TEAS for Sedation During ERCP: A Multicenter Trial With Mechanistic Substudy

1. Background and Rationale:

Endoscopic retrograde cholangiopancreatography (ERCP) is a complex procedure essential for diagnosing and treating various pancreaticobiliary disorders. Adequate sedation is critical for patient comfort and procedural success. Traditional conscious sedation with meperidine and diazepam remains widely used, particularly in resource-limited settings, but is associated with risks of respiratory depression, hypoxemia, hypotension, and inadequate sedation.

Transcutaneous electrical acupoint stimulation (TEAS) is a non-invasive modality derived from traditional acupuncture principles that delivers controlled electrical currents to specific acupoints via surface electrodes. TEAS has been shown to exert analgesic effects through the release of endogenous opioid peptides (elevating β-endorphin), modulate autonomic nervous system activity, reduce perioperative opioid requirements, suppress excessive inflammatory responses (reducing TNF-α and IL-6), and decrease the incidence of postoperative nausea and vomiting.

However, robust evidence on its efficacy and safety specifically during ERCP with traditional conscious sedation is lacking. This multicenter trial with an embedded mechanistic substudy aims to rigorously evaluate whether adjunctive TEAS improves procedural safety, tolerance, and clinical outcomes in patients undergoing ERCP, while simultaneously exploring the underlying neuro-endocrine-immune mechanisms. 2. Study Design and Methodology:

This is a prospective, randomized, sham-controlled, double-blind, parallel-group, multicenter trial with an embedded mechanistic substudy conducted at four centers: The Fifth Medical Center (lead site), The First Medical Center, The Third Medical Center of Chinese PLA General Hospital, and one additional participating site.

Patients scheduled for elective diagnostic or therapeutic ERCP will be assessed for eligibility. Eligible and consenting participants will be randomly assigned (1:1) using a computer-generated random allocation sequence with stratified block randomization (block sizes 4 and 6), with allocation concealment in sequentially numbered, opaque, sealed envelopes.

Participants will be allocated to one of two groups:

1. Active TEAS Group: Receives real TEAS stimulation applied bilaterally to four predefined acupoints: Neiguan (PC6), Xuehai (SP10), Yinlingquan (SP9), and Yanglingquan (GB34). The acupoint combination was designed based on traditional Chinese meridian theory and modern neuroanatomical evidence by the team from the PLA Institute of Traditional Chinese Medicine. Acupoint locations will be determined according to WHO Standard Acupuncture Point Locations. Disposable self-adhesive electrodes will be connected to a Hwato SDZ-III electronic acupoint stimulator (Suzhou Medical Supplies Factory Co., Ltd., China). Stimulation parameters are set to dense-disperse wave mode (alternating frequencies of 2 Hz and 10 Hz, each for 3 seconds). The intensity is adjusted to the patient's maximum tolerable level without pain (typically 2-10 mA). Stimulation begins 30 minutes before sedation induction and continues until 15 minutes after the completion of ERCP. 2. Sham TEAS Group: Receives identical electrode placement at the same four bilateral acupoints using the same device, but no electrical current is delivered. The device appears active (indicator lights on) to maintain blinding. All patients in both groups are informed that they may or may not feel any sensation during the stimulation, which is normal. 3. Standardized Sedation Protocol (Both Groups): All participants receive standardized conscious sedation. Sedation is induced with intravenous meperidine at an initial dose of 0.5 mg/kg and intravenous diazepam at an initial dose of 0.1 mg/kg, both administered slowly. The target sedation level is a Ramsay Sedation Scale score of 2-4. If adequate sedation is not achieved within 3-5 minutes, supplementary doses of diazepam (0.05 mg/kg, approximately one-third to one-half of the initial dose) may be administered at the discretion of the blinded anesthesiologist until the target Ramsay score is reached. The total doses of meperidine and diazepam are recorded for analysis. All patients receive topical pharyngeal anesthesia with 10 mL dyclonine hydrochloride mucilage and supplemental oxygen (3-5 L/min) via nasal cannula. ERCP procedures are performed by experienced endoscopists (each with \>500 prior ERCPs) who are also blinded to group assignment. 4. Blinding: A designated research assistant not involved in patient care, outcome assessment, or data analysis performs the TEAS or sham-TEAS intervention. The device display is shielded from the patient's view with opaque tape. Patients, endoscopists, recovery room nurses, outcome assessors, laboratory personnel performing ELISA assays, and data analysts are all blinded to group assignment. Blood samples are labeled only with the participant's study ID code. The TEAS practitioner cannot be blinded but is not involved in any outcome assessments or data collection.

