04492nas a2200409 4500008004100000022001400041245016200055210006900217260000900286300001300295490000700308520319000315653001003505653001103515653001103526653001703537653000903554653001603563653002403579653004203603653002803645653002203673653002803695100002003723700001803743700002303761700001903784700001803803700002103821700001803842700002203860700002003882700002003902700001903922700002003941856012103961 2024 eng d a1932-620300aNon-invasive Auricular Vagus nerve stimulation for Subarachnoid Hemorrhage (NAVSaH): Protocol for a prospective, triple-blinded, randomized controlled trial.0 aNoninvasive Auricular Vagus nerve stimulation for Subarachnoid H c2024 ae03011540 v193 a

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. Registered on September 21, 2020, and the first patient was enrolled on January 4, 2021.

10aAdult10aFemale10aHumans10aInflammation10aMale10aMiddle Aged10aProspective Studies10aRandomized Controlled Trials as Topic10aSubarachnoid Hemorrhage10aTreatment Outcome10aVagus Nerve Stimulation1 aHuguenard, Anna1 aTan, Gansheng1 aJohnson, Gabrielle1 aAdamek, Markus1 aCoxon, Andrew1 aKummer, Terrance1 aOsbun, Joshua1 aVellimana, Ananth1 aLimbrick, David1 aZipfel, Gregory1 aBrunner, Peter1 aLeuthardt, Eric uhttps://neurotechcenter.org/publications/2024/non-invasive-auricular-vagus-nerve-stimulation-subarachnoid-hemorrhage