Prolonging the therapeutic window for valproic acid treatment in a swine model of traumatic brain injury and hemorrhagic shock.
Journal
The journal of trauma and acute care surgery
ISSN: 2163-0763
Titre abrégé: J Trauma Acute Care Surg
Pays: United States
ID NLM: 101570622
Informations de publication
Date de publication:
01 11 2023
01 11 2023
Historique:
medline:
26
10
2023
pubmed:
14
6
2023
entrez:
14
6
2023
Statut:
ppublish
Résumé
It has previously been shown that administration of valproic acid (VPA) can improve outcomes if given within an hour following traumatic brain injury (TBI). This short therapeutic window (TW) limits its use in real-life situations. Based upon its pharmacokinetic data, we hypothesized that TW can be extended to 3 hours if a second dose of VPA is given 8 hours after the initial dose. Yorkshire swine (40-45 kg; n = 10) were subjected to TBI (controlled cortical impact) and 40% blood volume hemorrhage. After 2 hours of shock, they were randomized to either (1) normal saline resuscitation (control) or (2) normal saline-VPA (150 mg/kg × two doses). First dose of VPA was started 3 hours after the TBI, with a second dose 8 hours after the first dose. Neurologic severity scores (range, 0-36) were assessed daily for 14 days, and brain lesion size was measured via magnetic resonance imaging on postinjury day 3. Hemodynamic and laboratory parameters of shock were similar in both groups. Valproic acid-treated animals had significantly less neurologic impairment on days 2 (16.3 ± 2.0 vs. 7.3 ± 2.8) and 3 (10.9 ± 3.6 vs. 2.8 ± 1.1) postinjury and returned to baseline levels 54% faster. Magnetic resonance imaging showed no differences in brain lesion size on day 3. Pharmacokinetic data confirmed neuroprotective levels of VPA in the circulation. This is the first study to demonstrate that VPA can be neuroprotective even when given 3 hours after TBI. This expanded TW has significant implications for the design of the clinical trial.
Sections du résumé
BACKGROUND
It has previously been shown that administration of valproic acid (VPA) can improve outcomes if given within an hour following traumatic brain injury (TBI). This short therapeutic window (TW) limits its use in real-life situations. Based upon its pharmacokinetic data, we hypothesized that TW can be extended to 3 hours if a second dose of VPA is given 8 hours after the initial dose.
METHOD
Yorkshire swine (40-45 kg; n = 10) were subjected to TBI (controlled cortical impact) and 40% blood volume hemorrhage. After 2 hours of shock, they were randomized to either (1) normal saline resuscitation (control) or (2) normal saline-VPA (150 mg/kg × two doses). First dose of VPA was started 3 hours after the TBI, with a second dose 8 hours after the first dose. Neurologic severity scores (range, 0-36) were assessed daily for 14 days, and brain lesion size was measured via magnetic resonance imaging on postinjury day 3.
RESULTS
Hemodynamic and laboratory parameters of shock were similar in both groups. Valproic acid-treated animals had significantly less neurologic impairment on days 2 (16.3 ± 2.0 vs. 7.3 ± 2.8) and 3 (10.9 ± 3.6 vs. 2.8 ± 1.1) postinjury and returned to baseline levels 54% faster. Magnetic resonance imaging showed no differences in brain lesion size on day 3. Pharmacokinetic data confirmed neuroprotective levels of VPA in the circulation.
CONCLUSION
This is the first study to demonstrate that VPA can be neuroprotective even when given 3 hours after TBI. This expanded TW has significant implications for the design of the clinical trial.
Identifiants
pubmed: 37314445
doi: 10.1097/TA.0000000000004022
pii: 01586154-990000000-00405
doi:
Substances chimiques
Valproic Acid
614OI1Z5WI
Saline Solution
0
Types de publication
Randomized Controlled Trial, Veterinary
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
657-663Informations de copyright
Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
Références
Eastridge BJ, Mabry RL, Seguin P, Cantrell J, Tops T, Uribe P, et al. Death on the battlefield (2001–2011): implications for the future of combat casualty care. J Trauma Acute Care Surg . 2012;73(6 Suppl 5):S431–S437.
Peterson AB, Xu L, Daugherty J, Breiding MJ. Surveillance report of traumatic brain injury-related emergency department visits, hospitalizations, and deaths, United States, 2014. Centers for Disease Control and Prevention, U.S. Department of Health and Human Services. 2019. Available at: https://www.cdc.gov/traumaticbraininjury/pdf/TBI-Surveillance-Report-FINAL_508.pdf . Accessed January 15, 2023.
