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.

Study Design: Swine underwent traumatic brain injury and 40% blood volume hemorrhage. After 2 hours of shock, they were randomized to (1) normal saline (NS), (2) NS + 250 mL FFP (NS + FFP), or (3) NS + FFP + 150 mg/kg VPA (NS + FFP + VPA). At 72 hours, they were transfused packed RBCs before being euthanized. Intraoperative variables and neurological outcomes were compared. Brain lesion size was measured, and gene expression profiles were analyzed using RNA sequencing. Pathway and network analyses were performed on differentially expressed genes. Real-time polymerase chain reaction was performed to validate key genes.

Results: NS + FFP and NS + FFP + VPA required significantly less crystalloid resuscitation (974 mL: NS + FFP; 1,461 mL: NS + FFP + VPA vs 4,540 mL: NS, p < 0.001), had smaller brain lesion size (2,477 mm 3 : NS + FFP; 3,018.0 mm 3 : NS + FFP + VPA vs 4,517.0 mm 3 : NS, p < 0.01), and required less functional neurologic impairment compared with NS. Per pathway analysis of differentially expressed genes, VPA was associated with enrichment of numerous metabolic changes in injured brains, which were not observed with FFP. Network analysis showed enrichment of various gene networks. Mitochondrially encoded ATP synthase membrane subunit 8 gene was downregulated in VPA-treated animals.

Conclusions: The addition of FFP to the resuscitation protocol resulted in a significant reduction in crystalloid requirements. Both the NS + FFP and NS + FFP + VPA groups showed improved neurological recovery compared with NS alone and had distinctive transcriptomic profiles in injured brains at 72 hours. The mitochondrially encoded ATP synthase membrane subunit 8 gene, involved in worsening ischemia following brain injury, was downregulated in VPA-treated animals.