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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

Halaweish, Ihab MD; Bambakidis, Ted MS; Chang, Zhigang MD; Wei, He MD; Liu, Baoling MD; Li, Yongqing MD, PhD; Bonthrone, Toby; Srinivasan, Ashok MD; Bonham, Tess MS; Chtraklin, Kiril DVM; Alam, Hasan B. MD

Journal of Trauma and Acute Care Surgery: December 2015 - Volume 79 - Issue 6 - p 911–919
doi: 10.1097/TA.0000000000000789
WTA Plenary Papers

BACKGROUND Combined traumatic brain injury (TBI) and hemorrhagic shock (HS) is highly lethal. In a nonsurvival model of TBI + HS, addition of high-dose valproic acid (VPA) (300 mg/kg) to hetastarch reduced brain lesion size and associated swelling 6 hours after injury; whether this would have translated into better neurologic outcomes remains unknown. It is also unclear whether lower doses of VPA would be neuroprotective. We hypothesized that addition of low-dose VPA to normal saline (NS) resuscitation would result in improved long-term neurologic recovery and decreased brain lesion size.

METHODS TBI was created in anesthetized swine (40–43 kg) by controlled cortical impact, and volume-controlled hemorrhage (40% volume) was induced concurrently. After 2 hours of shock, animals were randomized (n = 5 per group) to NS (3× shed blood) or NS + VPA (150 mg/kg). Six hours after resuscitation, packed red blood cells were transfused, and animals were recovered. Peripheral blood mononuclear cells were analyzed for acetylated histone-H3 at lysine-9. A Neurological Severity Score (NSS) was assessed daily for 30 days. Brain magnetic resonance imaging was performed on Days 3 and 10. Cognitive performance was assessed by training animals to retrieve food from color-coded boxes.

RESULTS There was a significant increase in histone acetylation in the NS + VPA–treated animals compared with NS treatment. The NS + VPA group demonstrated significantly decreased neurologic impairment and faster speed of recovery as well as smaller brain lesion size compared with the NS group. Although the final cognitive function scores were similar between the groups, the VPA-treated animals reached the goal significantly faster than the NS controls.

CONCLUSION In this long-term survival model of TBI + HS, addition of low-dose VPA to saline resuscitation resulted in attenuated neurologic impairment, faster neurologic recovery, smaller brain lesion size, and a quicker normalization of cognitive functions.

Supplemental digital content is available in the text.

From the Department of Surgery (I.H., T.Ba., B.L., Y.L., T.Bont., T.Bonh., K.C., H.B.A.), and Section of Neuroradiology (A.S.), Department of Radiology, University of Michigan, Ann Arbor, Michigan; Department of Surgical Critical Care (Z.C.), Beijing Hospital Ministry of Health, Beijing; and Department of Cardiothoracic Surgery (H.W.), Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.

Submitted: January 23, 2015, Revised: May 1, 2015, Accepted: June 3, 2015, Published online: October 1, 2015.

This study was presented at the 45th annual meeting of the Western Trauma Association, March 1–6, 2015, in Telluride, Colorado.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (

Address for reprints: Hasan B. Alam, MD, University of Michigan Hospital, 2920 Taubman Center/5331, University of Michigan Hospital, 1500 E Medical Center Dr, Ann Arbor, MI 48109–5331; email:

© 2015 Lippincott Williams & Wilkins, Inc.