Dewan MC, Rattani A, Gupta S, Baticulon RE, Hung YC, Punchak M, et al. Estimating the global incidence of traumatic brain injury. J Neurosurg . 2018;1–18.
GBD 2016 Traumatic Brain Injury and Spinal Cord Injury Collaborators. Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol . 2019;18(1):56–87.
Nikolian VC, Georgoff PE, Pai MP, Dennahy IS, Chtraklin K, Eidy H, et al. Valproic acid decreases brain lesion size and improves neurologic recovery in swine subjected to traumatic brain injury, hemorrhagic shock, and polytrauma. J Trauma Acute Care Surg . 2017;83(6):1066–1073.
Biesterveld BE, Williams AM, Pai MP, Dennahy IS, Graham NJ, Chtraklin K, et al. Dose optimization of valproic acid in a lethal model of traumatic brain injury, hemorrhage, and multiple trauma in swine. J Trauma Acute Care Surg . 2019;87(5):1133–1139.
Williams AM, Bhatti UF, Biesterveld BE, Graham NJ, Chtraklin K, Zhou J, et al. Valproic acid improves survival and decreases resuscitation requirements in a swine model of prolonged damage control resuscitation. J Trauma Acute Care Surg . 2019;87(2):393–401.
Kim K, Li Y, Jin G, Chong W, Liu B, Lu J, et al. Effect of valproic acid on acute lung injury in a rodent model of intestinal ischemia reperfusion. Resuscitation . 2012;83(2):243–248.
Wakam GK, Biesterveld BE, Pai MP, Kemp MT, O'Connell RL, Rajanayake KK, et al. A single dose of valproic acid improves neurologic recovery and decreases brain lesion size in swine subjected to an isolated traumatic brain injury. J Trauma Acute Care Surg . 2021;91(5):867–871.
Wakam GK, Biesterveld BE, Pai MP, Kemp MT, O'Connell RL, Williams AM, et al. 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. J Trauma Acute Care Surg . 2021;90(2):346–352.
Korley FK, Nikolian VC, Williams AM, Dennahy IS, Weykamp M, Alam HB. Valproic acid treatment decreases serum glial fibrillary acidic protein and neurofilament light chain levels in swine subjected to traumatic brain injury. J Neurotrauma . 2018;35(10):1185–1191.
Jin G, Duggan M, Imam A, Demoya MA, Sillesen M, Hwabejire J, et al. Pharmacologic resuscitation for hemorrhagic shock combined with traumatic brain injury. J Trauma Acute Care Surg . 2012;73(6):1461–1470.
Imam AM, Jin G, Duggan M, Sillesen M, Hwabejire JO, Jepsen CH, et al. Synergistic effects of fresh frozen plasma and valproic acid treatment in a combined model of traumatic brain injury and hemorrhagic shock. Surgery . 2013;154(2):388–396.
Halaweish I, Bambakidis T, Chang Z, Wei H, Liu B, Li Y, et al. 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. J Trauma Acute Care Surg . 2015;79(6):911–919; discussion 9.
Delage C, Palayer M, Etain B, Hagenimana M, Blaise N, Smati J, et al. Valproate, divalproex, valpromide: are the differences in indications justified? Biomed Pharmacother . 2022;158:114051.
Dekker SE, Bambakidis T, Sillesen M, Liu B, Johnson CN, Jin G, et al. Effect of pharmacologic resuscitation on the brain gene expression profiles in a swine model of traumatic brain injury and hemorrhage. J Trauma Acute Care Surg . 2014;77(6):906–912 discussion 12.
Bambakidis T, Dekker SE, Sillesen M, Liu B, Johnson CN, Jin G, et al. Resuscitation with valproic acid alters inflammatory genes in a porcine model of combined traumatic brain injury and hemorrhagic shock. J Neurotrauma . 2016;33(16):1514–1521.
Nikolian VC, Dennahy IS, Higgins GA, Williams AM, Weykamp M, Georgoff PE, et al. Transcriptomic changes following valproic acid treatment promote neurogenesis and minimize secondary brain injury. J Trauma Acute Care Surg . 2018;84(3):459–465.
Georgoff PE, Nikolian VC, Bonham T, Pai MP, Tafatia C, Halaweish I, et al. Safety and tolerability of intravenous valproic acid in healthy subjects: a phase I dose-escalation trial. Clin Pharmacokinet . 2018;57(2):209–219.
