Neuromodulation to Regulate Inflammation and Autonomic Imbalance in Sepsis (NERINASEPSIS)

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.

Study Overview

• Status: Recruiting
• Conditions: Septic Shock
• Intervention / Treatment: Device: Low Level Transcutaneous Vagus Nerve Stimulation; Device: Low Level Transcutaneous Vagus Nerve Stimulation

• Study Type: Interventional
• Enrollment (Estimated): 34
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Houssein Youness, MD; Phone Number: 405-271-6173; Email: Houssein-Youness@ouhsc.edu
• Study Contact Backup: Name: Zain Ul Abideen Asad, MD; Phone Number: 405-271-5963; Email: Zain-Asad@ouhsc.edu

Study Locations

• United States
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Recruiting
      • University of Oklahoma Health Sciences Center
      • Contact: Houssein Youness, MD; Phone Number: 405-271-6173; Email: Houssein-Youness@ouhsc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active Treatment; Patients will receive a single 4-hour session of active transcutaneous vagus nerve stimulation.	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.
Sham Comparator: Sham Control; Patients will receive a single 4-hour session of sham transcutaneous vagus nerve stimulation.	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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Oklahoma
• Collaborators: Oklahoma City VA Medical Center
• Investigators: Principal Investigator: Houssein Youness, MD, University of Oklahoma; Principal Investigator: Zain Ul Abideen Asad, MD, University of Oklahoma

Study record dates

Study Major Dates

• Study Start (Actual): October 10, 2019
• Primary Completion (Estimated): June 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: June 5, 2019
• First Submitted That Met QC Criteria: June 18, 2019
• First Posted (Actual): June 20, 2019

Study Record Updates

• Last Update Posted (Actual): March 8, 2024
• Last Update Submitted That Met QC Criteria: March 7, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Sepsis
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Sepsis; Inflammation
• Other Study ID Numbers: 9227 (UKCRN)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes