ST36 acupoint injection with anisodamine for postoperative nausea and vomiting in female patients after bariatric surgery: a prospective, randomized controlled trial

Background The use of multimodal pharmacological prophylactic regimes has decreased postoperative nausea and vomiting (PONV) in general but it still occurs in over 60% of female patients after bariatric surgery. This study aimed to evaluate the efficacy of ST36 acupoint injection with anisodamine in prevention of PONV among female patients after bariatric surgery. Methods Ninety patients undergoing laparoscopic sleeve gastrectomy were randomly allocated to anisodamine or control group at the ratio of 2:1. Anisodamine or normal saline was injected into Zusanli (ST36) bilaterally after induction of general anesthesia. The incidence and severity of PONV were assessed during the first 3 postoperative days and at 3 months. The quality of early recovery of anesthesia, gastrointestinal function, sleep quality, anxiety, depression, and complications were also evaluated. Results Baseline and perioperative characteristics were comparable between two groups. In the anisodamine group, 25 patients (42.4%) experienced vomiting within postoperative 24 h compared with 21 (72.4%) in the control group (relative risk 0.59; 95% confidence interval 0.40–0.85). Time to first rescue antiemetic was 6.5 h in anisodamine group, and 1.7 h in the control group (P = 0.011). Less rescue antiemetic was required during the first 24 h in the anisodamine group (P = 0.024). There were no differences in either postoperative nausea or other recovery characteristics. Conclusions The addition of ST36 acupoint injection with anisodamine significantly reduced postoperative vomiting without affecting nausea in female patients with obesity undergoing laparoscopic sleeve gastrectomy. Supplementary Information The online version contains supplementary material available at 10.1007/s00464-023-10037-6.

among others [6]. However, there is little work exploring the preventive efficacy of anisodamine in PONV.
There are substantial evidence supporting acupuncture as an adjunctive treatment for postoperative or chemotherapyinduced nausea and vomiting [7,8]. Repeated acupuncture or continuous electrical acupoint stimulation on Zusanli (ST36) has been used to alleviate PONV [9] and enhance bowel function recovery [10]. However, this repetitive and continuous maneuver is accompanied by the risk of needle dislodgement and requires continual attention throughout surgery. Therefore, reducing the duration and complexity while ensuring efficacy is a priority when using acupuncture to prevent nausea and vomiting.
We hypothesized that adding anisodamine to ST36 acupoint injection would obviate the need for repeated needling and improve its efficacy in preventing PONV. To compare this form of acupuncture to combination prophylaxis, we designed this double-blinded, randomized controlled trial among female patients undergoing laparoscopic sleeve gastrectomy (LSG).

Trial design and ethics
This single-center prospective, randomised, double-blinded study was approved by the Ethics Committee of the Second Affiliated Hospital of Anhui Medical University, Anhui province, China (Chairperson Prof. Yanghua Tian) on December 2, 2021 in accordance to the principles of the Declaration of Helsinki. The trial was registered in clinicaltrials.gov (NCT05240482) and carried out at the Second Affiliated Hospital of Anhui Medical University from 20 February to 6 July 2022. Written informed consent was obtained from all participants. The time period of this trial consisted of a 72-h follow-up after bariatric surgery in the hospital and a follow-up period of an additional 3 months after discharge.
The LSG was performed by the same bariatric surgical team, basically referring to the International Sleeve Gastrectomy Expert Panel Consensus Statement [11]. Gastric resection began 4-6 cm proximal to the pylorus and reserved 1 cm lateral to the angle of His, with a calibration 36 F bougie.

Participants
All adult female patients with an American Society of Anesthesia (ASA) physical status I-III, scheduled for elective LSG surgery were screened. The exclusion criteria: contraindications to acupoint injection, such as a local rash at the site of skin injection or systemic infection, any history of allergic diathesis for drugs used in the study, gastroesophageal reflux, severe obstructive sleep apnea hypopnea syndrome (OSAHS), uncontrolled systemic diseases of the heart, lung, kidney, or liver, coagulation derangements, psychological disorder, current use of medications before surgery that would interference with relevant assessments (including the use of opioids, antiemetics or glucocorticoids), obesity due to a diagnosed endocrine disorder and without consent.

