Vagus Nerve Stimulation for Sepsis

(NERINASEPSIS Trial)

Recruiting in Palo Alto (17 mi)

Overseen by Zain Ul Abideen Asad, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: University of Oklahoma

Disqualifiers: Vagotomy, Myocardial infarction, Stroke, others

No Placebo Group

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it mentions that all participants will continue to receive the standard care for sepsis, so it's likely you can keep taking your usual sepsis treatments.

What data supports the effectiveness of the treatment Low Level Transcutaneous Vagus Nerve Stimulation for sepsis?

Research shows that vagus nerve stimulation, including transcutaneous methods, has been used successfully for conditions like epilepsy and depression, and it may help reduce organ dysfunction in sepsis based on animal studies.

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Is transcutaneous vagus nerve stimulation (tVNS) safe for humans?

Transcutaneous vagus nerve stimulation (tVNS) is generally considered safe and well-tolerated in humans, including children, as it is non-invasive and has a good safety profile compared to invasive methods.

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How is the treatment Low Level Transcutaneous Vagus Nerve Stimulation different from other treatments for sepsis?

Low Level Transcutaneous Vagus Nerve Stimulation (tVNS) is unique because it is a non-invasive treatment that stimulates the vagus nerve through the skin, potentially offering anti-inflammatory benefits without the need for surgery or drugs. This approach is different from traditional sepsis treatments, which often involve medications and invasive procedures.

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Eligibility Criteria

This trial is for patients with septic shock who have low blood pressure even after fluid treatment. It's not for those with certain heart conditions, recent heart attack or stroke, autonomic dysfunction, vagotomy (vagus nerve cut), pregnant women, prisoners, suicidal individuals, or people prone to fainting.

Inclusion Criteria

I have septic shock with low blood pressure despite treatment.

Exclusion Criteria

I have low blood pressure due to a nerve system issue.

You have a specific type of heart block called bifascicular heart block.

You are currently pregnant.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive a single 4-hour session of either active or sham transcutaneous vagus nerve stimulation

4 hours

1 visit (in-person)

Follow-up

Participants are monitored for changes in inflammatory cytokines, heart rate variability, and Sequential Organ Failure Assessment Score

24 hours

Monitoring at baseline, 4 hours, and 24 hours post stimulation

Participant Groups

The study tests if stimulating the ear's vagus nerve can reduce inflammation and balance the nervous system in sepsis patients. Participants are randomly placed into two groups: one receives real stimulation while both get standard care; effects on inflammation and organ failure scores are compared.

Group I: Active Treatment Experimental Treatment 1 Intervention

Patients will receive a single 4-hour session of active transcutaneous vagus nerve stimulation.

Group II: Sham Control Placebo Group 1 Intervention

Patients will receive a single 4-hour session of sham transcutaneous vagus nerve stimulation.

Low Level Transcutaneous Vagus Nerve Stimulation is already approved in United States, European Union for the following indications:

🇺🇸 Approved in United States as GammaCore for:

• Migraine
• Cluster headaches

🇪🇺 Approved in European Union as Transcutaneous Vagus Nerve Stimulation for:

• Rheumatoid arthritis
• Primary Sjögren’s syndrome

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

University of Oklahoma Health Sciences Center Oklahoma City, OK

Who Is Running the Clinical Trial?

University of Oklahoma Lead Sponsor

Oklahoma City VA Medical Center Collaborator

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Cardiovascular responses to low-level transcutaneous vagus nerve stimulation. [2021] The aim was to determine cardiovascular responses to an arbitrary protocol of transcutaneous low-level vagus nerve electrical stimulation (tVNS).

2. England pubmed.ncbi.nlm.nih.gov

Transvenous vagus nerve stimulation does not modulate the innate immune response during experimental human endotoxemia: a randomized controlled study. [2022] Vagus nerve stimulation (VNS) exerts beneficial anti-inflammatory effects in various animal models of inflammation, including collagen-induced arthritis, and is implicated in representing a novel therapy for rheumatoid arthritis. However, evidence of anti-inflammatory effects of VNS in humans is very scarce. Transvenous VNS (tVNS) is a newly developed and less invasive method to stimulate the vagus nerve. In the present study, we determined whether tVNS is a feasible and safe procedure and investigated its putative anti-inflammatory effects during experimental human endotoxemia.

