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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether stimulating the vagus nerve, a major nerve that helps control inflammation, can treat sepsis. Sepsis is a serious condition where the body's response to infection causes organ damage. Participants will be divided into two groups: one receiving active nerve stimulation through Low Level Transcutaneous Vagus Nerve Stimulation (a non-invasive procedure) and the other receiving a sham (inactive) treatment, while both continue with standard sepsis care. The researchers aim to determine if this nerve stimulation can reduce harmful inflammation and improve heart function. Those with septic shock who have persistently low blood pressure despite treatment might be eligible to join. As an unphased trial, this study offers a unique opportunity to contribute to groundbreaking research that could lead to new treatments for sepsis.

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 prior data suggests that this vagus nerve stimulation is safe for sepsis patients?

Research has shown that low-level transcutaneous vagus nerve stimulation (TVNS) is generally safe and well-tolerated. A review of multiple studies found that this type of stimulation can be used in medical settings without major safety concerns. Other research demonstrated that TVNS has been safely used in patients with chronic heart failure, suggesting it could serve as a safe additional treatment. While minor side effects can occur, they are usually not serious and may include skin irritation where the device is applied. Overall, current evidence supports the safety of TVNS in humans. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about low level transcutaneous vagus nerve stimulation for sepsis because it offers a non-invasive approach that differs from traditional treatments like antibiotics and intravenous fluids. This method uses mild electrical impulses to stimulate the vagus nerve through the skin, potentially tapping into the body's natural anti-inflammatory pathways. Unlike conventional therapies, which focus on fighting infections directly, this technique aims to modulate the immune response, offering a novel way to manage sepsis without relying solely on drugs. Plus, it could provide quicker relief by directly targeting the body's nervous system, potentially reducing inflammation more effectively.

What evidence suggests that transcutaneous vagus nerve stimulation is effective for sepsis?

Research has shown that transcutaneous vagus nerve stimulation (TVNS) can help reduce inflammation in people with sepsis. In this trial, participants will receive either active TVNS or a sham control. One study found that TVNS lowered levels of certain proteins that cause inflammation and increased levels of proteins that reduce it. This suggests that TVNS might help balance the body's nervous system, particularly the part that controls inflammation. Early research in other health conditions also indicates that TVNS can improve heart function, which could benefit sepsis patients. These encouraging results suggest that TVNS might effectively reduce harmful inflammation in sepsis. ^{2 3 6 7 8}

Who Is on the Research Team?

Zain Ul Abideen Asad, MD

Principal Investigator

University of Oklahoma

Houssein Youness, MD

Principal Investigator

University of Oklahoma

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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) 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]

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]

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 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]

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) 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]

Citations

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Effects of transcutaneous auricular vagus nerve stimulation on ... This study employs a novel, non-invasive transcutaneous auricular vagus nerve stimulation intervention within a randomised, controlled, single- ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S1935861X23016947

Transcutaneous auricular vagus nerve stimulation reduces ... Conclusions. TaVNS resulted in significantly lower serum pro-inflammatory cytokines and higher serum anti-inflammatory cytokines in sepsis patients.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06510985

Transcutaneous Vagus Nerve Stimulation (tVNS) for ... In the proposed study, the investigators aim to investigate the effectiveness of transcutaneous vagus nerve stimulation (tVNS) as a non-invasive ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12231624/

The efficacy of transcutaneous vagus nerve stimulation in ... Low-level transcutaneous vagus nerve stimulation attenuates cardiac remodelling in a rat model of heart failure with preserved ejection ...

5. withpower.com withpower.com/trial/phase-sepsis-10-2020-8d8a5

Vagus Nerve Stimulation for Sepsis (NERINASEPSIS Trial) Transcutaneous low-level vagus nerve stimulation (tVNS) in 15 male volunteers showed significant reductions in left ventricular contractility and output, ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9772204/

Safety of transcutaneous auricular vagus nerve stimulation ... This is the first systematic review and meta-analysis of transcutaneous auricular stimulation safety. Overall, taVNS is a safe and feasible option for clinical ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S0965229925001001

Clinical outcome of electrical transcutaneous auricular ... Low-level transcutaneous auricular vagus nerve stimulation (Ta-VNS) may be a safe complementary treatment option for CHF patients. Methods. In this randomized ...

8. ahajournals.org ahajournals.org/doi/10.1161/JAHA.123.030539

Vagus Nerve Stimulation and Inflammation in ... Low‐level transcutaneous vagus nerve stimulation attenuates cardiac remodelling in a rat model of heart failure with preserved ejection fraction ...