The protocol for this trial is reported based on the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Checklist: defining standard protocol items for clinical trials (Additional file 1). The study has been approved by the Ethics Committee of Beijing Friendship Hospital (the approval number from the Ethics Committee is 2019-P-065-01) and has been registered in the Chinese Clinical Trial Registry (Chictr) (registration number: ChiCTR1900023263).
In the sham group, the sham points are at 7 cun and 9 cun above Shenmen (HT7) and outside 1 cun (Fig.3). The other two sham points are at 9 and 12 cun above the Kunlun (BL60) (Fig.3). There are no meridian and channels through these four sites, and thus we will use these positions as our sham points. We will put the electrode on the sham points and connect it to the HANS stimulator but not administer any stimulation. The same doctor will go to the ward, put the electrode on these points and connect it to the stimulator (not open) at the same time after surgery, until the first flatus recovery.
Postoperative analgesia measures and remedial plan: The analgesic pump configuration: after the operation, the intravenous analgesic pump (PCIA) was connected, and the analgesic formula sufentanil 250ug was added with normal saline to 250ml, 2ml/h, and PCA 3ml at an interval of 15min.①Analgesia recovery: subjects were given Flubiprofen 50 mg/ivgtt in the ward when the pain VAS score was ≥4 points and the pain score was still ≥4 points after 5 consecutive effective PCA compressions.②Remedy of nausea and vomiting: NRS method was used for nausea score. When nausea score ≥7 points or vomiting ≥1time, serotonin 3 receptor antagonist was given. The remedial medication should be recorded in the remedial medication list.③Concomitant medication record: concomitant medication during the trial period (from the start of surgery to 5 days after the end of surgery).
2.5 Outcome assessment
A blind observer from the data monitoring committee will collect all outcome data after surgery. The primary outcomes of this study will be time to first bowel motion, time to fist flatus and time to defecation. This information will be obtained from participant questionnaires filled out once daily with the help of nurse staff. The same surgical residents will listen to the bowel sounds every 4 h postoperatively. Time to first bowel motion is the duration until regular bowel sounds (more than two sounds every minute) are first heard after surgery . To observe changes in plasma brain-gut peptides, such as 5-HT, substance P (SP), vasoactive gut peptide (VIP), gastrin and cholecystokinin (CCK), we will collect venous blood from patients before the operation and 1st day and 3rd day after the operation and then will centrifuge and freeze the plasma supernatant for later testing. We cooperate with our clinical experimental center to collect, code, centrifuge, freeze store, store and test blood samples by a professional team.
Secondary endpoints will include the VAS score of postoperative pain, vomitting and nausea, length of stay in the ICU, length of stay in the hospital, and cost of stay in the hospital, as well as clinical complications such as fever, pneumonia, wound infection and bleeding. Secondary outcome will be assessed by the medical team. The length of hospital stay is calculated as the number of days from the date of the operation to the date of discharge. Criteria for hospital discharge will include stable vital signs, the ability to tolerate solid foods after defecation without nausea or vomiting, and the occurrence of no other complications after the operation.
2.6 Sample size calculation
Due to a lack of related reports on the preventive usage of TEAS in patients undergoing GI surgery, we evaluated the effectiveness of TEAS according to our pre-experimental results. A priority-effectiveness test was used, and the ratio between the groups was 1:1. According to the pre-experimental results, the odds ratio (OR) of the TEAS group over the sham TEAS group was 1.5, estimating that 80% of patients were followed up for endpoint events. The COX regression sample size calculation formula was used to complete the sample size estimation. We set unilateral α = 0.05, power = 0.80, and β = 0.10, PASS 2011 software was used for sample estimation, and a total of 256 effective cases were estimated. According to the above sample estimation result and assuming 10% patient loss, a minimum of 280 cases is required. Therefore, we have set the required number of cases in this study to 280 cases, including 140 cases in the TEAS group and 140 cases in the sham TEAS group. Our General Surgery Department performs 400-500 cases of GI surgery per year, and consequently, this study period is set at 2 years.
2.7 Statistical methods
Statisticians are responsible for negotiating with major researchers to develop statistical analysis plans, establish databases, and conduct statistics with the SPSS statistical analysis system. All data will be collated by statisticians. The intention processing principle in SPSS 22.0 will be used for the data analysis. A unilateral test will be used for statistical results, and a P value < 0.05 will be considered statistically significant. The results will be expressed as the mean ± standard deviation. The t-test will be used for the normality and homogeneity of data, the hypothesis test of superiority will be used for major outcome indicators, the chi-square test will be used for normal distribution data, and the rank sum test or Fisher exact probability method will be used for non-normal distribution data. Statistical methods for the main efficacy indicators have been determined by the Capital Medical University statistical department.
2.8 Data collection methods and monitoring
The statistical professionals are responsible for formulating the statistical analysis plan through consultation with the main researchers, establishing the database, and using the SPSS statistical analysis system for statistics. A comprehensive efficacy analysis was conducted in accordance with the program set, and the whole analysis set, demographic and other baseline characteristics, and other efficacy indicators were analyzed in accordance with the program set.
The Data Monitoring Committee (DMC) is consisting by a doctor in charge of data collection and sorting, a scientific research manager and a statistician. Doctor from DMC will record the actual number of subjects enrolled, the cases of exclusion, demographic and other baseline characteristics, compliance analysis, safety analysis, incidence of complications and combined treatment, and comprehensive efficacy evaluation. The demographic characteristics, medical history and treatment history of the patients will be described, including the comparison of age, gender, disease course and disease condition at the time of enrollment. The scientific research management committee will have access to the final trial dataset. At the end of the study, the original data and results will be submitted to the scientific research management committee, and they will be disclosed to the public after the results are published.
2.9 Safety evaluation
Adverse events (AEs) are the appearance or progression of any symptoms of discomfort, syndromes or diseases that occur during a clinical trial and affect the health of the subject. Any abnormalities in clinical testing that indicate the presence of disease and/or organ toxicity and serious abnormalities requiring active treatment (such as withdrawal of medication, increased follow-up, and diagnostic studies) are considered AEs. In the process of clinical research, researchers should fill in the AEs record form truthfully and in detail, recording the clinical manifestations, occurrence time, severity, duration, measures taken and outcomes of AEs.
When an AE occurs, the observing physician may decide whether to suspend the observation or not according to the condition. All AEs should be tracked and documented in detail until the subject is properly resolved or is in stable condition, and if laboratory tests are abnormal and clinically significant, they should be tracked back to pretreatment levels.