This randomized clinical trial investigates if electroacupuncture promotes postoperative recovery in patients after laparoscopic bowel resection for colorectal cancer compared with sham electroacupuncture.
Key Points
Question
In the current medical practice adopting the Enhanced Recovery After Surgery (ERAS) protocol, does electroacupuncture promote postoperative recovery in patients after laparoscopic bowel resection for colorectal cancer compared with sham electroacupuncture?
Findings
In this randomized clinical trial of 248 patients, compared with sham electroacupuncture, electroacupuncture shortened the duration of postoperative ileus and reduced the incidence of prolonged postoperative ileus after laparoscopic resection of colorectal cancer, and no serious adverse events were reported.
Meaning
Results of this trial show that electroacupuncture is effective in promoting gastrointestinal function recovery within the ERAS protocol.
Abstract
Importance
Despite the adoption of the optimized Enhanced Recovery After Surgery (ERAS) protocol, postoperative ileus (POI) severely impairs recovery after colorectal resection and increases the burden on the health care system.
Objective
To assess the efficacy of electroacupuncture (EA) in reducing the duration of POI with the ERAS protocol.
Design, Setting, and Participants
This multicenter, randomized, sham-controlled trial was conducted in China from October 12, 2020, through October 17, 2021. There was a 1:1 allocation using the dynamic block random method, and analyses were by intention to treat. Patients 18 years or older undergoing laparoscopic resection of colorectal cancer for the first time were randomly assigned to treatment group by a central system.
Interventions
Patients were randomly assigned to 4 sessions of EA or sham electroacupuncture (SA) after surgery. All patients were treated within the ERAS protocol.
Main Outcomes and Measures
The primary outcome was the time to first defecation. Secondary outcomes included other patient-reported outcome measures, length of postoperative hospital stay, readmission rate within 30 days, and incidence of postoperative complications and adverse events.
Results
A total of 249 patients were randomly assigned to treatment groups. After the exclusion of 1 patient because of a diagnosis of intestinal tuberculosis, 248 patients (mean [SD] age, 60.2 [11.4] years; 153 men [61.7%]) were included in the analyses. The median (IQR) time to first defecation was 76.4 (67.6-96.8) hours in the EA group and 90.0 (73.6-100.3) hours in the SA group (mean difference, −8.76; 95% CI, −15.80 to −1.73; P = .003). In the EA group compared with the SA group, the time to first flatus (median [IQR], 44.3 [37.0-58.2] hours vs 58.9 [48.2-67.4] hours; P < .001) and the tolerability of semiliquid diet (median [IQR], 105.8 [87.0-120.3] hours vs 116.5 [92.0-137.0] hours; P = .01) and solid food (median [IQR], 181.8 [149.5-211.4] hours vs 190.3 [165.0-228.5] hours; P = .01) were significantly decreased. Prolonged POI occurred in 13 of 125 patients (10%) in the EA group vs 25 of 123 patients (20%) in the SA group (risk ratio [RR], 0.51; 95% CI, 0.27-0.95; P = .03). Other secondary outcomes were not different between groups. There were no severe adverse events.
Conclusions and Relevance
Results of this randomized clinical trial demonstrated that in patients undergoing laparoscopic surgery for colorectal cancer with the ERAS protocol, EA shortened the duration of POI and decreased the risk for prolonged POI compared with SA. EA may be considered as an adjunct to the ERAS protocol to promote gastrointestinal function recovery and prevent prolonged POI after surgery.
