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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
TRIPLE
Enrollment
152
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.
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.
Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University
Hangzhou, Zhejiang, China
RECRUITINGIncidence of Acute Kidney Injury (AKI) Within 7 Days After Surgery
Time frame: Within 7 days after surgery
Severity of Acute Kidney Injury (AKI) by KDIGO Stage
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.
Time frame: Within 7 days after surgery
Requirement of Renal Replacement Therapy (RRT)
Proportion of participants requiring acute RRT during index hospitalization.
Time frame: From surgery to hospital discharge, assessed daily, up to 90 days
Duration of RRT
Number of days of RRT received during index hospitalization (calculated only for participants who required RRT).
Time frame: From initiation to discontinuation of RRT, assessed daily, up to 90 days
Persistent AKI at 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.
Time frame: Postoperative day 7
Time to Kidney Function Recovery Among Participants With AKI
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.
Time frame: From AKI diagnosis to recovery, assessed daily, up to 30 days after surgery
Serum Creatinine Level at 30 Days After Surgery
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.
Time frame: At postoperative day 30
Estimated Glomerular Filtration Rate (eGFR) at 30 Days Post-Surgery
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.
Time frame: At postoperative day 30
Duration of Mechanical Ventilation
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.
Time frame: From the end of surgery until the time of first successful extubation, assessed up to 30 days.
Vasoactive-Inotropic Score (VIS) - Peak and Mean Values
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.
Time frame: Within the first 7 postoperative days, assessed daily
Incidence of Postoperative Delirium Within 7 Days After Surgery
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.
Time frame: Daily from postoperative day 1 through day 7
Change in Mini-Mental State Examination (MMSE) Score From Baseline
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.
Time frame: Preoperative day 1, postoperative day 3, and postoperative day 7
Sleep Quality Assessed by Richards-Campbell Sleep Questionnaire (RCSQ)
RCSQ total score (range 0-100, higher scores indicate better sleep quality). Unit of measure: score points. Measurement tool: Richards-Campbell Sleep Questionnaire.
Time frame: Preoperative day 1 (baseline), postoperative day 1 morning (assessing night of surgery), and postoperative day 3 morning (assessing night of day 2)
Quality of Recovery Measured by QoR-15 Questionnaire
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.
Time frame: Preoperative day 1, postoperative day 1, postoperative day 3, and postoperative day 7
Postoperative Pain Intensity Measured by Numeric Rating Scale (NRS)
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.
Time frame: Within the first 48 postoperative hours (assessed at least daily)
Total Postoperative Opioid Consumption
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.
Time frame: Within the first 48 postoperative hours
Heart Rate Variability (HRV) Parameters
Time frame: Preoperative, 24 hours, 48 hours, and 72 hours post-surgery
Incidence of Perioperative Complications
Time frame: Within 30 days after surgery
Hospital Length of Stay
Total number of days from the date of surgery to the date of hospital discharge. Unit of measure: days. Measurement tool: hospital medical records.
Time frame: From surgery admission to hospital discharge, assessed daily, up to 90 days
Intensive Care Unit (ICU) Length of Stay
Total number of days from ICU admission following surgery to ICU discharge. Unit of measure: days. Measurement tool: ICU medical records.
Time frame: From ICU admission after surgery to ICU discharge, assessed daily, up to 30 days
Readmission Rate
Time frame: Within 30 days after discharge
Postoperative Serum C-reactive Protein (CRP) Levels
Serum concentration of C-reactive protein (CRP) measured to monitor systemic inflammatory response after cardiac surgery. Unit of Measure: mg/L
Time frame: Preoperative (baseline) and daily from postoperative day 1 through day 7.
Postoperative Neutrophil-to-Lymphocyte Ratio (NLR)
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)
Time frame: Preoperative (baseline) and daily from postoperative day 1 through day 7.
Postoperative Cardiac Troponin I (cTnI) Levels
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)
Time frame: Preoperative (baseline) and daily from postoperative day 1 through day 7.
Postoperative Creatine Kinase-MB (CK-MB) Levels
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)
Time frame: Preoperative (baseline) and daily from postoperative day 1 through day 7.
Postoperative N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) Levels
Plasma concentration of NT-proBNP, used as a marker for cardiac wall stress and heart failure severity. Unit of Measure: pg/mL
Time frame: Preoperative (baseline) and daily from postoperative day 1 through day 7.
Postoperative Serum Cystatin C Levels
Serum concentration of Cystatin C, a sensitive biomarker for early detection of changes in glomerular filtration rate (GFR). Unit of Measure: mg/L
Time frame: Preoperative (baseline) and daily from postoperative day 1 through day 7.
Postoperative Plasma Interleukin-6 (IL-6) Levels
Plasma concentration of Interleukin-6 (IL-6) measured as a pro-inflammatory cytokine to assess the systemic inflammatory response.Unit of Measure: $pg/mL$
Time frame: 24, 48, and 72 hours after surgery.
Postoperative Plasma Neutrophil Gelatinase-Associated Lipocalin (NGAL) Levels
Plasma concentration of NGAL, a sensitive biomarker for the early detection of acute kidney injury (AKI). Unit of Measure: ng/mL
Time frame: 24, 48, and 72 hours after surgery.
Expression Level of α7nAChR on CD14+ Monocytes by Flow Cytometry
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)
Time frame: 24, 48, and 72 hours after surgery.
Percentage of IL-6+ CD14+ Monocytes by Flow Cytometry
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
Time frame: 24, 48, and 72 hours after surgery.
Percentage of Th17 Cells in CD4+ T Cells by Flow Cytometry
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
Time frame: 24, 48, and 72 hours after surgery.
Percentage of Treg Cells in CD4+ T Cells by Flow Cytometry
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
Time frame: 24, 48, and 72 hours after surgery.
Ratio of Th17 Cells to Treg Cells
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)
Time frame: 24, 48, and 72 hours after surgery.
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