Non-invasive Auricular Vagus nerve stimulation for Subarachnoid Hemorrhage (NAVSaH): Protocol for a prospective, triple-blinded, randomized controlled trial

Background Inflammation has been implicated in driving the morbidity associated with subarachnoid hemorrhage (SAH). Despite understanding the important role of inflammation in morbidity following SAH, there is no current effective way to modulate this deleterious response. There is a critical need for a novel approach to immunomodulation that can be safely, rapidly, and effectively deployed in SAH patients. Vagus nerve stimulation (VNS) provides a non-pharmacologic approach to immunomodulation, with prior studies demonstrating VNS can reduce systemic inflammatory markers, and VNS has had early success treating inflammatory conditions such as arthritis, sepsis, and inflammatory bowel diseases. The aim of the Non-invasive Auricular Vagus nerve stimulation for Subarachnoid Hemorrhage (NAVSaH) trial is to translate the use of non-invasive transcutaneous auricular VNS (taVNS) to spontaneous SAH, with our central hypothesis being that implementing taVNS in the acute period following spontaneous SAH attenuates the expected inflammatory response to hemorrhage and curtails morbidity associated with inflammatory-mediated clinical endpoints. Materials and methods The overall objectives for the NAHSaH trial are to 1) Define the impact that taVNS has on SAH-induced inflammatory markers in the plasma and cerebrospinal fluid (CSF), 2) Determine whether taVNS following SAH reduces radiographic vasospasm, and 3) Determine whether taVNS following SAH reduces chronic hydrocephalus. Following presentation to a single enrollment site, enrolled SAH patients are randomly assigned twice daily treatment with either taVNS or sham stimulation for the duration of their intensive care unit stay. Blood and CSF are drawn before initiation of treatment sessions, and then every three days during a patient’s hospital stay. Primary endpoints include change in the inflammatory cytokine TNF-α in plasma and cerebrospinal fluid between day 1 and day 13, rate of radiographic vasospasm, and rate of requirement for long-term CSF diversion via a ventricular shunt. Secondary outcomes include exploratory analyses of a panel of additional cytokines, number and type of hospitalized acquired infections, duration of external ventricular drain in days, interventions required for vasospasm, continuous physiology data before, during, and after treatment sessions, hospital length of stay, intensive care unit length of stay, and modified Rankin Scale score (mRS) at admission, discharge, and each at follow-up appointment for up to two years following SAH. Discussion Inflammation plays a central role in morbidity following SAH. This NAVSaH trial is innovative because it diverges from the pharmacologic status quo by harnessing a novel non-invasive neuromodulatory approach and its known anti-inflammatory effects to alter the pathophysiology of SAH. The investigation of a new, effective, and rapidly deployable intervention in SAH offers a new route to improve outcomes following SAH. Trial registration Clinical Trials Registered, [NCT04557618][1]. Registered on September 21, 2020, and the first patient was enrolled on January 4, 2021 ### Competing Interest Statement I have read the journal's policy and the authors of this manuscript have the following competing interests: ALH and ECL hold equity in the company Aurenar, LLC. The COI as it relates to this trial has been managed by Washington University. ### Clinical Trial NCT04557618 ### Funding Statement This study was supported by the NIH/NINDS under Award Number 1R21NS128307 (to ECL, PB, and GJZ), The American Association of Neurological Surgeons Robert J. Dempsey, MD, Cerebrovascular Resident Research Award (to ALH), The Aneurysm and AVM Foundation Cerebrovascular Research Grant (to ALH), and Just-In-Time (JIT) Core Usage Funding Program from the Washington University Institute of Clinical and Translational Sciences (to ALH and ECL). ### 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: Ethics committee/IRB of Washington University in St. Louis gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as [ClinicalTrials.gov][2]. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors * #### Abbreviations AE : adverse event CSF : cerebrospinal fluid IRB : institutional review board NAVSaH : Non-invasive Auricular Vagus nerve stimulation for Subarachnoid Hemorrhage NIH : National Institutes of Health PI : principal investigator SAE : serious adverse event SAH : subarachnoid hemorrhage taVNS : transcutaneous auricular vagus nerve stimulation VNS : vagus nerve stimulation [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04557618&atom=%2Fmedrxiv%2Fearly%2F2024%2F03%2F19%2F2024.03.18.24304239.atom [2]: http://ClinicalTrials.gov