Trial Registration
Chinese Clinical Trial Registry Identifier: ChiCTR2000038444
Introduction
Postoperative outcomes in colorectal cancer surgery have improved with the implementation of the Enhanced Recovery After Surgery (ERAS) protocol.1,2 However, postoperative ileus (POI), an inevitable complication of gastrointestinal (GI) function, continues to impair recovery, increase health care costs into the billions, and is associated with extended hospitalizations.3,4
Despite the use of multiple strategies to promote the recovery of postoperative GI function, few studies of those strategies demonstrated a clear benefit since the introduction of the ERAS protocol.5 Conflicting data on efficacy and costs and concerns over cardiovascular complications limit the clinical application of alvimopan, particularly in light of the adoption of the ERAS protocol.6,7 The practice of gum chewing and coffee consumption were found to reduce the time to first bowel movement but only in patients with prolonged fasting.6,8,9 Lipid-enriched enteral nutrition was not superior to standard care for postoperative complications in laparoscopic colorectal surgery with the ERAS protocol.2
The inflammatory response induced by surgical trauma and gut manipulation is essential in the development of GI dysmotility associated with POI.10 Electroacupuncture (EA), a potential treatment option for postoperative nausea and vomiting and functional GI disorders,11,12 was recently found to reduce inflammation via activating the vagal-adrenal pathway.13 Similarly, we reported that EA protected smooth muscle cells and improved GI transit by reducing local intestinal musculature inflammation in POI.14 Several systematic reviews over recent years reported the promising effects of acupuncture for the recovery of GI function after surgery,15,16,17 but the benefits of acupuncture for patients after laparoscopic bowel resection remain unclear, especially in the current medical practice adopting the ERAS protocol.18 We therefore conducted this large-scale, multicenter, randomized clinical trial to assess the efficacy and safety of EA for POI in patients after laparoscopic surgery for colorectal cancer using the ERAS protocol.
Methods
Trial Design and Participants
This study was a multicenter, randomized, sham-controlled, clinical trial conducted in 4 tertiary hospitals in China. The study was approved by the institutional review boards at the coordinating center and each study site. The study was registered at the Chinese Clinical Trial Registry. Details of trial design and analysis plans are presented in Supplement 1. All patients signed written informed consent prior to participation. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.
Patients at least 18 years or older undergoing first-time laparoscopic resection of colorectal cancer with primary anastomosis were screened for inclusion. Patients were excluded if they were to receive epidural anesthesia, enterostomy, or other abdominal organ resection; had a psychiatric disorder; had a history of drug or alcohol abuse; received acupuncture within 1 month before enrollment; and had a pacemaker or other electrical stimulation device.
Randomization and Masking
Eligible postoperative patients were randomly assigned (1:1) to the EA group or the sham electroacupuncture (SA) group using dynamic block randomization. Randomization was achieved via a central web-based system for clinical research (Yale Joint Center for Biostatistics) and stratified within the 4 enrollment hospitals. The randomization sequence was created by a statistician who did not participate in the study. Patients, surgeons, and outcome assessors were masked to group assignment, but acupuncturists were not.
Interventions
Needling procedures of both the EA and SA groups were administered by licensed acupuncturists with 5 to 12 years education of acupuncture and at least 3 years of clinical experience. They had all undergone unified and standardized training before trial initiation. Patients received 30-minute EA or SA once a day for 4 consecutive days after surgery.
Patients in the EA group received acupuncture at acupoint Zhongwan (RN12) and bilateral acupoints Tianshu (ST25), Zusanli (ST36), and Shangjuxu (ST37) (eTable 1 and eFigure in Supplement 2). Disposable stainless-steel needles were used in all acupuncture treatments, and manual manipulation was applied to all needles to elicit acupuncture de qi sensation (aching, soreness, swelling, heaviness, or numbness) after needle insertion.19 The blinding procedure was validated in a previous study.20 Paired electrodes from the HANS acupoint nerve stimulator (HANS-200A; Nanjing Jisheng Medical Co) were attached transversely to the needle handles at bilateral ST36. The stimulation frequency was 2 per 100 Hz, and the intensity was adjusted to trigger slight vibration of the needle handles.
Patients in the SA group received minimally invasive acupuncture at 4 nonacupoints (eTable 2 in Supplement 2). Similar needles were inserted to a depth of 2 to 3 mm without manipulation or de qi. Electrodes were attached at bilateral nonacupoints in a similar pattern as the EA group but without electric current as the internal cord of the stimulator was cut off. Patients treated in the same room were separated by a curtain for privacy and to avoid communication.
During this trial, guidelines of the ERAS protocol were implemented according to the Consensus and Guidelines on ERAS in China.21 The ERAS protocol at each of the participating hospitals was compared and found to be similar in the preventive use of antibiotics, perioperative multimodal analgesia, avoidance of opioid use, early removal of urinary catheter and nasogastric tubes, early mobilization, nutritional support, and others.
