The Relevance and Implications of Monoclonal Antibody Therapies on Traumatic Brain Injury Pathologies.

Traumatic brain injury (TBI) is a global public health concern. It remains one of the leading causes of morbidity and mortality. TBI pathology involves complex secondary injury cascades that are associated with cellular and molecular dysfunction, including oxidative stress, coagulopathy, neuroinflammation, neurodegeneration, neurotoxicity, and blood-brain barrier (BBB) dysfunction, among others.

Supra-Prophylactic Doses of Enoxaparin Reduces Fibrin Deposition Without Exacerbation of Intracerebral Hemorrhage in a Rat Model of Penetrating Traumatic Brain Injury.

Deep vein thrombosis and pulmonary embolism prophylaxis is an important part of trauma care. Despite an increased risk of thrombotic complications, the use of venous thrombosis chemoprophylaxis in penetrating traumatic brain injury (pTBI) patients is met with reluctance from neurosurgeons because of concern for the exacerbation of intracerebral hemorrhage. The objective of this study was to provide initial pre-clinical evidence of the effects of Lovenox (LVX) administration following pTBI with significant intracerebral hemorrhage.

Intravenous Administration of Anti-CD47 Antibody Augments Hematoma Clearance, Mitigates Acute Neuropathology, and Improves Cognitive Function in a Rat Model of Penetrating Traumatic Brain Injury.

Traumatic brain injury (TBI)-induced intracerebral hematoma is a major driver of secondary injury pathology such as neuroinflammation, cerebral edema, neurotoxicity, and blood-brain barrier dysfunction, which contribute to neuronal loss, motor deficits, and cognitive impairment. Cluster of differentiation 47 (CD47) is an antiphagocytic cell surface protein inhibiting hematoma clearance. This study was designed to evaluate the safety and efficacy of blockade of CD47 via intravenous (i.

Mitochondria-Targeted Antioxidant Therapeutics for Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major global health problem that affects both civilian and military populations worldwide. Post-injury acute, sub-acute, and chronic progression of secondary injury processes may contribute further to other neurodegenerative diseases. However, there are no approved therapeutic options available that can attenuate TBI-related progressive pathophysiology.

Revert total protein normalization method offers a reliable loading control for mitochondrial samples following TBI.

Owing to evidence that mitochondrial dysfunction plays a dominant role in the traumatic brain injury (TBI) pathophysiology, the Western blot (WB) based immunoblotting method is widely employed to identify changes in the mitochondrial protein expressions after neurotrauma. In WB method, the housekeeping proteins (HKPs) expression is routinely used as an internal control for sample normalization. However, the traditionally employed HKPs can be susceptible to complex cascades of TBI pathogenesis, leading to their inconsistent expression.

PEG hydrogel containing dexamethasone-conjugated hyaluronic acid reduces secondary injury and improves motor function in a rat moderate TBI model.

Traumatic brain injury (TBI) leads to long-term impairments in motor and cognitive function. TBI initiates a secondary injury cascade including a neuro-inflammatory response that is detrimental to tissue repair and limits recovery. Anti-inflammatory corticosteroids such as dexamethasone can reduce the deleterious effects of secondary injury; but challenges associated with dosing, administration route, and side effects have hindered their clinical application.

EFFECTS OF TRANEXAMIC ACID ON NEUROPATHOLOGY, ELECTROENCEPHALOGRAPHY, AND CEREBRAL FIBRIN DEPOSITION IN A RAT MODEL OF POLYTRAUMA WITH CONCOMITANT PENETRATING TRAUMATIC BRAIN INJURY.

Several studies have demonstrated the clinical utility of tranexamic acid (TXA) for use in trauma patients presenting with significant hemorrhage. Tranexamic acid is an antifibrinolytic that inhibits plasminogen activation, and plasmin activity has been shown to mitigate blood loss and reduce all-cause mortality in the absence of adverse vascular occlusive events. Recent clinical developments indicate TXA is safe to use in patients with concomitant traumatic brain injury (TBI); however, the prehospital effects are not well understood.

Comprehensive evaluation of mitochondrial redox profile, calcium dynamics, membrane integrity and apoptosis markers in a preclinical model of severe penetrating traumatic brain injury.

