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NCT Number: NCT07549243

Transcutaneous Auricular Vagus Nerve Stimulation for Preventing Acute Kidney Injury in Patients Undergoing Cardiac Surgery With Cardiopulmonary Bypass

Acute kidney injury (AKI) is a common complication after cardiac surgery using cardiopulmonary bypass, leading to longer hospital stays and worse outcomes. Effective preventive therapies are lacking.

This randomized controlled trial investigates whether transcutaneous auricular vagus nerve stimulation (taVNS)-a non-invasive ear stimulation technique-can reduce AKI after cardiac surgery. A total of 152 patients undergoing elective cardiac surgery with cardiopulmonary bypass will be randomly assigned to receive either taVNS or sham stimulation. The intervention begins before surgery and continues daily through postoperative day 5.

The primary outcome is the incidence of AKI within 7 days after surgery. Secondary outcomes include AKI severity, need for dialysis, kidney function recovery, complications, and inflammatory biomarkers.

This study is approved by the institutional ethics committee. All participants will provide written informed consent.

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Key information

Conditions

Acute Kidney Injury Cardiac Surgery Cardiopulmonary Bypass Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Kidney Diseases Male Urogenital Diseases Renal Insufficiency Urogenital Diseases Urologic Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University

Hangzhou, Zhejiang, 310016, China

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Age ≥18 years
  • Scheduled for elective cardiac surgery with cardiopulmonary bypass under general anesthesia
  • Baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m² (CKD-EPI formula)
  • American Society of Anesthesiologists (ASA) physical status classification I-III
  • New York Heart Association (NYHA) functional classification I-III
  • Able to understand and cooperate with study procedures
  • Willing to participate and provide written informed consent. For participants unable to read or sign due to incapacity or illiteracy, consent may be obtained from a legally authorized representative or witnessed by an impartial third party as per ethical guidelines

Exclusion criteria

  • Solitary kidney, history of kidney transplantation, pre-existing renal replacement therapy, or pre-existing acute kidney injury (KDIGO criteria)
  • Contraindications to transcutaneous auricular vagus nerve stimulation, including active infection, dermatitis, skin breakdown, or severe psoriasis in the bilateral auricular region; allergy to silicone, electrode gel, or device materials; uncontrolled arrhythmia, symptomatic bradycardia, sick sinus syndrome, second- or third-degree atrioventricular block, implanted pacemaker or defibrillator; carotid sinus hypersensitivity; uncontrolled epilepsy; or active peptic ulcer disease
  • Received vagus nerve stimulation, auricular acupuncture, or transcutaneous electrical nerve stimulation within 1 month prior to enrollment
  • Long-term use of medications that significantly affect autonomic nervous system tone or renal blood flow and cannot be safely paused before surgery
  • Active systemic infection or sepsis (Sepsis-3 criteria) prior to surgery
  • Acute ischemic or hemorrhagic stroke, or acute myocardial infarction within 3 months prior to enrollment
  • Severe hepatic dysfunction (Child-Pugh Class C), acute liver failure, or other serious life-threatening conditions
  • Vulnerable populations (excluding elderly or illiterate individuals) including critically ill patients, individuals with psychiatric disorders, cognitive impairment, or pregnant women
  • Any other condition deemed by the investigator to make the participant unsuitable for study participation

Treatment and study plan

Transcutaneous Auricular Vagus Nerve Stimulation

Device

Participants in this arm receive active transcutaneous auricular vagus nerve stimulation (ta-VNS) using the tVNS501 device. Stimulation is delivered to the left cymba conchae (auricular branch of the vagus nerve) with the following parameters: frequency 25 Hz, pulse width 250 µs, 30 seconds on / 30 seconds off cycling. Intensity is adjusted starting from 0.4 V and increased in 0.4 V increments until the participant perceives mild discomfort, then reduced to the highest tolerable non-painful level. The intervention begins on the day of surgery (from the preoperative holding area through 6 hours postoperatively in the ICU) and continues on postoperative days 1 through 5 with two 120-minute sessions per day (at 9:00 and 14:00). The device is applied by trained non-blinded operators.

