Neuromodulation to Regulate Inflammation and Autonomic Imbalance in Sepsis

Study Overview
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Brief Summary
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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.

Official Title
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Neuromodulation to Regulate Inflammation and Autonomic Imbalance in Sepsis

Conditions
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Septic Shock

Intervention / Treatment
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* Device: Low Level Transcutaneous Vagus Nerve Stimulation
* Device: Low Level Transcutaneous Vagus Nerve Stimulation


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized controlled trial
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active Treatment<br>Patients will receive a single 4-hour session of active transcutaneous vagus nerve stimulation. | Device: Low Level Transcutaneous Vagus Nerve Stimulation<br>* Stimulation of the auricular branch of the vagus nerve at tragus of the external ear delivered by Parasym device.<br>|
| Sham Comparator: Sham Control<br>Patients will receive a single 4-hour session of sham transcutaneous vagus nerve stimulation. | Device: Low Level Transcutaneous Vagus Nerve Stimulation<br>* Stimulation of the ear lobe delivered by Parasym device.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Inflammatory Cytokine Tumor Necrosis Factor Alpha | Serum inflammatory cytokine | Baseline to 4 hours and baseline to 24 hours post stimulation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Heart Rate Variability | Time domain and frequency domain measures of heart rate variability | Baseline to 4 hours post stimulation | 
| Change in Sequential Organ Failure Assessment Score | Sequential Organ Failure Assessment Score calculation | Baseline to 24 hours post stimulation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sepsis