Traumatic Brain Injury (TBI) is caused by the external physical assaults damages the brain. It is a heterogeneous disorder that remains a leading cause of death and disability in the military and civilian population of the United States. Preclinical investigations of mitochondrial responses in TBI have ascertained that mitochondrial dysfunction is an acute indicator of cellular damage and plays a pivotal role in long-term injury progression through cellular excitotoxicity.

Effects of sequential aeromedical evacuations following traumatic brain injury in swine.

Introduction: Traumatic brain injuries (TBI) represent a significant percentage of critical injuries in military conflicts. Following injury, wounded warfighters are often subjected to multiple aeromedical evacuations (AE) and associated hypobaria, yet the impact in TBI patients remains to be characterized. This study evaluated the impact of two consecutive simulated AEs in a fluid-percussion TBI model in swine to characterize these effects.

Treatment of Swine Closed Head Injury with Perfluorocarbon NVX-428.

Pre-hospital treatment of traumatic brain injury (TBI) with co-existing polytrauma is complicated by requirements for intravenous fluid volume vs. hypotensive resuscitation. A low volume, small particle-size-oxygen-carrier perfluorocarbon emulsion NVX-428 (dodecafluoropentane emulsion; 2% / could improve brain tissue with minimal additional fluid volume.

Histopathological Evidence of Multiple Organ Damage After Simulated Aeromedical Evacuation in a Swine Acute Lung Injury Model.

Introduction: Rapid aeromedical evacuation (AE) is standard of care in current conflicts. However, not much is known about possible effects of hypobaric conditions. We investigated possible effects of hypobaria on organ damage in a swine model of acute lung injury.

Hypobaria during aeromedical evacuation exacerbates histopathological injury and modifies inflammatory response in rats exposed to blast overpressure injury.

Background: Aeromedical evacuation (AE) is often used as a rapid and effective way to evacuate patients. However, little is known about the possible effects of AE on patients with blast and traumatic brain injury. In the current study, we used blast overpressure (BOP) as a method to introduce traumatic brain injury in rats and investigated the effects of hypobaria during AE on histology and inflammatory response.

Hypobaria during long-range flight resulted in significantly increased histopathological evidence of lung and brain damage in a swine model.

Background: Aeromedical evacuation to definitive care is standard in current military conflicts. However, there is minimal knowledge on the effects of hypobaria (HYPO) on either the flight crew or patients. The effects of HYPO were investigated using healthy swine.

Brain oxygenation with a non-vasoactive perfluorocarbon emulsion in a rat model of traumatic brain injury.

Objective: The aim of this study was to assess, in two experiments, the safety and efficacy of the PFC emulsion Oxycyte as an oxygen therapeutic for TBI to test the hypothesis that early administration of this oxygen-carrying fluid post-TBI would improve brain tissue oxygenation (P O ).

Methods: The first experiment assessed the effects of Oxycyte on cerebral vasoactivity in healthy, uninjured rats using intravital microscopy. The second experiment investigated the effect of Oxycyte on cerebral P O using the PQM in TBI model.

Cerebral Microvascular and Systemic Effects Following Intravenous Administration of the Perfluorocarbon Emulsion Perftoran.

Oxygen-carrying perfluorocarbon (PFC) fluids have the potential to increase tissue oxygenation during hypoxic states and to reduce ischemic cell death. Regulatory approval of oxygen therapeutics was halted due to concerns over vasoconstrictive side effects. The goal of this study was to assess the potential vasoactive properties of Perftoran by measuring brain pial arteriolar diameters in a healthy rat model.

The Emulsified PFC Oxycyte Improved Oxygen Content and Lung Injury Score in a Swine Model of Oleic Acid Lung Injury (OALI).

Purpose: Perfluorocarbons (PFCs) can transport 50 times more oxygen than human plasma. Their properties may be advantageous in preservation of tissue viability in oxygen-deprived states, such as in acute lung injury. We hypothesized that an intravenous dose of the PFC emulsion Oxycyte would improve tissue oxygenation and thereby mitigate the effects of acute lung injury.

Sanguinate's effect on pial arterioles in healthy rats and cerebral oxygen tension after controlled cortical impact.