Sham stimulation

Device

Participants in this arm receive sham stimulation using the same tVNS501 device. Electrodes are placed on the left cymba conchae following the same procedure as the active group, but no electrical current is delivered. The stimulation settings are displayed on the device to maintain blinding, but the output is turned off. The schedule and duration of device application are identical to those in the active stimulation group.

Primary outcomes

  1. Incidence of Acute Kidney Injury (AKI) Within 7 Days After Surgery

    Time frame: Within 7 days after surgery

Secondary outcomes

  1. Severity of Acute Kidney Injury (AKI) by KDIGO Stage

    Time frame: Within 7 days after surgery

    The severity of AKI will be assessed using the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Patients are staged from Stage 1 to Stage 3 based on the maximal change in serum creatinine from baseline or the duration and intensity of oliguria (reduced urine output). Stage 1 is defined as a 1.5-1.9 fold increase in baseline creatinine; Stage 2 as a 2.0-2.9 fold increase; and Stage 3 as a ≥ 3.0 fold increase, a creatinine level ≥ 4.0 mg/dL, or the initiation of renal replacement therapy. Higher stages represent greater severity of kidney dysfunction and are associated with worse clinical outcomes.

  2. Requirement of Renal Replacement Therapy (RRT)

    Time frame: From surgery to hospital discharge, assessed daily, up to 90 days

    Proportion of participants requiring acute RRT during index hospitalization.

  3. Duration of RRT

    Time frame: From initiation to discontinuation of RRT, assessed daily, up to 90 days

    Number of days of RRT received during index hospitalization (calculated only for participants who required RRT).

  4. Persistent AKI at Postoperative Day 7

    Time frame: Postoperative day 7

    Percentage of participants who developed AKI within the first 7 postoperative days and still meet KDIGO criteria for AKI on postoperative day 7.

  5. Time to Kidney Function Recovery Among Participants With AKI

    Time frame: From AKI diagnosis to recovery, assessed daily, up to 30 days after surgery

    Number of days from AKI diagnosis to the first day when serum creatinine returns to <1.5 times baseline and no renal replacement therapy is required. Measurement tool: serum creatinine (μmol/L) per KDIGO criteria. Unit of measure: days. Participants who do not recover within 30 days will be censored.

  6. Serum Creatinine Level at 30 Days After Surgery

    Time frame: At postoperative day 30

    Serum creatinine concentration measured at 30 days after surgery. Measurement tool: serum creatinine assay (enzymatic or Jaffe method) from venous blood sample. Unit of measure: μmol/L.

  7. Estimated Glomerular Filtration Rate (eGFR) at 30 Days Post-Surgery

    Time frame: At postoperative day 30

    eGFR calculated using the CKD-EPI equation based on serum creatinine, age, sex, and race. Measurement tool: CKD-EPI formula applied to serum creatinine value. Unit of measure: mL/min/1.73 m².

  8. Duration of Mechanical Ventilation

    Time frame: From the end of surgery until the time of first successful extubation, assessed up to 30 days.

    Time from surgical procedure completion to first successful extubation. Unit of measure: hours (or days, if >24 hours). Measurement tool: clinical documentation of intubation and extubation times.

  9. Vasoactive-Inotropic Score (VIS) - Peak and Mean Values

    Time frame: Within the first 7 postoperative days, assessed daily

    Peak (maximum) and mean vasoactive-inotropic score calculated daily using standard formula (dopamine, dobutamine, epinephrine, norepinephrine, vasopressin, milrinone). Unit of measure: score (unitless). Measurement tool: documented medication doses and calculation formula per institutional protocol.