Randomization and blinding
All participants were randomly assigned to anisodamine group (bilateral ST36 acupoint injection with anisodamine) or control group (bilateral ST36 injection with normal saline) in a 2:1 ratio. The randomization was computergenerated by using www. random. org.
The allocation sequence was concealed until the end of data collection, and the drug or placebo was prepared by the independent researcher thus maintaining blinding of the patients, acupuncturist, outcome assessors.

ST36 acupoint injection and PONV management
Acupuncture treatment was performed by a licensed acupuncturist who had at least 5 years of acupuncture experience. All participants received bilateral ST36 acupuncture injection with anisodamine (5 mg/1 ml per site) or normal saline (1 ml per site) [12].
All patients received prophylaxis for PONV with dexamethasone (10 mg i.v.) during GA induction, and dorasetron (12.5 mg) at 20 min before the end of surgery [13].

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Droperidol (1.25 mg i.v.) followed by dorasetron (12.5 mg i.v.) was administered as rescue medication if patients experienced PONV during AICU stay. All patients were routinely received ondansetron to prevent PONV on postoperative day (POD) 1.

Outcomes
The primary outcome is the incidence of vomiting within the first 24 h postoperatively.
The secondary outcomes include: the time to the first rescue antiemetic; the incidence of PONV assessed at 2, 6, 48, and 72 h after surgery; the severity of PONV measured by the Verbal Rating Scale (VRS) (none, mild, moderate, or severe) at the same time points; the incidence of postoperative complications; the early recovery outcomes indicators (the time of first drink, ambulate and flatus) and the postoperative LOS. Time to first rescue antiemetic was defined as the time from extubation to the first rescue antiemetic. The changes in gastrointestinal function, sleep-related quality of life, anxiety and depression status from baseline to postoperative 3 months were assessed by the Gastrointestinal Symptom Rating Scale (GSRS) [14], the Pittsburgh Sleep Quality Index Scale (PSQI) [15], Hamilton Anxiety Rating Scale (HAMA) [16] and Hamilton Depression Rating Scale (HAMD) [17], respectively. The higher scores indicate the worse symptoms.

Statistical analysis
Based on the incidence of postoperative vomiting in our pilot study, the proportions of patients who experienced vomiting within 24 h after surgery in the control group and anisodamine group were 80% and 40% respectively (Table S1). The sample size was calculated to be 84 patients (28 in control and 56 in anisodamine), with a significance level of 5% in the two-sided test and a detection power of 95% which allowing for 15% loss to follow-up.
Continuous variables were presented as mean ± standard deviation (SD) if normally distributed or median (interquartile ranges, IQR) if not. The assumption of data normality was confirmed using a Shapiro-Wilk test. The comparisons between groups were conducted with t-tests or Wilcoxon rank sum tests as appropriate. Categorical data were presented as frequencies (percentages) and analyzed with Chisquare tests or Fisher's exact tests. Relative risks (RR) with 95% CIs (confidence intervals) were estimated with the logbinomial model for the incidence of postoperative vomiting. For the time to first rescue antiemetic, we calculated the estimates of the median with 95% CIs using the Kaplan-Meier method and the difference between curves were assessed with the log-rank test. Hazard ratio with 95% CI of incidence of vomiting in 24 h after surgery between two groups was estimated with a Cox proportional hazard model. We further assessed their BMI, gastrointestinal function, sleep-related quality of life, anxiety and depression status from baseline to postoperative 3 months with paired t-tests or Wilcoxon signed-rank tests. Analyses were performed with SAS version 9.4 (SAS Institute Inc.). Two-sided P values less than 0.05 were considered statistically significant.