3.Sample Size Calculation: Based on the primary outcome measure (composite incidence of SRAEs), from pilot data (n=30; SRAE rates: TEAS 13.3%, sham 33.3%) and published literature, the estimated incidence of SRAEs under traditional sedation is 25%. We hypothesize that active TEAS can reduce this to 12.5% (a 50% relative risk reduction). Using a two-sided α = 0.05 and a power of 80%, a total of 118 patients (59 per group) is required (χ² test). To account for a 10% dropout rate, the target sample size is increased to 130 patients (65 per group). This sample size is also sufficient to detect moderate-to-large effect sizes (Cohen's d ≈ 0.5-0.6) for the mechanistic biomarker analyses.

4.Statistical Analysis Plan:

1. Descriptive Statistics: Continuous variables: mean ± standard deviation (SD) if normally distributed, or median with interquartile range (IQR) if non-normally distributed. Categorical variables: frequencies and percentages (n, %). Baseline comparability: continuous variables using independent samples t-test or Mann-Whitney U test; categorical variables using χ² test or Fisher's exact test. 2. Primary Outcome Analysis: The composite incidence of SRAEs will be compared between groups using χ² test. Center stratification will be performed using Cochran-Mantel-Haenszel test to account for potential center effects. 3. Secondary Outcome Analysis: Continuous variables (sedative doses, VAS scores, recovery time, discharge time): independent samples t-test for normally distributed data, Mann-Whitney U test for non-normally distributed data. Repeated measures (MAP, HR at multiple time points): linear mixed model with group, time, and group-by-time interaction as fixed effects and center as a random effect. Categorical variables (satisfaction scores, adverse events): χ² test or Fisher's exact test. 4. Mechanistic Outcome Analysis: Changes in serum biomarkers (Δ = post-procedure - baseline) will be compared between groups using independent samples t-test or Mann-Whitney U test. Correlations between biomarker changes and clinical outcomes will be explored using Pearson or Spearman correlation coefficients. 5. Multivariable Analysis: Binary logistic regression for factors influencing sedation success rate and adverse events. Multiple linear regression for factors influencing VAS score, recovery time, and discharge time. 6. Center Effect: Heterogeneity across centers will be assessed using Cochran-Mantel-Haenszel test. If significant heterogeneity is detected, generalized linear mixed models (GLMM) with center as random effect will be used. 7. Statistical Software and Significance Level: SPSS version 27.0. Two-sided tests with significance level α = 0.05; P \< 0.05 considered statistically significant.

5.Scientific Justification: The selection of specific acupoints (PC6, SP10, SP9, GB34) is based on traditional Chinese medicine principles and modern physiological understanding: PC6 calms the spirit, suppresses nausea, and regulates cardiovascular function via modulation of autonomic tone; SP10 invigorates blood circulation, alleviates pain, and has anti-inflammatory properties; SP9 strengthens the spleen, resolves dampness, and provides adjunctive analgesia; GB34 relaxes tendons, activates collaterals, produces analgesia, and enhances dynamic cerebral autoregulation. The sham-controlled design is crucial for isolating the specific effects of electrical neuromodulation from non-specific placebo effects. The embedded mechanistic substudy, measuring β-endorphin, cortisol, TNF-α, and IL-6, will provide insights into the neuro-endocrine-immune pathways through which TEAS exerts its clinical effects. This trial addresses a significant gap in optimizing sedation for ERCP by evaluating a readily deployable, non-pharmacological adjunctive strategy that could enhance patient safety and procedural quality, particularly in settings where newer sedative agents or dedicated anesthesia services are not readily available.

• Procedure Success Rate [Срок оценки: Immediately after the endoscopy procedure]
• Total Dose of Sedatives and Analgesics [Срок оценки: Immediately after procedure]
• Mean Arterial Pressure (MAP) [Срок оценки: From baseline through PACU discharge (approximately 1-3 hours)]
• Heart Rate (HR) [Срок оценки: From baseline through PACU discharge (approximately 1-3 hours)]
• Patient Tolerance [Срок оценки: 30 minutes post-procedure]
• Recovery Time [Срок оценки: Post-procedure (approximately 10-60 minutes)]
• Discharge Time [Срок оценки: Post-procedure (approximately 0.5-2 hours)]
• Patient Satisfaction [Срок оценки: At post-anesthesia care unit discharge (approximately 1-2 hours post-procedure)]
• Endoscopist Satisfaction [Срок оценки: Immediately after the endoscopy procedure]
• Incidence of Postoperative Nausea and Vomiting (24 Hours) [Срок оценки: Within 24 hours post-procedure]
• Incidence of Post-ERCP Pancreatitis [Срок оценки: Within 7 days post-procedure]