  10. Incidence of Postoperative Delirium Within 7 Days After Surgery

    Time frame: Daily from postoperative day 1 through day 7

    Proportion of participants who develop delirium as assessed by the Confusion Assessment Method (CAM) for non-ICU patients or CAM-ICU for ICU patients. Unit of measure: percentage of participants. Measurement tool: CAM or CAM-ICU. Postoperative delirium will be assessed using the Confusion Assessment Method (CAM) or the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). These tools evaluate four clinical features: (1) acute onset and fluctuating course, (2) inattention, (3) disorganized thinking, and (4) altered level of consciousness. A diagnosis of delirium is positive if features 1 and 2 are present, along with either feature 3 or 4. This is a binary outcome (Yes/No); no numerical scale score will be reported. Therefore, the outcome is reported as the proportion of participants who meet the diagnostic criteria.

  11. Change in Mini-Mental State Examination (MMSE) Score From Baseline

    Time frame: Preoperative day 1, postoperative day 3, and postoperative day 7

    MMSE total score (range 0-30, higher scores indicate better cognitive function) assessed at three time points. Unit of measure: score points. Measurement tool: Mini-Mental State Examination.

  12. Sleep Quality Assessed by Richards-Campbell Sleep Questionnaire (RCSQ)

    Time frame: Preoperative day 1 (baseline), postoperative day 1 morning (assessing night of surgery), and postoperative day 3 morning (assessing night of day 2)

    RCSQ total score (range 0-100, higher scores indicate better sleep quality). Unit of measure: score points. Measurement tool: Richards-Campbell Sleep Questionnaire.

  13. Quality of Recovery Measured by QoR-15 Questionnaire

    Time frame: Preoperative day 1, postoperative day 1, postoperative day 3, and postoperative day 7

    QoR-15 total score (range 0-150, higher scores indicate better recovery). Unit of measure: score points. Measurement tool: 15-item Quality of Recovery questionnaire.

  14. Postoperative Pain Intensity Measured by Numeric Rating Scale (NRS)

    Time frame: Within the first 48 postoperative hours (assessed at least daily)

    NRS pain score (range 0-10, 0=no pain, 10=worst possible pain). Peak and mean values may be reported. Unit of measure: score points. Measurement tool: Numeric Rating Scale.

  15. Total Postoperative Opioid Consumption

    Time frame: Within the first 48 postoperative hours

    Cumulative opioid dose converted to oral morphine equivalents (milligrams). Unit of measure: milligrams of oral morphine equivalents. Measurement tool: medication administration records and standard conversion table.

  16. Heart Rate Variability (HRV) Parameters

    Time frame: Preoperative, 24 hours, 48 hours, and 72 hours post-surgery

  17. Incidence of Perioperative Complications

    Time frame: Within 30 days after surgery

  18. Hospital Length of Stay

    Time frame: From surgery admission to hospital discharge, assessed daily, up to 90 days

    Total number of days from the date of surgery to the date of hospital discharge. Unit of measure: days. Measurement tool: hospital medical records.

  19. Intensive Care Unit (ICU) Length of Stay

    Time frame: From ICU admission after surgery to ICU discharge, assessed daily, up to 30 days

    Total number of days from ICU admission following surgery to ICU discharge. Unit of measure: days. Measurement tool: ICU medical records.

  20. Readmission Rate

    Time frame: Within 30 days after discharge

  21. Postoperative Serum C-reactive Protein (CRP) Levels

    Time frame: Preoperative (baseline) and daily from postoperative day 1 through day 7.

    Serum concentration of C-reactive protein (CRP) measured to monitor systemic inflammatory response after cardiac surgery.

    Unit of Measure: mg/L

  22. Postoperative Neutrophil-to-Lymphocyte Ratio (NLR)

    Time frame: Preoperative (baseline) and daily from postoperative day 1 through day 7.

    The ratio of the absolute neutrophil count to the absolute lymphocyte count, calculated from the routine complete blood count (CBC) to assess the balance of the inflammatory and immune systems.

    Unit of Measure: Ratio (unitless)

  23. Postoperative Cardiac Troponin I (cTnI) Levels

    Time frame: Preoperative (baseline) and daily from postoperative day 1 through day 7.

    Serum concentration of cardiac troponin I (cTnI) measured as a specific biomarker for myocardial injury during the perioperative period.

    Unit of Measure: ng/mL (or pg/mL per lab standard)

  24. Postoperative Creatine Kinase-MB (CK-MB) Levels

    Time frame: Preoperative (baseline) and daily from postoperative day 1 through day 7.