Outcomes
The primary outcome was the time to first defecation. Secondary outcomes included the time to first flatus (with bowel sound to recover), first tolerance of semiliquid diet, first tolerance of solid food, and first ambulation; severity of postoperative nausea, pain, and abdominal distension (measured with the 0-100 mm visual analog scale [VAS]); number of episodes of postoperative nausea and vomiting (with an interval of 5 minutes defining separate episodes); length of postoperative hospital stay; and readmission rate within 30 days after discharge. The exact time of first occurrence of these events and severity of symptoms were recorded in a diary by patients and caregivers, and the completion of diary status was checked daily by local outcome assessors during hospitalization. Patient expectations and masking were assessed after the first treatment.
Postoperative complications were defined as any deviation from the normal postoperative course and were recorded and scored by severity using the Clavien-Dindo classification.22 Patients who met at least 2 of the following criteria after postoperative day 4 were classified as prolonged POI: nausea or vomiting, inability to tolerate any oral diet over the last 24 hours, abdominal distension, or radiologic confirmation.23 Anastomotic leakage was diagnosed with radiologic or visualization during reoperation or both.24 All adverse events (AEs) were appropriately managed, monitored, and documented by investigators, and were categorized by the acupuncturist and surgeons as either acupuncture related or not acupuncture related within 24 hours of occurrence. Serious AEs were immediately reported to the principal investigator (C.Z.L.) and the institutional review board at the clinical sites within 24 hours.
Statistical Analysis
The sample size was calculated based on our previous pilot study which included 105 patients who underwent laparoscopic surgery for colorectal cancer. We anticipated that the mean time to first defecation in the EA and SA groups was 76 hours and 88 hours, respectively, in this trial. Based on this estimate, with a level of significance α of .05 and a power of 80%, we calculated that 112 patients per group were required. We aimed to recruit a total of 248 patients considering a 10% dropout rate.
We conducted our analyses using the intention-to-treat principles regardless of whether patients had received the assigned intervention or completed all treatment sessions. Continuous variables are reported as mean (SD) or median (IQR); an independent t test was used for normally distributed values, and the Mann-Whitney U test was used for skewed data. Categorical variables were summarized with frequencies and percentages and were analyzed with the χ2 or Fisher exact test as appropriate. Estimated mean group differences and risk ratios (RRs) were reported with 95% CIs and 2-sided P values, with values less than .05 considered significant. Prespecified subgroup analyses included type of operation. A sensitivity analysis for primary outcome with most conservative data (the worst or best result of this indicator in the group) assessed the robustness of the missing data at random assumption. Secondary outcomes in the observed cases were analyzed without imputation of missing data. All analyses were performed using SAS software, version 9.4 (SAS Institute) by an independent statistician.
Results
Trial Flow
From October 12, 2020, to October 17, 2021, a total of 385 patients were screened, of whom, 249 were randomly assigned to the trial (Figure). One patient in the SA group was excluded from the analysis after randomization because he was diagnosed with intestinal tuberculosis, leaving a total of 248 patients (mean [SD] age, 60.2 [11.4] years; 153 men [61.7%]; 95 women [38.3%]) included in the analyses. Six patients withdrew from the trial because of the lack of efficacy (n = 1), withdrawal of consent (n = 2), or AEs (n = 3). Thus, 125 patients in the EA group and 123 in the SA group were included in the intention-to-treat analyses. The patients in the 2 groups had similar baseline characteristics (Table 1).
Figure. Study Flowchart.
Table 1. Demographics and Baseline Characteristics.
