Vagus Nerve Stimulation for Sepsis

(NERINASEPSIS Trial)

Overseen By Zain Ul Abideen Asad, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Oklahoma

Disqualifiers: Vagotomy, Myocardial infarction, Stroke, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: 4 hours

34 Participants Needed

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. ^{1 2 3 4 5}

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. ^{1 4 6 7 8}

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. ^{1 2 5 7 8}

Research Team

Zain Ul Abideen Asad, MD

Principal Investigator

University of Oklahoma

Houssein Youness, MD

Principal Investigator

University of Oklahoma

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.

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

Treatment Details

Interventions

• Low Level Transcutaneous Vagus Nerve Stimulation

Trial Overview 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.

Participant Groups

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

Who Is Running the Clinical Trial?

University of Oklahoma

Lead Sponsor

Trials

484

Recruited

95,900+

Oklahoma City VA Medical Center

Collaborator

Trials

2

Recruited

730+

Findings from Research

Transcutaneous low-level vagus nerve stimulation (tVNS) in 15 male volunteers showed significant reductions in left ventricular contractility and output, indicating a potential for cardiac autonomic modulation.

While tVNS reduced heart workload, it also led to increased blood pressure and total peripheral resistance, suggesting a reflex response that needs further investigation to understand its therapeutic implications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular responses to low-level transcutaneous vagus nerve stimulation. Sinkovec, M., Trobec, R., Meglic, B.[2021]

Transvenous vagus nerve stimulation (tVNS) is a feasible and safe procedure, as no serious adverse events were reported during the study involving 20 healthy male volunteers.

However, tVNS did not show any significant effects on the inflammatory response during experimental endotoxemia, as plasma cytokine levels and immune responses were similar between the tVNS and sham groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transvenous vagus nerve stimulation does not modulate the innate immune response during experimental human endotoxemia: a randomized controlled study. Kox, M., van Eijk, LT., Verhaak, T., et al.[2022]

A pilot study involving 24 patients with chronic tinnitus demonstrated that transcutaneous vagus nerve stimulation (tVNS) is a feasible and generally safe treatment method, with only two adverse cardiac events reported, which were unlikely linked to the device.

Preliminary data suggest that tVNS does not cause arrhythmic effects in patients without known heart conditions, indicating its potential safety for cardiac function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous vagus nerve stimulation: retrospective assessment of cardiac safety in a pilot study. Kreuzer, PM., Landgrebe, M., Husser, O., et al.[2022]

Transcutaneous vagus nerve stimulation (tVNS) was found to significantly increase salivary alpha amylase (SAA) levels and reduce the decline of salivary cortisol in healthy participants, indicating a modulation of hormonal indices related to noradrenergic function.

However, tVNS did not show any significant effects on psychophysiological measures such as P3 amplitude or pupil size, suggesting that while it may influence hormonal responses, it does not impact certain cognitive or physiological indices in the same way.

NCBI (Pubmed)

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. Warren, CM., Tona, KD., Ouwerkerk, L., et al.[2019]

In a study involving 25 domestic pigs, vagus nerve stimulation significantly reduced the severity of multiple organ dysfunction in a model of progressive sepsis, indicating its potential as a therapeutic intervention.

The stimulation led to improved hemodynamics, reduced vasopressor needs, and decreased levels of activated monocytes, suggesting that it may help stabilize the body's response to severe infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vagus Nerve Stimulation Attenuates Multiple Organ Dysfunction in Resuscitated Porcine Progressive Sepsis. Kohoutova, M., Horak, J., Jarkovska, D., et al.[2020]

Transcutaneous vagus nerve stimulation (tVNS) shows promise for treating various conditions in pediatric patients, but current studies lack specific protocols and justification for its use in this age group, as none of the 15 identified studies focused exclusively on children.

There are no dedicated tVNS devices for pediatric use, and existing studies do not adequately address neurodevelopmental considerations, highlighting the need for more research on age-appropriate stimulation parameters and protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous Auricular Vagus Nerve Stimulation in Pediatric Patients: A Systematic Review of Clinical Treatment Protocols and Stimulation Parameters. Sigrist, C., Torki, B., Bolz, LO., et al.[2023]

Transcutaneous vagus nerve stimulation (tVNS) was found to be feasible and safe for patients with persistent impairment of consciousness after severe traumatic brain injury (TBI), with minimal side effects reported during an eight-week treatment period.

Out of five patients treated, three showed significant improvements in consciousness as measured by the Coma Recovery Scale-Revised (CRS-R), suggesting that tVNS may have potential benefits for recovery following severe TBI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous Vagus Nerve Stimulation in Patients With Severe Traumatic Brain Injury: A Feasibility Trial. Hakon, J., Moghiseh, M., Poulsen, I., et al.[2022]

Transcutaneous vagus nerve stimulation (tVNS) is gaining interest for its non-invasive application in research and clinical settings, but there is a need for better reporting practices to ensure safety and comparability across studies.

The review proposes a set of minimal reporting items for future tVNS studies, including technical details, participant criteria, and outcome measures, to enhance the reliability and effectiveness of this therapeutic approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (Version 2020). Farmer, AD., Strzelczyk, A., Finisguerra, A., et al.[2023]

References

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

Cardiovascular responses to low-level transcutaneous vagus nerve stimulation. [2021]

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]

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

Transcutaneous vagus nerve stimulation: retrospective assessment of cardiac safety in a pilot study. [2022]

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]

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

Vagus Nerve Stimulation Attenuates Multiple Organ Dysfunction in Resuscitated Porcine Progressive Sepsis. [2020]

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]

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

Transcutaneous Vagus Nerve Stimulation in Patients With Severe Traumatic Brain Injury: A Feasibility Trial. [2022]

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]