Transauricular Vagus Nerve Stimulation (taVNS) for Hospitalized Patients with Delirium: Early Results from a Feasibility Trial
DOI: Pending DOI
Synopsis
Delirium affects over 30% of hospitalized patients and is associated with increased risk of morbidity, mortality, and institutionalization, yet no FDA-approved therapies exist. Vagus nerve stimulation may modulate neuroinflammation and cortical networks implicated in delirium. This single-arm feasibility study evaluates transauricular vagus nerve stimulation (taVNS) in hospitalized patients with active delirium. To date, two participants have completed study procedures. 100% of prescribed stimulation was delivered and stimulation was well tolerated with no adverse events. These interim findings suggest that taVNS can be feasibly delivered in this challenging inpatient population.
Background
Delirium, an acute confusional state often associated with illness or injury, affects >30% of hospitalized patients¹. Delirium increases the risk of morbidity, mortality, and institutionalization². At present, there is no FDA-approved therapy for delirium.
Although the exact mechanism is complex, some data suggest that delirium may result from disruption of functional connectivity in brain networks supporting attention and consciousness, particularly within the dorsolateral prefrontal cortex (DLPFC). This disruption may be secondary to neuroinflammation¹. Of note, one of the major anti-inflammatory pathways in the brain is mediated by the vagus nerve¹,³. For these reasons, neuromodulation of the vagus nerve represents a potential therapeutic approach to target the underlying pathophysiology of delirium.
Transauricular vagus nerve stimulation (taVNS), in which a wearable device on the ear delivers transcutaneous stimulation to vagal afferents, has been reported to decrease neuroinflammation⁴ as well as to modulate neural activity in the DLPFC⁴,⁵. We hypothesize that taVNS can be feasibly administered to hospitalized patients with active delirium.
Methods
This single-arm, single-site feasibility study enrolls hospitalized inpatients aged >22 years, right-handed, and screening positive for delirium on the Confusion Assessment Method for the ICU (CAM-ICU) instrument. Delirium diagnosis is confirmed by a physician. Exclusion criteria include severe neurologic disability (e.g., severe TBI or dementia), pacemaker or implanted VNS device, epilepsy, facial/ear trauma or pain, recent substance or alcohol abuse, and endotracheal intubation.
Consent is obtained from the patient’s legally authorized representative. Participants receive taVNS to the left tragus. Stimulation parameters: 500 μs pulse width, 25 Hz, 30 s on / 30 s off, 30 min per session, twice daily (≥6 h apart) for up to 7 days. Current (0.5–5.0 mA) is titrated to perceptual threshold as previously described in the literature⁶; if a patient is unable to participate in perceptual threshold titration, a fixed dose of 1.25 mA is used. Safety monitoring includes pre- and post-session clinical assessment. Patients are discharged from the study if delirium resolves or changes in clinical status result in ineligibility to continue. EEG data are obtained on the first day of stimulation for patients willing to comply with limited EEG montage application.
Primary endpoint is feasibility, prospectively defined as: (1) mean proportion of stimulation delivered / stimulation prescribed across the cohort ≥10%, based on prior fMRI data demonstrating signal change with similarly brief stimulation⁵; (2) at least 80% of patients achieve ≥10% of prescribed stimulation time.
Results
To date, two of a planned ten participants have been enrolled and completed study procedures. The first participant was a male with postoperative hyperactive delirium. The second participant was a female with hypoactive/mixed delirium in the setting of presumed sepsis. Both met eligibility criteria and underwent transauricular vagus nerve stimulation (taVNS) after consent was obtained from their respective legally authorized representatives.
Both participants were unable to meaningfully participate in formal perceptual threshold determination due to delirium severity. The first participant demonstrated physical evidence of discomfort (wincing) when stimulation was initiated at 1.25 mA per protocol, prompting reduction to 0.6 mA, which was subsequently well tolerated. The second participant was initiated at 0.6 mA and tolerated stimulation without behavioral signs of discomfort. All sessions in both participants were completed at 0.6 mA.
Each participant received four 30-minute stimulation sessions prior to discontinuation from the study due to resolution of delirium. Compliance with prescribed stimulation was 100% in both cases, with no missed or prematurely terminated sessions. Both participants received 100% of prescribed stimulation time, exceeding the predefined feasibility criteria.
The study taVNS device provides real-time monitoring of quality of electrode contact. Across all sessions, electrode contact was adequate, with the exception of 2 seconds in the first participant and 23 seconds in the second participant. In both cases, brief periods of suboptimal contact were identified and corrected with minor adjustment of the auricular earpiece. Despite the propensity of some delirious patients to remove lines and monitoring devices, taVNS electrodes were well tolerated and maintained adequate contact in both participants.
No adverse events, device-related complications, serious adverse events, or unanticipated adverse device effects were observed. There were no clinically significant hemodynamic changes or auricular skin injury or irritation.
Discussion
This interim analysis from our ongoing feasibility pilot study suggests that taVNS can be delivered to hospitalized patients with delirium. To our knowledge, neuromodulation for active delirium in hospitalized patients has not been previously reported. Both enrolled participants completed all prescribed stimulation sessions prior to study discontinuation due to resolution of delirium. No device-related adverse events, hemodynamic instability, or auricular injury were observed. Device use was operationally straightforward in the inpatient environment.
Real-time monitoring of electrode contact allowed rapid identification and correction of brief periods of suboptimal contact, resulting in near-complete stimulation delivery across sessions. These early cases provide practical information regarding protocol adherence, tolerability, and device use in delirious inpatients. Interpretation is limited by the very small interim sample. Ongoing enrollment will provide additional information regarding feasibility across a broader range of delirium presentations and clinical contexts.
This pilot study is designed to evaluate feasibility and operational considerations in this challenging patient population. Upon completion, these data will inform the design of future efficacy studies in larger randomized patient populations.
This study is registered at ClinicalTrials.gov (NCT07258082).
Disclosures
The authors have nothing to disclose.
References
1. Wilson, J. E. et al. Delirium. Nat Rev Dis Primers 6, 90 (2020).
2. Witlox, J. et al. Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and dementia: a meta-analysis. JAMA 304, 443–451 (2010).
3. Pavlov, V. A. & Tracey, K. J. The cholinergic anti-inflammatory pathway. Brain Behav Immun 19, 493–499 (2005).
4. Huffman, W. J. et al. Modulation of neuroinflammation and memory dysfunction using percutaneous vagus nerve stimulation in mice. Brain Stimul 12, 19–29 (2019).
5. Badran, B. W. et al. Neurophysiologic effects of transcutaneous auricular vagus nerve stimulation (taVNS) via electrical stimulation of the tragus: a concurrent taVNS/fMRI study and review. Brain Stimul 11, 492–500 (2018).
6. Badran, B. W. et al. Laboratory Administration of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS): technique, targeting, and considerations. J Vis Exp (2019). doi:10.3791/58984.