    Serum concentration of creatine kinase-MB (CK-MB) isoenzyme, used as a marker for myocardial damage.

    Unit of Measure: ng/mL (or U/L per lab standard)

  25. Postoperative N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) Levels

    Time frame: Preoperative (baseline) and daily from postoperative day 1 through day 7.

    Plasma concentration of NT-proBNP, used as a marker for cardiac wall stress and heart failure severity.

    Unit of Measure: pg/mL

  26. Postoperative Serum Cystatin C Levels

    Time frame: Preoperative (baseline) and daily from postoperative day 1 through day 7.

    Serum concentration of Cystatin C, a sensitive biomarker for early detection of changes in glomerular filtration rate (GFR).

    Unit of Measure: mg/L

  27. Postoperative Plasma Interleukin-6 (IL-6) Levels

    Time frame: 24, 48, and 72 hours after surgery.

    Plasma concentration of Interleukin-6 (IL-6) measured as a pro-inflammatory cytokine to assess the systemic inflammatory response.Unit of Measure: $pg/mL$

  28. Postoperative Plasma Neutrophil Gelatinase-Associated Lipocalin (NGAL) Levels

    Time frame: 24, 48, and 72 hours after surgery.

    Plasma concentration of NGAL, a sensitive biomarker for the early detection of acute kidney injury (AKI).

    Unit of Measure: ng/mL

  29. Expression Level of α7nAChR on CD14+ Monocytes by Flow Cytometry

    Time frame: 24, 48, and 72 hours after surgery.

    The surface expression level of alpha-7 nicotinic acetylcholine receptor (α7nAChR) on CD14+ monocytes will be measured. Peripheral blood mononuclear cells (PBMC) are isolated from EDTA-anticoagulated blood. Measurement is performed using a CytoFLEX flow cytometer and analyzed with FlowJo software.

    Unit of Measure: Mean Fluorescence Intensity (MFI)

  30. Percentage of IL-6+ CD14+ Monocytes by Flow Cytometry

    Time frame: 24, 48, and 72 hours after surgery.

    The proportion of CD14+ monocytes expressing intracellular Interleukin-6 (IL-6). Measurement is performed using a CytoFLEX flow cytometer and analyzed with FlowJo software.

    Unit of Measure: Percentage of CD14+ cells

  31. Percentage of Th17 Cells in CD4+ T Cells by Flow Cytometry

    Time frame: 24, 48, and 72 hours after surgery.

    The proportion of Th17 cells (defined as CD3+CD4+IL-17A+) within the CD4+ T-lymphocyte population. Measurement is performed using a CytoFLEX flow cytometer and analyzed with FlowJo software.

    Unit of Measure: Percentage of CD4+ T cells

  32. Percentage of Treg Cells in CD4+ T Cells by Flow Cytometry

    Time frame: 24, 48, and 72 hours after surgery.

    The proportion of Regulatory T cells (Treg, defined as CD3+CD4+CD25+CD127low/-) within the CD4+ T-lymphocyte population. Measurement is performed using a CytoFLEX flow cytometer and analyzed with FlowJo software.

    Unit of Measure: Percentage of CD4+ T cells

  33. Ratio of Th17 Cells to Treg Cells

    Time frame: 24, 48, and 72 hours after surgery.

    The ratio of the percentage of Th17 cells to the percentage of Treg cells, calculated from flow cytometry data (CytoFLEX/FlowJo) to assess immune homeostasis.

    Unit of Measure: Ratio (unitless)

Sponsors and collaborators

Lead sponsor

Sir Run Run Shaw Hospital

Other

Registry information

Official study title

Transcutaneous Auricular Vagus Nerve Stimulation for Preventing Acute Kidney Injury in Patients Undergoing Cardiac Surgery With Cardiopulmonary Bypass: A Randomized Controlled Trial

Important dates

Study start
2026
Primary completion
2026
Study completion
2027
First posted
Apr 24, 2026
Registry last updated
May 22, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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