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

Abstract

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. We, therefore, performed the current study to determine the lowest dose at which VPA administration improves survival in a model of lethal injuries. METHODS Swine were subjected to traumatic brain injury (10-mm cortical impact), 40% blood volume hemorrhage, and multiple trauma (femur fracture, rectus crush, and Grade V liver laceration). After 1 hour of shock, animals were randomized (n = 6/group) to four groups: normal saline (NS) resuscitation; or NS with VPA doses of 150 mg/kg (VPA 150) or 100 mg/kg (VPA 100) administered over 3 hours or 100 mg/kg over 2 hours (VPA 100 over 2 hours). Three hours after shock, packed red blood cells were given, and animals were monitored for another 4 hours. Survival was assessed using Kaplan-Meier and log-rank test. RESULTS Without resuscitation, all of the injured animals died within 5 hours. Similar survival rates were observed in the NS (17%) and VPA 100 (0%) resuscitation groups. Survival rates in the 100-mg/kg VPA groups were significantly (p < 0.05) better when it was given over 2 hours (67%) compared to 3 hours (0%). 83% of the animals in the VPA 150 group survived, which was significantly higher than the NS and VPA 100 over 3 hours groups (p < 0.05). CONCLUSION A single dose of VPA (150 mg/kg) significantly improves survival in an otherwise lethal model of multiple injuries. This is a much lower dose than previously shown to have a survival benefit and matches the dose that is tolerated by healthy human subjects with minimal adverse effects. LEVEL OF EVIDENCE Therapeutic, level V.

Validation of intraosseous delivery of valproic acid in a swine model of polytrauma

“…Though we are reluctant to make strong claims on the survival benefit from VPA given the small sample size in this study, previous studies with more power have also demonstrated that VPA can improve survival in swine models of polytrauma and hemorrhagic shock. 6 If a survival difference exists between intravenous and IO administration, this presented work is not adequately powered to detect that difference, and a much larger study would need to be done. Ethical and cost considerations would be prohibitive to doing such a study.…”

“…The animal protocol and injury pattern has been described in detail previously, and a timeline of the experiment is outlined in figure 1. 6 Briefly, animals underwent placement of femoral venous and arterial lines, a pulmonary artery catheter and open cystostomy for invasive monitoring, hemorrhage and resuscitation. For the injury protocol, animals had a rectus muscle crush injury on one side, femur…”

“…Preclinical studies in realistic swine models of lethal hemorrhage and polytrauma have demonstrated that early administration of VPA improves survival. [6][7][8][9] In survival models of traumatic brain injury (TBI), VPA decreases brain lesion size and improves neurocognitive outcomes. 10 11 These studies, however, all entailed administration of VPA via a peripheral intravenous infusion.…”

The ‘Omics’ of Epigenetic Modulation by Valproic Acid Treatment in Traumatic Brain Injury—What We Know and What the Future Holds

“…A stereotactic computer‐controlled cortical impact (CCI) device that is developed by the University of Michigan Innovation Centre is used to induce the TBI. VPA, at the dose of 150 mg kg −1 , is administered via a peripheral intravenous catheter . Details of the model are already published …”

Brain proteomic changes by histone deacetylase inhibition after traumatic brain injury

“…VPA has been shown to decrease injury lesion size after TBI, decrease lesion size and improve neurologic recovery after combined TBI and hemorrhagic shock (HS). [5][6][7] Transcriptomic analyses of injured brain tissue and peripheral blood mononuclear cells (PBMCs) demonstrated VPA's efficacy in altering expression of genes critical for determining cell fate. [8][9][10] However, although TBI associated with hemorrhage and polytrauma is a common injury pattern in combat theatres, isolated TBI without extracranial injuries is more common in civilian settings.…”