Septic ShockNERINASEPSISNCT03992378
Neuromodulation to Regulate Inflammation and Autonomic Imbalance in Sepsis
A study testing Low Level Transcutaneous Vagus Nerve Stimulation in people with Septic Shock, run by University of Oklahoma at 1 site in United States.
Trial summary
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%. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Septic Shock
- What is being tested?
- Low Level Transcutaneous Vagus Nerve Stimulation
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 34 participants
- Where
- 1 siteUnited States
- Study dates
- 10 Oct 2019to Dec 2027
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Septic shock (meeting severe sepsis and having persistent systolic blood pressure <90mmHg despite adequate fluid resuscitation).
Who cannot join
- 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
Show all 9Show fewer
- Hypotension due to autonomic dysfunction
- Pregnant women
- Prisoners and patients with suicidal ideation
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104
Houssein Youness, MD, 405-271-6173, Houssein-Youness@ouhsc.edu
About this study
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.
- Conditions
- Septic Shock
- Being tested
- Low Level Transcutaneous Vagus Nerve Stimulation
- Keywords
- Sepsis
- Medical subject headings
- Shock, Septic, Sepsis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Low Level Transcutaneous Vagus Nerve StimulationDevice
Stimulation of the auricular branch of the vagus nerve at tragus of the external ear delivered by Parasym device.
Low Level Transcutaneous Vagus Nerve StimulationDevice
Stimulation of the ear lobe delivered by Parasym device.
| Study group | Role | What they receive |
|---|---|---|
| Active Treatment | Experimental | Patients will receive a single 4-hour session of active transcutaneous vagus nerve stimulation. Receives: Device: Low Level Transcutaneous Vagus Nerve Stimulation |
| Sham Control | Sham comparator | Patients will receive a single 4-hour session of sham transcutaneous vagus nerve stimulation. Receives: Device: Low Level Transcutaneous Vagus Nerve Stimulation |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Inflammatory Cytokine Tumor Necrosis Factor Alpha
Serum inflammatory cytokine
Measured: Baseline to 4 hours and baseline to 24 hours post stimulation
Secondary outcomes (2)
Change in Heart Rate Variability
Time domain and frequency domain measures of heart rate variability
Measured: Baseline to 4 hours post stimulation
Change in Sequential Organ Failure Assessment Score
Sequential Organ Failure Assessment Score calculation
Measured: Baseline to 24 hours post stimulation
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Jun 2019
- Study start10 Oct 2019
- Primary completionJun 2027 (estimated)
- Study completionDec 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Septic ShockStudies of the same condition, open and under way.
- More trials run by University of OklahomaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Randomized controlled trial
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 34 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Oklahoma
- Sponsor type
- University, hospital or other
- Collaborators
- Oklahoma City VA Medical Center
- Responsible party
- Sponsor
- Investigators
- Houssein Youness, MD, Principal investigator, University of OklahomaZain Ul Abideen Asad, MD, Principal investigator, University of Oklahoma
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03992378
- Sponsor's protocol ID
- 9227
- Acronym
- NERINASEPSIS
- Status last verified
- Mar 2026
- First submitted
- 5 Jun 2019
- Last updated
- 1 Apr 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- Yes
Publications
Goggins E, Inoue H, Okusa MD. Neuroimmune Control of Inflammation in Acute Kidney Injury and Multiorgan Dysfunction. J Am Soc Nephrol. 2025 Dec 1;36(12):2473-2484. doi: 10.1681/ASN.0000000813. Epub 2025 Jul 7.
PubMed 40622772
Study at a glance
From the registry record, last updated by the sponsor on 1 Apr 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Neuromodulation to Regulate Inflammation and Autonomic Imbalance in Sepsis
- ClinicalTrials.gov ID
- NCT03992378
- Acronym / sponsor ID
- NERINASEPSIS / 9227
- Conditions
- Septic Shock
- Keywords
- Sepsis
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 34 participants (estimated)
- Lead sponsor
- University of OklahomaUniversity, hospital or other
- Collaborators
- Oklahoma City VA Medical Center
- Study start
- 10 Oct 2019 (actual)
- Primary completion
- Jun 2027 (estimated)
- Study completion
- Dec 2027 (estimated)
- First posted
- 20 Jun 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 2
- Model description
- Randomized controlled trial
| Arm | Type | Receives |
|---|---|---|
| Active Treatment | Experimental | Device: Low Level Transcutaneous Vagus Nerve StimulationPatients will receive a single 4-hour session of active transcutaneous vagus nerve stimulation. |
| Sham Control | Sham comparator | Device: Low Level Transcutaneous Vagus Nerve StimulationPatients will receive a single 4-hour session of sham transcutaneous vagus nerve stimulation. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Septic shock (meeting severe sepsis and having persistent systolic blood pressure <90mmHg despite adequate fluid resuscitation).
Key exclusion criteria (9 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Low Level Transcutaneous Vagus Nerve StimulationStimulation of the auricular branch of the vagus nerve at tragus of the external ear delivered by Parasym device. | Device | Active Treatment |
| Low Level Transcutaneous Vagus Nerve StimulationStimulation of the ear lobe delivered by Parasym device. | Device | Sham Control |
Primary outcome
Change in Inflammatory Cytokine Tumor Necrosis Factor Alpha
Time frame: Baseline to 4 hours and baseline to 24 hours post stimulation
Serum inflammatory cytokine
2 secondary outcomes
Change in Heart Rate Variability
Time frame: Baseline to 4 hours post stimulation
Change in Sequential Organ Failure Assessment Score
Time frame: Baseline to 24 hours post stimulation
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Apr 2026.
- Derived from this study: PubMed 40622772Goggins E, Inoue H, Okusa MD. Neuroimmune Control of Inflammation in Acute Kidney Injury and Multiorgan Dysfunction. J Am Soc Nephrol. 2025 Dec 1;36(12):2473-2484. doi: 10.1681/ASN.0000000813. Epub 2025 Jul 7.
Related trials for Septic Shock
Active, not recruitingPhase 4
Thymosin Alpha 1 and IgM Levels in Sepsis
Sepsis, Septic Shock
Not yet recruiting
Vitamin C for Acute Kidney Injury in ACLF With Septic Shock: A Randomized Controlled Trial
Acute-on-Chronic Liver Failure (ACLF)
Not yet recruiting
ICU-SUCCEED for Survivors of Acute Respiratory Failure and Their Caregivers
Acute Respiratory Failure, Critical Illness
Not yet recruitingObservational study
Longitudinal Trajectories of Myocardial Work in Patients With Sepsis
Sepsis, Septic Shock Hyperdynamic
RecruitingObservational study
Immunothrombosis With Septic Shock Undergoing Renal Replacement Therapy With the OXIRIS Membrane
Sepsis
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Houssein Youness, MD principal investigator
University of Oklahoma
Zain Ul Abideen Asad, MD principal investigator
University of Oklahoma
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Low Level Transcutaneous Vagus Nerve Stimulation in people with Septic Shock, run by University of Oklahoma at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 1 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Houssein Youness, MD (405-271-6173, Houssein-Youness@ouhsc.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Inflammatory Cytokine Tumor Necrosis Factor Alpha (time frame: Baseline to 4 hours and baseline to 24 hours post stimulation). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03992378, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Apr 2026.