (controlled cortical impact), hemorrhage (40% volume), grade III liver and splenic injuries, rib fracture, and rectus abdominis crush.

Addition of low-dose valproic acid to saline resuscitation provides neuroprotection and improves long-term outcomes in a large animal model of combined traumatic brain injury and hemorrhagic shock.

Background: Combined traumatic brain injury (TBI) and hemorrhagic shock (HS) is highly lethal. In a nonsurvival model of TBI + HS, addition of high-dose valproic acid (VPA) (300 mg/kg) to hetastarch reduced brain lesion size and associated swelling 6 hours after injury; whether this would have translated into better neurologic outcomes remains unknown. It is also unclear whether lower doses of VPA would be neuroprotective.

Hypothermia and valproic acid activate prosurvival pathways after hemorrhage.

Background: Therapeutic hypothermia (hypo) and valproic acid (VPA, a histone deacetylase inhibitor) have independently been shown to be protective in models of trauma and hemorrhagic shock but require logistically challenging doses to be effective. Theoretically, combined treatment may further enhance effectiveness, allowing us to use lower doses of each modality. The aim of this study was to determine whether a combination of mild hypo and VPA treatments would offer better cytoprotection compared with that of individual treatments in a hemorrhage model.