ArticleThe Journal of surgical research2014
Valproic acid for the treatment of hemorrhagic shock: a dose-optimization study.
Article in The Journal of surgical research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it, 29 citations in OpenAlex.
- Adjuvant therapies for management of hemorrhagic shock: a narrative review.Critical care (London, England) · 2025Pooled it
- The protective effect of irisin against hemorrhagic injury is mediated by PI3K and p38 pathways in hemorrhage/resuscitation.The Journal of pharmacology and experimental therapeutics · 2025Article
- Article
- Effect of valproic acid upon skeletal muscle subjected to prolonged tourniquet application.Trauma surgery & acute care open · 2023Article
- Pathophysiology of Hemorrhage as It Relates to the Warfighter.Physiology (Bethesda, Md.) · 2022Review
- Valproic acid improves survival and decreases resuscitation requirements in a swine model of prolonged damage control resuscitation.The journal of trauma and acute care surgery · 2019Article
- Comparative analysis of isoform-specific and non-selective histone deacetylase inhibitors in attenuating the intestinal damage after hemorrhagic shock.Trauma surgery & acute care open · 2019Article
- Valproic acid prevents glucocorticoid‑induced osteonecrosis of the femoral head of rats.International journal of molecular medicine · 2018Article
- Histone deacetylase inhibitors: Isoform selectivity improves survival in a hemorrhagic shock model.The journal of trauma and acute care surgery · 2018Article
- Energy metabolism regulated by HDAC inhibitor attenuates cardiac injury in hemorrhagic rat model.Scientific reports · 2016Article
- Inhibition of peptidylarginine deiminase attenuates inflammation and improves survival in a rat model of hemorrhagic shock.The Journal of surgical research · 2016Article
- New perspectives of volemic resuscitation in polytrauma patients: a review.Burns & trauma · 2016Review
- Valproic acid protects against haemorrhagic shock-induced signalling changes via PPARγ activation in an in vitro model.British journal of pharmacology · 2015Article
- Creating a "Prosurvival Phenotype" Through Histone Deacetylase Inhibition: Past, Present, and Future.Shock (Augusta, Ga.) · 2015Review
- Selective histone deacetylase 6 inhibition prolongs survival in a lethal two-hit model.The Journal of surgical research · 2015Article
- Hypothermia and valproic acid activate prosurvival pathways after hemorrhage.The Journal of surgical research · 2015Article
- Modern resuscitation of hemorrhagic shock: what is on the horizon?European journal of trauma and emergency surgery : official publication of the European Trauma Society · 2014Article
- Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundValproic acid (VPA) has been shown to improve survival in animal models of hemorrhagic shock at a dose of 300 mg/kg. Our aim was to identify the ideal dose through dose-escalation, split-dosing, and dose de-escalation regimens. MATERIALS AND
methodsRats were subjected to sublethal 40% hemorrhage and treated with vehicle or VPA (dose of 300, 400, or 450 mg/kg) after 30 min of shock. Acetylated histones and activated proteins from the PI3K-Akt-GSK-3β survival pathway at different time points were quantified by Western blot analysis. In a similar model, a VPA dose of 200 mg/kg followed 2 h later by another dose of 100 mg/kg was administered. Finally, animals were subjected to a lethal 50% hemorrhage and VPA was administered in a dose de-escalation manner (starting at dose of 300 mg/kg) until a significant drop in percent survival was observed.
resultsLarger doses of VPA resulted in greater acetylation of histone 3 and increased activation of PI3K pathway proteins. Dose-dependent differences were significant in histone acetylation but not in the activation of the survival pathway proteins. Split-dose administration of VPA resulted in similar results to a single full dose. Survival was as follows: 87.5% with 300 and 250 mg/kg of VPA, 50% with 200 mg/kg of VPA, and 14% with vehicle-treated animals.
conclusionsAlthough higher doses of VPA result in greater histone acetylation and activation of prosurvival protein signaling, doses as low as 250 mg/kg of VPA confer the same survival advantage in lethal hemorrhagic shock. Also, VPA can be given in a split-dose fashion without a reduction in its cytoprotective effectiveness.
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Registered trials
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