Results
A total of 124 patients with obesity who underwent LSG were screened and 90 patients were randomly assigned to receive bilateral ST36 acupoint injection with either anisodamine (60 patients) or control (30 patients) (Fig. 1). Eightyeight patients (59 in the anisodamine group and 29 in the control group) were included in the final analyses as two patients did not complete the postoperative assessments during the first 72 h. Overall baseline and perioperative characteristics of patients were similar between the two groups (Table 1). Moreover, seven patients lost follow-up at postoperative 3 months, and their data were excluded from the followed-up analysis.
The number of patients who experienced vomiting within postoperative 24 h was 25 (42.4%) in the anisodamine group compared with 21 (72.4%) in the control group (relative risk, RR 0.59; 95% CI 0.40-0.85; P = 0.005). There was a significant difference in the proportion of vomiting in the first 2 h (22.0% for anisodamine group vs. 44.8% for control group) with RR of 0.49 (95% CI 0.26-0.92; P = 0.027). The difference was nearly reached statistical significance until postoperative 6 h (RR 0.44; 95% CI 0.19 to 1.01; P = 0.054). There was no difference in the incidence of vomiting between the two groups from 6 h to 3 days postoperatively ( Fig. 2 and Table S2).
The time to first rescue antiemetic was significantly longer in the anisodamine group than in the control group (hazard ratio, HR 0.47; 95% CI 0.25-0.89; P = 0.011). Median time to first rescue antiemetic was 6.5 h (95% CI 4.5-7.9) in the anisodamine group, and 1.7 h (95% CI 0.0-4.4) in the control group (Fig. 3). There was also less use of rescue dorasetron in the first postoperative 24 h in the anisodamine group than the control group (P = 0.024) ( Table 2).
A similar incidence of postoperative nausea during the first 24 h were seen in the two groups with 47 patients (79.7%) in the anisodamine group and 26 patients (89.7%) in the control group (RR 0.89; 95% CI 0.74-1.06; P = 0.195). Also, a similar proportion of nausea were also found in the two groups within postoperative 3 days. The severity of PONV during postoperative 3 days in the anisodamine group and control group showed no significant difference (P > 0.05). Moreover, we found no significant difference between the two groups in the early recovery outcomes, the scores of Quality of Recovery-15, as well as the postoperative LOS (Table 2). Table 3 shows a similar incidence of adverse events in the participants. One patient experienced pulmonary infection on POD2, and two patients experienced of staple-line leak on POD8 and POD12, respectively. The overall rate of reported adverse events in 3 months postoperatively was similar between the anisodamine group (49.0%) and the control group (46.2%). The most common event was alopecia with a total incidence of 43.2% (Table 3).
Patients reported significant weight loss after 3 months in both groups, with a similar level in %Excess BMI Lost (median 66.8, IQR, 50.5, 84.8 in the anisodamine group and median 66.8, IQR, 45.1, 77.9 in the control group, P = 0.459). The total scores of the PSQI, GSRS, and HAMD in both groups also decreased at the end of 3 months postoperatively (POM3) (P < 0.05) with a similar degree. However, the scores of HAMA were similar in both groups at baseline and POM3 (Table S3).

