2.1 Trial Design and Study Population
This study was a single-center, prospective, randomized, sham-controlled clinical trial conducted at Beijing Friendship Hospital affiliated to Capital Medical University in China. It was approved by the Bioethics Committee of Beijing Friendship Hospital, Capital Medical University (No. 2021-P2-315-01) and registered in the China Clinical Trials Registry (No.ChiCTR2100052837), and the first format of this study protocol is 10/10/2021/V1.0. It followed the Consolidated Standards of Reporting Trials (CONSORT) guidelines. The study protocol for this trial has been published in BMC Complement Med Ther [22]. All participants signed the informed consent form after being recruited by the anesthesiologist at the preoperative visit.
This study was performed from December 2021 to March 2023. A total of 275 patients undergoing elective gastric and esophageal endoscopic submucosal dissection were assessed for eligibility, and 129 patients were enrolled by study staff. The inclusion criteria were 18-75 years old, American Society of Anesthesiologists (ASA) Physical Status of I-III, 18 ≤ BMI ≤ 30 [body mass index = weight (kg)/height (m)2], and undergoing gastric and esophageal ESD. They will be excluded from the trial if they have the following conditions: ① With surgical incision or scar on the meridian of the acupoints of Hegu (L14), Neiguan (PC6), Shangjvxu (ST37), and Zusanli (ST36); ② Local skin infection at the acupoints above; ③ There is nerve injury on the upper or lower limbs; ④ The patient participated in other clinical trials within the last 4 weeks; ⑤ The patient does not understand the Visual Analogue Scale (VAS) score and Numeric Rating Scale (NRS) score or the patient is unable to perform the scoring; ⑥ Fitted with a pacemaker; ⑦ Pregnancy, in labor, or with a positive urine pregnancy test; ⑧ Preoperative pain, ongoing use of central analgesic medications, and addiction or dependence on opioids; ⑨ Severe central nervous system disease or psychiatric disorders; ⑩ Considered unsuitable for participation.
2.2 Randomization and Blinding
Randomization was performed using computer-generated random numbers with a block size of 4, the allocation was sealed in an opaque envelope. Subjects were randomly assigned to the sham group or the TEAS group with a ratio of 1:1 by the anesthesiologist. As a single-blind trial, only the anesthesiologist and acupuncturist who was in charge of the TEAS stimulation were aware of the grouping, the patients, surgeons, and physicians responsible for follow-up were unaware.
2.3 Intervention
Both TEAS and sham stimulation were performed by a licensed acupuncturist with more than 3 years of practice. Patients in both groups received the intervention from 30 minutes before surgery until the end of surgery.
Patients in the TEAS group were treated bilaterally at the Hegu (L14), Neiguan (PC6), Zusanli (ST36), and Shangjuxu (ST37) (The detail of the location of acupoints were in the Figure 1. The location of acupoints. A. The location of L14, PC6. L14 is Hegu acupoint; PC6 is Neiguan acupoint. B. The location of ST36, ST37. ST36 is Zusanli acupoint; ST37 is Shangjvxu acupoint.). Self-adhesive electrodes with wires were attached to the location of these 4 acupoints and connected to the HANS acupoint nerve stimulator (HANS-200A, Nanjing Jisheng Medical Technology Co., Ltd., China), setting the current frequency to 2/100Hz (the wave width at 2 Hz was 0.6 ms, and at 100 Hz was 0.2ms), alternating frequency for 3s, and stimulation intensity to the patient's maximum tolerance level.
Figure 1. The location of acupoints. A. The location of L14, PC6. L14 is Hegu acupoint; PC6 is Neiguan acupoint. B. The location of ST36, ST37. ST36 is Zusanli acupoint; ST37 is Shangjvxu acupoin
In the sham group, two of the sham points were located at 7 cun above and 1 cun outside Shenmen (HT7), and 7 cun above and 1 cun outside HT7. The other two sham points were at 9 cun and 12 cun above Kunlun (BL60) (Figure 2. The location of sham points. A. The location of sham points 1 and 2. HT7 is Shenmen acupoint. B. The location of sham points 3 and 4. BL60 is Kunlun acupoint.). Self-adhesive electrodes were glued to these points, but no electrical stimulation was given from the HANS stimulator.
