Article Text

Validation of intraosseous delivery of valproic acid in a swine model of polytrauma
  1. Ben E Biesterveld1,
  2. Rachel O’Connell1,2,
  3. Michael T Kemp1,
  4. Glenn K Wakam1,
  5. Aaron M Williams1,
  6. Manjunath P Pai3,
  7. Hasan B Alam1,2
  1. 1Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
  2. 2Department of Surgery, Northwestern University, Evanston, Illinois, USA
  3. 3Department of Clinical Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
  1. Correspondence to Dr Ben E Biesterveld; bbiester{at}


Background Intraosseous (IO) drug delivery may be necessary in emergency situations when intravenous access is unattainable. Valproic acid (VPA) is a histone deacetylase inhibitor that has previously been shown to improve survival in preclinical models of lethal polytrauma. In this study, we sought to compare serum levels of intravenously and IO-delivered VPA, and to analyze the effect of IO-delivered VPA.

Methods Swine were subjected to 40% blood volume hemorrhage, brain injury, femur fracture, rectus crush injury and liver laceration. After 1 hour of shock, animals were randomized (n=3/group) to receive normal saline resuscitation (control), normal saline+intravenous VPA 150 mg/kg (intravenous group) or normal saline +IO VPA 150 mg/kg (IO group). Serum levels of VPA were assessed between groups, and proteomics analyses were performed on IO and control groups on heart, lung and liver samples.

Results Intravenous and IO serum VPA levels were similar at 1, 3, 5 and 7 hours after starting the infusion (p>0.05). IO-delivered VPA induced significant proteomics changes in the heart, lung and liver, which were most pronounced in the lung. Biologic processes affected included inflammation, metabolism and transcriptional & translational machinery. The control group had 0% survival, and the intravenous and IO group both had 100% survival to the end of the experiment (p<0.05).

Discussion IO-delivered VPA is noninferior to intravenous administration and is a viable option in emergent situations when intravenous access is unattainable.

Level of evidence Not applicable (animal study).

  • proteomics
  • brain injuries
  • traumatic
  • hemorrhage
  • histone deacetylase inhibitors

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  • MPP and HBA are joint senior authors.

  • Contributors BEB, MP and HA contributed to experimental design. BEB, ROC, MTK, GKW, AMW, MP and HA contributed to data collection and analysis and drafting of the article.

  • Funding This work was supported by the Frederick A. Coller Society Surgical Research Fellowship awarded to BEB. BEB was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number F32GM130010.

  • Disclaimer The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval All animal protocols were approved by the University of Michigan Institutional Animal Care & Use Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. Proteomics dataset uploaded in supplemental table.