Discussion
In this trial, anisodamine was creatively used on ST36 acupoint injection in female patients during LSG. During the first postoperative 24 h, we successfully observed a significant reduction of the incidence of vomiting, an increase of the time to first rescue antiemetic, as well as less rescue antiemetic in patients with anisodamine injection. It's noted that ST36 acupoint injection without or with anisodamine had no effect on the early recovery in the hospital and quality of life after discharge.
Since female gender is one of the strongest patients-specific predictors among recognized independent risk factors for PONV [18], we targeted female patients with obesity in this trial. The International Society for the Perioperative Care of the Patient with Obesity (ISPCOP) and the American Society for Metabolic and Bariatric Surgery (ASMBS) recommended using multimodal pharmacologic antiemetic regimens for the prophylaxis of PONV in bariatric surgery, regardless of the preoperative risk scores for PONV [18]. To manage PONV, we used a combination of antiemetics for prophylaxis and rescue. As indicative of the high rate of PONV in bariatric surgery, the proportion of vomiting within postoperative 24 h in the control group was 72.4%, which is similar to the rates reported in the previous study [19]. Compared with female patients undergoing laparoscopic gynecological surgeries, female patients who underwent LSG had a significantly higher occurrence of PONV (23.0% vs. 66.2%) [20]. Operation-and anesthesia-related risk factors may also increase the occurrence of PONV, including intravascular volume deficits, intraoperative opioid consumption, and volatile anesthetic use [13,21,22]. The operations were performed with 15 mmHg intra-abdominal pressure insufflated by carbon dioxide in the reverse Trendelenburg position, gastrointestinal hypoperfusion caused by pneumoperitoneum may impair gastrointestinal function and promote the occurrence of PONV [23]. Anisodamine, scopolamine and atropine are common tropine alkaloids with similar pharmacological effects [6], which are widely used for treating spasms, inflammation, septic shock and gastric disorders [24]. Among these, scopolamine, when used as an antiemetics, can provide a similar effect as antihistamines in preventing PONV [25]. However, several randomized controlled trials (RCTs) have shown that the preventive effect of scopolamine against PONV was not significant [26,27], but can cause dry mouth and blurry vision [28]. Compared to scopolamine, anisodamine has less adverse effect on central nervous system [6] and has similar efficacy as an anti-spasmodic. A multicenter trial indicated that anisodamine and scopolamine have similar efficacy in reliving gastric or intestinal spasm-like pain by inhibiting smooth muscle contractility [29]. The suggested mechanisms are direct acting on the cholinoceptor in the lateral reticular formation of the medulla oblongata, antagonising cholinergic transmission to the vomiting center [30] and producing peripheral and central antimuscarinic actions [31]. Since the cholinoceptors are also located in cardiac vascular and airway smooth muscle, one should carefully monitor any potential side effects with anisodamine [32]. In this trial, no adverse events such as tachyarrhythmia, palpitations, blurred vision, and bowel obstruction, were observed in the anisodamine group. This indicates a better safety margin of anisodamine. In addition, the pilot trial showed that intravenous injection with anisodamine has similar preventive effect as the standard prophylaxis.
Acupuncture, as a nonpharmacologic prophylaxis therapy, has been proposed as an alternative option for multiple multimodal antiemetic therapy because of its safety and affordability [33]. Studies have shown that multiple or prolonged stimulation at one acupoint or multiple acupoints would lower the incidence of PONV. Preoperative bilateral stimulation on PC6 and ST36 acupoints on the day of surgery and the next morning for 30 min lowered the incidence of vomiting by 7.4% in a study of 1655 patients from 12 hospitals undergoing laparoscopic non-gastrointestinal surgery [34]. In female patients undergoing LSG, thrice transcutaneous electrical acupoint stimulation at ST36 acupoint for 30 min (before induction, postoperative 2 h and 6 h) decreased PONV in the first 48 h from 77.4 to 41.9% [9]. In contrast to these complex interventions, we succeeded in reducing the incidence of postoperative vomiting by 30% with a single injection of anisodamine at one acupoint thus simplifying the process while maintaining its effectiveness. Another RCT also found that a combination of ondansetron and ST36 acupoint injections with vitamin B1 provided a significant preventive effect of PONV in laparoscopic surgery [35].
In addition to prophylactic antiemetics, minimizing opioid use through multimodal analgesic regimens can also be effective in reducing the risk of PONV. We established a multimodal analgesic regimen, including perioperative administration of dexmedetomidine and transverse abdominal plane block, in the standardized GA protocol to partially reduce the risk of PONV. A meta-analysis including 697 participants underwent bariatric surgery also indicated that dexmedetomidine significantly reduced PONV in post  anesthesia care unit and POD1 with OR from 0.24 to 0.28 [36]. The addition with transversus abdominis plane block was also related with less proportion of PONV [37]. For safety outcomes, a total of three patients (3.4%) were diagnosed with leaks within the two groups, which is higher than the previous reported of less than 1.0% [38,39]. One of the patients in the anisodamine group has suffered from staple-line leak for almost 2 months. It may be related to her diabetes and might cause in a decreased ability of the tissue to heal. It is reported that, besides complications (i.e., diabetes, sleep apnea), age, surgical technique and operation (i.e. stapling technique, Bougies size) may also cause the high incidence [40,41], as well as preoperative factors, like weight loss [42]. Therefore, follow-up studies are needed to address this issue further.

Strengths and limitations
This trial, based on previous studies, simplifies the procedure and duration of acupuncture and provides a comparable preventive effect on postoperative vomiting, which contributes to the popularization of acupuncture in preventing PONV. The results also provide strong evidence using anisodamine for PONV prevention.
This trial has several limitations. First, this study was conducted in a population with a high risk of PONV and achieved a 30% reduction. It was considered unlikely that this intervention could achieve a comparable effect among female patients undergoing other surgical groups. Vomiting

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in postoperative 24 h still occurred in 42% of patients who received ST36 acupoint injection with anisodamine. Thirdly, compared to standard prophylaxis, ST36 acupoint injection with anisodamine did not reduce the incidence of postoperative nausea. In addition, the leak rate in this study was higher than the previous reported. Further exploration of effective preventions for this population is still needed.

Conclusions
ST36 acupoint injection with anisodamine had incremental benefit when used as part of combination prophylaxis for reducing PONV. It could be a new option contained in multimodal prophylactic antiemetic regime in female patients undergoing laparoscopic sleeve gastrectomy.
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