Neuromodulation to Regulate Inflammation and Autonomic Imbalance in Sepsis

Overview

Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection. It is the most expensive healthcare condition to treat in United States and has a mortality rate of nearly 30%. It is widely known that exaggerated inflammation and imbalance between sympathetic and parasympathetic arms of the autonomic nervous system (ANS) contribute to progression and adverse outcomes in sepsis. The role of unchecked inflammation and unregulated ANS as a potential treatment target is an important gap in our knowledge that should be explored. Cholinergic anti-inflammatory pathway (CAP) is an intricate network where the ANS senses inflammation by vagus nerve afferents and tries to regulate it by vagus nerve efferents to the reticuloendothelial system. The central hypothesis of this pilot clinical trial is that transcutaneous vagus nerve stimulation (TVNS) at tragus of the external ear can activate the CAP to suppress inflammation and improve autonomic imbalance as measured by inflammatory cytokine levels and heart rate variability (HRV) analysis. The investigators plan to randomize patients with septic shock into active and sham stimulation groups and study the effects of vagal stimulation on inflammatory cytokines, HRV and a clinical severity score of sepsis. Both groups will continue to receive the standard of care treatment for sepsis irrespective of group assignments. The investigators hypothesize that 4 hours of TVNS will suppress inflammatory markers and improve the balance between sympathetic and parasympathetic arms of ANS as measured by HRV, resulting in improved Sequential Organ Failure Assessment Score (SOFA). The preliminary data generated from this pilot study will lay the foundation for a larger clinical trial.

Interventions

• Device Low Level Transcutaneous Vagus Nerve Stimulation
  Stimulation of the auricular branch of the vagus nerve at tragus of the external ear delivered by Parasym device.
• Device Low Level Transcutaneous Vagus Nerve Stimulation
  Stimulation of the ear lobe delivered by Parasym device.

Primary outcome measures

• Change in Inflammatory Cytokine Tumor Necrosis Factor Alpha [Time frame: Baseline to 4 hours and baseline to 24 hours post stimulation]

Secondary outcome measures (2)

• Change in Heart Rate Variability [Time frame: Baseline to 4 hours post stimulation]
• Change in Sequential Organ Failure Assessment Score [Time frame: Baseline to 24 hours post stimulation]

Eligibility criteria

Inclusion criteria

Septic shock (meeting severe sepsis and having persistent systolic blood pressure <90mmHg despite adequate fluid resuscitation).

Exclusion criteria

• Unilateral or bilateral vagotomy
• History of myocardial infarction or stroke in the last 1 year
• Recurrent vasovagal syncope
• Sick sinus syndrome without pacemaker
• Bifascicular heart block
• 2nd or 3rd-degree heart block
• Hypotension due to autonomic dysfunction
• Pregnant women
• Prisoners and patients with suicidal ideation

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

United States · 1 center

• University of Oklahoma Health Sciences Center — Oklahoma City

Publications

• Goggins E, Inoue H, Okusa MD. Neuroimmune Control of Inflammation in Acute Kidney Injury and Multiorgan Dysfunction. J Am Soc Nephrol. 2025 Dec 1;36(12):2473-2484. doi: 10.1681/ASN.0000000813. Epub 2025 Jul 7. PMID 40622772

Identifiers

NCT: NCT03992378 · 9227

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