| Characteristic | Group, No. (%) | |
|---|---|---|
| Electroacupuncture (n = 125) | Sham electroacupuncture (n = 123) | |
| Sex | ||
| Male | 70 (56) | 83 (67) |
| Female | 55 (44) | 40 (33) |
| Age, mean (SD), y | 60.2 (11.0) | 60.2 (11.8) |
| Body mass index, mean (SD)a | 24.5 (3.2) | 24.2 (3.1) |
| Current smoker | 31 (25) | 32 (26) |
| Diabetes, all forms | 19 (15) | 16 (13) |
| Neoadjuvant treatment | ||
| Chemotherapy only | 5 (4) | 2 (2) |
| Radiotherapy only | 0 | 1 (1) |
| Chemoradiotherapy | 7 (6) | 5 (4) |
| Type of operation | ||
| Left hemicolectomy | 30 (24) | 26 (21) |
| Right hemicolectomy | 25 (20) | 32 (26) |
| Rectal resection | 50 (40) | 52 (42) |
| Sigmoid resection | 20 (16) | 13 (11) |
| Tumor stageb | ||
| 0-I | 14 (11) | 10 (8) |
| II | 56 (45) | 66 (54) |
| III | 51 (41) | 38 (31) |
| IV | 4 (3) | 9 (7) |
| Degree of cancer differentiation | ||
| High differentiation | 7 (6) | 13 (11) |
| Moderately differentiated | 105 (84) | 104 (85) |
| Poorly differentiated | 12 (10) | 6 (5) |
| Undifferentiation | 1 (1) | 0 |
| Cancer type | ||
| Adenocarcinoma | 121 (97) | 122 (99) |
| Other | 4 (3) | 1 (1) |
| Duration of surgery, median (IQR), h | 3.0 (2.5-3.6) | 3.0 (2.7-3.7) |
| Intraoperative blood loss, median (IQR), mL | 50 (50-100) | 50 (50-100) |
Calculated as weight in kilograms divided by height in meters squared.
Tumor stages indicate the following: 0-I, the tumor invades mucosa or muscularis propria without lymph node metastasis; II, the tumor invades muscularis propria or peritoneum without lymph node metastasis; III, the tumor invades mucosa or muscularis propria or peritoneum with regional lymph node metastasis; IV, presence of tumor invasion with distant metastatic and regional lymph node metastasis.
Primary and Secondary End Points
After laparoscopic surgery while adopting the ERAS protocol, the median (IQR) time to first defecation was 76.4 (67.6-96.8) hours in the EA group and 90.0 (73.6-100.3) hours in the SA group (mean difference, −8.76 [95% CI, −15.80 to −1.73; P = .003]). The sensitivity analysis revealed similar findings (effect size, −8.16; 95% CI, −15.27 to −1.06; P = .004) (Table 2). No significant interactions were found between treatment group and type of resection in the prespecified subgroup analysis.
Table 2. Recovery of Gastrointestinal Function.
| Outcome | Group | Effect size (95% CI)a | P value | |
|---|---|---|---|---|
| Electroacupuncture (n = 125) | Sham electroacupuncture (n = 123) | |||
| Primary outcome | ||||
| Time to first defecation, median (IQR), h | ||||
| Without imputation | 76.4 (67.6 to 96.8) | 90.0 (73.6 to 100.3) | −8.76 (−15.80 to −1.73) | .003 |
| With imputationb | 76.4 (67.6 to 96.8) | 90.0 (73.1 to 100.3) | −8.16 (−15.27 to −1.06) | .004 |
| Secondary outcome | ||||
| Time to first flatus, median (IQR), h | 44.3 (37.0 to 58.2) | 58.9 (48.2 to 67.4) | −9.68 (−15.22 to −4.15) | <.001 |
| Time tolerability of semiliquid food, median (IQR), h | 105.8 (87.0 to 120.3) | 116.5 (92.0 to 137.0) | −10.74 (−19.56 to −1.93) | .01 |
| Time tolerability of solid food, median (IQR), h | 181.8 (149.5 to 211.4) | 190.3 (165.0 to 228.5) | −20.24 (−34.68 to −5.79) | .01 |
| Time to first ambulation, median (IQR), h | 41.2 (30.4 to 49.1) | 43.5 (33.6 to 53.4) | −3.74 (−8.79 to 1.31) | .24 |
| Length of postoperative hospital stay, median (IQR), d | 8.0 (6.8 to 9.6) | 8.0 (6.9 to 10.0) | −0.46 (−1.16 to 0.24) | .23 |
Estimated mean differences for continuous outcomes.
Interpolation using the most conservative data. Most of the dropout patients also recorded outcomes data, and only one dropout patient did not record all data.
