Citation

Biesterveld BE, Williams AM, Pai MP, Dennahy IS, Graham NJ, Chtraklin K, Siddiqui AZ, O'Connell RL, Bhatti UF, Liu B, Russo RM, Li Y, Alam HB. J. Trauma Acute Care Surg. 2019; ePub(ePub): ePub.

Affiliation

Department of Surgery, University of Michigan, Ann Arbor, MI.

Copyright

(Copyright © 2019, Lippincott Williams and Wilkins)

DOI

10.1097/TA.0000000000002460

PMID

31389922

Abstract

BACKGROUND: Trauma is a leading cause of death, and traumatic brain injury (TBI) is one of the hallmark injuries of current military conflicts. 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 TBI (10mm cortical impact), 40% blood volume hemorrhage and polytrauma (femur fracture, rectus crush and grade V liver laceration). After 1 hour of shock, animals were randomized (n=6/group) to 4 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 2h). 3 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 2h groups (p < 0.05).

CONCLUSIONS: 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.Preclinical study. STUDY TYPE: therapeutic.

Language: en