Moten DTB, Pyle M, Delk G, Clark R. Joint integrative solutions for combat casualty care in a pacific war at sea. Joint Force Quarterly . 2019;3rd quarter(94):54–63. Available at: https://ndupress.ndu.edu/Media/News/News-Article-View/Article/1913091/joint-integrative-solutions-for-combat-casualty-care-in-a-pacific-war-at-sea/ . Accessed January 15, 2023.
DePalma RG, Hoffman SW. Combat blast related traumatic brain injury (TBI): decade of recognition; promise of progress. Behav Brain Res . 2018;340:102–105.
Halaweish I, Bambakidis T, He W, Linzel D, Chang Z, Srinivasan A, et al. Early resuscitation with fresh frozen plasma for traumatic brain injury combined with hemorrhagic shock improves neurologic recovery. J Am Coll Surg . 2015;220(5):809–819.
Nikolian VC, Pan B, Mesar T, Dennahy IS, Georgoff PE, Duan X, et al. Lung protective effects of low-volume resuscitation and pharmacologic treatment of swine subjected to polytrauma and hemorrhagic shock. Inflammation . 2017;40(4):1264–1274.
Sy E, Amram O, Baer HJ, Hameed SM, Griesdale DEG. Transport time and mortality in critically ill patients with severe traumatic brain injury. Can J Neurol Sci . 2021;48(6):817–825.
Alam HB, Vercruysse G, Martin M, Brown CVR, Brasel K, Moore EE, et al. Western Trauma Association critical decisions in trauma: management of intracranial hypertension in patients with severe traumatic brain injuries. J Trauma Acute Care Surg . 2020;88(2):345–351.
Georgoff PE, Nikolian VC, Halaweish I, Chtraklin K, Bruhn PJ, Eidy H, et al. 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. J Neurotrauma . 2017;34(13):2167–2175.
Sperber C. The strange role of brain lesion size in cognitive neuropsychology. Cortex . 2022;146:216–226.
Williams AM, Dennahy IS, Bhatti UF, Biesterveld BE, Graham NJ, Li Y, et al. Histone deacetylase inhibitors: a novel strategy in trauma and Sepsis. Shock . 2019;52(3):300–306.
Wanczyk M, Roszczenko K, Marcinkiewicz K, Bojarczuk K, Kowara M, Winiarska M. HDACi—going through the mechanisms. Front Biosci (Landmark Ed) . 2011;16(1):340–359.
Das C, Kundu TK. Transcriptional regulation by the acetylation of nonhistone proteins in humans — a new target for therapeutics. IUBMB Life . 2005;57(3):137–149.
Georgoff PE, Halaweish I, Nikolian VC, Higgins GA, Bonham T, Tafatia C, et al. Alterations in the human proteome following administration of valproic acid. J Trauma Acute Care Surg . 2016;81(6):1020–1027.
Georgoff PE, Higgins G, Nikolian VC, Bambakidis T, Dekker SE, Sillesen M, et al. Valproic acid induces the NEUROD1 transcriptional program of neurogenesis after traumatic brain injury. J Am Coll Surg . 2016;223(4):S160.
Chang P, Williams AM, Bhatti UF, Biesterveld BE, Liu B, Nikolian VC, et al. Valproic acid and neural apoptosis, inflammation, and degeneration 30 days after traumatic brain injury, hemorrhagic shock, and polytrauma in a swine model. J Am Coll Surg . 2019;228(3):265–275.
Dekker SE, Biesterveld BE, Bambakidis T, Williams AM, Tagett R, Johnson CN, et al. Modulation of brain transcriptome by combined histone deacetylase inhibition and plasma treatment following traumatic brain injury and hemorrhagic shock. Shock . 2021;55(1):110–120.
Halaweish I, Nikolian V, Georgoff P, Li Y, Alam HB. Creating a “prosurvival phenotype” through histone deacetylase inhibition: past, present, and future. Shock . 2015;44 Suppl 1(1):6–16.
Li Y, Alam HB. Modulation of acetylation: creating a pro-survival and anti-inflammatory phenotype in lethal hemorrhagic and septic shock. J Biomed Biotechnol . 2011;2011:523481.
LaPlaca MC, Huie JR, Alam HB, Bachstetter AD, Bayir H, Bellgowan PF, et al. Pre-clinical common data elements for traumatic brain injury research: progress and use cases. J Neurotrauma . 2021;38(10):1399–1410.
Biesterveld BE, Pumiglia L, Iancu A, Shamshad AA, Remmer HA, Siddiqui AZ, et al. Valproic acid treatment rescues injured tissues after traumatic brain injury. J Trauma Acute Care Surg . 2020;89(6):1156–1165.