3. Switzerland pubmed.ncbi.nlm.nih.gov

Transcutaneous vagus nerve stimulation: retrospective assessment of cardiac safety in a pilot study. [2022] Vagus nerve stimulation has been successfully used as a treatment strategy for epilepsy and affective disorders for years. Transcutaneous vagus nerve stimulation (tVNS) is a new non-invasive method to stimulate the vagus nerve, which has been shown to modulate neuronal activity in distinct brain areas.

4. United States pubmed.ncbi.nlm.nih.gov

The neuromodulatory and hormonal effects of transcutaneous vagus nerve stimulation as evidenced by salivary alpha amylase, salivary cortisol, pupil diameter, and the P3 event-related potential. [2019] Transcutaneous vagus nerve stimulation (tVNS) is a new, non-invasive technique being investigated as an intervention for a variety of clinical disorders, including epilepsy and depression. It is thought to exert its therapeutic effect by increasing central norepinephrine (NE) activity, but the evidence supporting this notion is limited.

5. United States pubmed.ncbi.nlm.nih.gov

Vagus Nerve Stimulation Attenuates Multiple Organ Dysfunction in Resuscitated Porcine Progressive Sepsis. [2020] To investigate the potential benefits of vagus nerve stimulation in a clinically-relevant large animal model of progressive sepsis.

6. United States pubmed.ncbi.nlm.nih.gov

Transcutaneous Auricular Vagus Nerve Stimulation in Pediatric Patients: A Systematic Review of Clinical Treatment Protocols and Stimulation Parameters. [2023] Noninvasive transcutaneous vagus nerve stimulation (tVNS) has promising therapeutic potential in a wide range of applications across somatic and psychiatric conditions. Compared with invasive vagus nerve stimulation, good safety and tolerability profiles also support the use of tVNS in pediatric patients. Potential neurodevelopment-specific needs, however, raise concerns regarding the age-appropriate adjustment of treatment protocols and applied stimulation parameters.

7. United States pubmed.ncbi.nlm.nih.gov

Transcutaneous Vagus Nerve Stimulation in Patients With Severe Traumatic Brain Injury: A Feasibility Trial. [2022] Preclinical studies have shown that surgically implanted vagus nerve stimulation (VNS) promotes recovery of consciousness and cognitive function following experimental traumatic brain injury (TBI). The aim of this study is to report the feasibility and safety of a noninvasive transcutaneous vagus nerve stimulation (tVNS) in patients with persistent impairment of consciousness following severe TBI.

8. Switzerland pubmed.ncbi.nlm.nih.gov

International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (Version 2020). [2023] Given its non-invasive nature, there is increasing interest in the use of transcutaneous vagus nerve stimulation (tVNS) across basic, translational and clinical research. Contemporaneously, tVNS can be achieved by stimulating either the auricular branch or the cervical bundle of the vagus nerve, referred to as transcutaneous auricular vagus nerve stimulation(VNS) and transcutaneous cervical VNS, respectively. In order to advance the field in a systematic manner, studies using these technologies need to adequately report sufficient methodological detail to enable comparison of results between studies, replication of studies, as well as enhancing study participant safety. We systematically reviewed the existing tVNS literature to evaluate current reporting practices. Based on this review, and consensus among participating authors, we propose a set of minimal reporting items to guide future tVNS studies. The suggested items address specific technical aspects of the device and stimulation parameters. We also cover general recommendations including inclusion and exclusion criteria for participants, outcome parameters and the detailed reporting of side effects. Furthermore, we review strategies used to identify the optimal stimulation parameters for a given research setting and summarize ongoing developments in animal research with potential implications for the application of tVNS in humans. Finally, we discuss the potential of tVNS in future research as well as the associated challenges across several disciplines in research and clinical practice.