Sanguinate, a polyethylene glycol-conjugated carboxyhemoglobin, was investigated for cerebral vasoactivity in healthy male Sprague-Dawley rats (Study 1) and for its ability to increase brain tissue oxygen pressure (PbtO2) after controlled cortical impact (CCI) - traumatic brain injury (TBI) (Study 2). In both studies ketamine-acepromazine anesthetized rats were ventilated with 40% O2. In Study 1, a cranial window was used to measure the diameters of medium - (50-100μm) and small-sized (<50μm) pial arterioles before and after four serial infusions of Sanguinate (8mL/kg/h, cumulative 16mL/kg IV), volume-matched Hextend, or normal saline.

Infusion of solutions of pre-irradiated components in rats.

Introduction: The objective of this study was to conduct a 14-day toxicology assessment for intravenous solutions prepared from irradiated resuscitation fluid components and sterile water.

Methods: Healthy Sprague Dawley rats (7-10/group) were instrumented and randomized to receive one of the following Field IntraVenous Resuscitation (FIVR) or commercial fluids; Normal Saline (NS), Lactated Ringer's, 5% Dextrose in NS. Daily clinical observation, chemistry and hematology on days 1,7,14, and urinalysis on day 14 were evaluated for equivalence using a two sample t-test (p<0.

Brain hypoxia is exacerbated in hypobaria during aeromedical evacuation in swine with traumatic brain injury.

Background: There is inadequate information on the physiologic effects of aeromedical evacuation on wounded war fighters with traumatic brain injury (TBI). At altitudes of 8,000 ft, the inspired oxygen is lower than standard sea level values. In troops experiencing TBI, this reduced oxygen may worsen or cause secondary brain injury.

Endovascular Cooling Method for Hypothermia in Injured Swine.

We evaluated an endovascular cooling method to modulate core temperature in trauma swine models with and without fluid support. Anesthetized swine (N = 80) were uninjured (SHAM) or injured through a bone fracture plus soft tissue injury or an uncontrolled hemorrhage and then subdivided to target body temperatures of 38°C (normothermia) or 33°C (hypothermia) by using a Thermogard endovascular cooling device (Zoll Medical). Temperature regulation began simultaneously at onset of injury (T0).

Perfluorocarbon NVX-108 increased cerebral oxygen tension after traumatic brain injury in rats.

Background: Hypoxia is a critical secondary injury mechanism in traumatic brain injury (TBI), and early intervention to alleviate post-TBI hypoxia may be beneficial. NVX-108, a dodecafluoropentane perfluorocarbon, was screened for its ability to increase brain tissue oxygen tension (PbtO2) when administered soon after TBI.

Methods: Ketamine-acepromazine anesthetized rats ventilated with 40% oxygen underwent moderate controlled cortical impact (CCI)-TBI at time 0 (T0).

Cerebral Vasoactivity and Oxygenation with Oxygen Carrier M101 in Rats.

The severity of traumatic brain injury (TBI) may be reduced if oxygen can be rapidly provided to the injured brain. This study evaluated if the oxygen-carrier M101 causes vasoconstricton of pial vasculature in healthy rats (Experiment 1) and if M101 improves brain tissue oxygen (PbtO) in rats with controlled cortical impact (CCI)-TBI (Experiment 2). M101 (12.

Effects of the Oxygen-Carrying Solution OxyVita C on the Cerebral Microcirculation and Systemic Blood Pressures in Healthy Rats.

The use of hemoglobin-based oxygen carriers (HBOC) as oxygen delivering therapies during hypoxic states has been hindered by vasoconstrictive side effects caused by depletion of nitric oxide (NO). OxyVita C is a promising oxygen-carrying solution that consists of a zero-linked hemoglobin polymer with a high molecular weight (~17 MDa). The large molecular weight is believed to prevent extravasation and limit NO scavenging and vasoconstriction.

Effects of perfluorocarbon dodecafluoropentane (NVX-108) on cerebral microvasculature in the healthy rat.

NVX-108, a dodecafluoropentane-based perfluorocarbon (PFC) emulsion, has therapeutic potential as an oxygen- carrying fluid for emergency medical treatment for traumatic brain injury (TBI) and hemorrhagic shock. Potential cerebral vasoactive properties were assessed by directly measuring pial arteriolar vessel diameters before and after a 30 minute intravenous (IV) infusion of 1.0 ml/kg (high dose [H]) or 0.