Abstract

Background and Purpose Animal studies have suggested that valproic acid (VPA) is neuroprotective in aneurysmal subarachnoid hemorrhage (SAH). Potential mechanisms include an effect on cortical spreading depolarizations (CSD), apoptosis, blood-brain barrier integrity, and inflammatory pathways. However, the effect of VPA on SAH outcomes in humans has not been investigated.

Methods We conducted a retrospective analysis of 123 patients with nontraumatic SAH. Eighty-seven patients had an aneurysmal source and 36 patients did not have a culprit lesion identified. We used stepwise logistic regression to determine the association between VPA and the following: delayed cerebral ischemia (DCI), radiographic vasospasm, and discharge modified Rankin Scale (mRS) score > 3.

Results All 18 patients who received VPA underwent coil embolization of their aneurysm. VPA use did not have a significant association with DCI on adjusted analysis (Odds Ratio, OR = 1.07, 95% CI: 0.20 – 5.80). The association between VPA use and vasospasm was OR = 0.64 (0.19 – 1.98) and discharge mRS > 3 was OR = 0.45 (0.10 – 1.64). Increased age (OR = 1.04, 1.01 - 1.07) and Hunt and Hess (HH) grade > 3 (OR = 14.5, 4.31 – 48.6) were associated with an increased likelihood for poor discharge outcome (mRS > 3). Younger age (OR = 0.96, 0.93 - 0.99), mFS score = 4 (OR = 4.14, 1.81 – 9.45), and HH grade > 3 (OR = 2.92, 1.11 – 7.69) were all associated with subsequent development of radiographic vasospasm. There were no complications associated with VPA administration.

Conclusion We did not observe an association between VPA and the rate of DCI. There may have been a protective association on discharge outcome and radiographic vasospasm that did not reach statistical significance. We found that VPA use was safe and is plausible to be used in a population of SAH patients who have undergone endovascular treatment of their aneurysm. Larger, prospective studies are needed to determine the effect of VPA on outcome after SAH.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This work was funded by the National Institutes of Health (K08NS112601 and R01NS136224 to DYC; K23NS116033 to CO, R01NS102574 and R01NS128342 to DG), the Andrew David Heitman Foundation (DYC), a Boston University Undergraduate Research Opportunity Program award (JY), and the Grinspoon Family Award (AD). This publication was also supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through BU-CTSI Grant Number 1UL1TR001430. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study was approved by the Institutional Review Board at Boston Medical Center (BMC IRB H-40681).

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Footnotes

Additional Details:

The manuscript complies with all instructions to authors.

Authorship requirements have been met and the final manuscript was approved by all authors.

This manuscript has not been published elsewhere.

We adhered to ethical guidelines. Ethical approvals (IRB) for human studies were obtained as stated in the manuscript.

MC, KS, HT, AD, and DYC conceptualized and designed the study. MC, KS, HT, AC, JY, AD, and DYC collected the data. MC and DYC performed statistical analysis. JW was consulted on statistical methods. MC and DYC made the figures. MC prepared the first draft of the manuscript. MC, SK, HT, AC, JY, JW, MKA, HHD, CO, AC, DG, TNN, AD, and DYC made substantial revisions to the article and gave approval of the final manuscript.

The authors state no conflict of interests.

Data availability

The data of this study are available from the corresponding author upon request.

AbbreviationsSAHsubarachnoid hemorrhageDCIdelayed cerebral ischemiaDSAdigital subtraction angiographyCTAcomputed tomography angiographyTCDtranscranial doppler sonographySDspreading depolarizationGCSGlasgow Coma ScaleVPAvalproic acidAVMarteriovenous malformationRCVSreversible cerebral vasoconstriction syndromeBMCBoston Medical CenterLOSlength of stayECoGelectrocorticographyEEGelectroencephalographyCMOcomfort measures only