Figure 2. The location of sham points. A. The location of sham points 1 and 2. HT7 is Shenmen acupoint. B. The location of sham points 3 and 4. BL60 is Kunlun acupoint.
2.4 Anesthesia procedures
On the day before surgery, all enrolled patients signed informed consent and received relevant education on the implementation and follow-up of this study. Electrocardiogram, blood pressure, pulse oxygen saturation, and bispectral (BIS) were monitored before anesthesia. TEAS and sham stimulation were conducted by the experienced acupuncturist 30 minutes before the surgery. Midazolam 0.03mg/kg, remifentanil 1-2μg/kg, etomidate 0.1-0.2mg/kg and rocuronium 0.6-0.8mg/kg were used before intubation. Anesthesia was maintained with a total intravenous infusion of propofol (4-6mg/kg/h), remifentanil (0.05-0.2µg/kg/min), and rocuronium (one-third of the induced dose every 40min). Anesthetic depth was controlled by the adjustment of intravenous propofol to maintain a bispectral index of 45-55 during the procedure. Tramadol 50mg was applied for analgesia 30 minutes before the end of ESD surgery. At the end of the surgery, the patient was extubated and transferred to the post-anesthesia care unit (PACU) in routine.
The Visual Analogue Scale (VAS) was used to assess the patient’s pain level. If the VAS score≥4 points or the patient requested analgesia during the follow-up, morphine 1mg was administered intravenously. The Numerical Rating Scale (NRS) was used to evaluate the degree of nausea. If NRS≥7 or vomiting occurred, a serotonin 3 receptor antagonist was given. The concomitant medication during the trial period from the start of surgery to 2 days after the end was recorded.
2.5 Outcomes
The primary outcome was a visual analog scale (VAS) score at different time points which were 5 minutes, 10 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 18 hours, 24 hours, 48 hours postoperatively. The scale was 0-10 cm, 1-3 cm for mild pain, 4-6 cm for moderate pain, and 7-10 cm for severe pain. Secondary outcomes included the incidence of post-ESD VAS≥4 and the consumption of morphine during follow-up, gastrointestinal function recovery time, the incidence of postoperative complications, and patient satisfaction. These outcomes were recorded by an anesthesiologist specializing in follow-up.
For recovery of gastrointestinal function, we mainly recorded the time of first flatus, defecation, drink, and solid food intake. The main recorded postoperative complications were hypertension, hypotension, tachycardia, bradycardia, nausea and vomiting [measured with the 0-10 cm numeric rating scale (NRS)], gastrointestinal perforation or bleeding, reoperation, and fever. Postoperative adverse events will also be recorded by the follow-up anesthesiologist, and in the event of a malignant event such as bleeding >500 ml, the trial will be immediately terminated and reported to the Principal Investigator and a review board will be established.
2.6 Statistical Analysis
The sample size was calculated based on the outcomes of our pre-trial. In the pre-trial, we observed that patients always felt no pain or tolerated pain completely within half an hour after extubation. It was only at approximately 1 hour postoperatively that patients felt obvious pain. Therefore, we applied the VAS score at 1 hour postoperatively to calculate the sample size: it was 0.86±1.14 (mean±SD) in the TEAS group and 1.68±1.46 (mean±SD) in the sham group. Setting an α of 0.05, a β of 0.1, and a power of 0.9, plus a 10% dropout rate, we calculated that a total of 120 cases were needed using PASS 11.0. 60 cases per group were required.
All data were described and analyzed using SPSS. Continuous variables were reported as mean±SD or median (IQR), where normally distributed data were analyzed for differences between groups by t-test, and skewed data were by Mann-Whitney U test. Categorical variables were reported as the number of cases (percentages) and intergroup differences were analyzed by chi-square test or Fisher's test. A P value less than 0.05 indicates a statistically significant difference. Perioperative factors were analyzed using univariate and multivariate logistic regression analysis, and the resulting odds ratio (OR) values, 95% confidence intervals (95%CI), and P values were provided. The potential influencing factors included in this trial were derived from previous investigations [7,8].