In the EA group compared with the SA group, the time to first flatus (median [IQR], 44.3 [37.0-58.2] hours vs 58.9 [48.2-67.4] hours; P < .001) and the tolerability of semiliquid diet (median [IQR], 105.8 [87.0-120.3] vs 116.5 [92.0-137.0] hours; P = .01) and solid food (median [IQR], 181.8 [149.5-211.4] hours vs 190.3 [165.0-228.5] hours; P = .01) were significantly decreased. No difference was detected in the median time to first ambulation and the mean length of postoperative hospital stay in the 2 groups (Table 2). Other secondary outcomes were not different between groups (Table 3; eTables 3 and 4 in Supplement 2).
Table 3. Severity of Postoperative Symptoms.
| Variable | Group, median (IQR) | Effect size (95% CI)a | P value | |
|---|---|---|---|---|
| Electroacupuncture (n = 125) | Sham electroacupuncture (n = 123) | |||
| VAS pain score | ||||
| Day 1 | 36 (20 to 50) | 37 (20 to 50) | 0.59 (−4.81 to 6.00) | .72 |
| Day 2 | 30 (13 to 45) | 30 (10 to 43) | 0.44 (−4.48 to 5.36) | .90 |
| Day 3 | 11 (0 to 30) | 11 (0 to 30) | −0.18 (4.90 to 4.54) | .99 |
| Day 4 | 0 (0 to 20) | 0 (0 to 20) | 0.82 (−3.10 to 4.75) | .88 |
| VAS abdominal distension score | ||||
| Day 1 | 10 (0 to 30) | 17 (0 to 25) | −1.50 (−6.87 to 3.87) | .55 |
| Day 2 | 10 (0 to 40) | 13.5 (0 to 31) | 1.13 (−3.80 to 6.06) | .86 |
| Day 3 | 3 (0 to 20) | 3 (0 to 30) | −1.50 (−6.03 to 3.02) | .73 |
| Day 4 | 0 (0 to 10) | 0 (0 to 10) | −0.83 (−3.84 to 2.18) | .61 |
| VAS nausea score | ||||
| Day 1 | 15 (0 to 40) | 20 (0 to 46) | −4.40 (−10.45 to 1.66) | .18 |
| Day 2 | 7 (0 to 25) | 4 (0 to 20) | 2.21 (−2.39 to 6.82) | .48 |
| Day 3 | 0 (0 to 1) | 0 (0 to 8) | −0.69 (−3.33 to 1.94) | .37 |
| Day 4 | 0 (0 to 0) | 0 (0 to 0) | −0.50 (−1.58 to 0.58) | .29 |
| Experienced nausea, No. (%)b | ||||
| Day 1 | 74 (59) | 80 (65) | 0.91 (0.75 to 1.11) | .34 |
| Day 2 | 53 (42) | 49 (40) | 1.06 (0.78 to 1.42) | .72 |
| Day 3 | 21 (17) | 25 (20) | 0.82 (0.49 to 1.38) | .46 |
| Day 4 | 8 (6) | 10 (8) | 0.78 (0.32 to 1.91) | .59 |
| Experienced vomiting, No. (%)c | ||||
| Day 1 | 25 (20) | 33 (27) | 0.75 (0.47 to 1.18) | .20 |
| Day 2 | 11 (9) | 14 (11) | 0.77 (0.36 to 1.62) | .49 |
| Day 3 | 5 (4) | 6 (5) | 0.81 (0.25 to 2.60) | .73 |
| Day 4 | 1 (0.8) | 3 (2) | 0.33 (0.03 to 3.08) | .24 |
Abbreviation: VAS, visual analog scale.
Estimated mean differences for continuous outcomes and risk ratios for categorical outcomes.
Patients who had at least 1 episode of nausea.
Patients who had at least 1 episode of vomiting.
Table 4 summarized the details of readmission rates and postoperative complications. Readmission rates within 30 days occurred equally frequently (EA group, 2 [2%] vs SA group, 1 [1%]; RR, 1.95; 95% CI, 0.18-21.24; P = .38). No between-group difference was found in the incidences of overall complications whereas prolonged POI in the EA group was significantly less common than that in the SA group (13 of 125 [10%] vs 25 of 123 [20%]; RR, 0.51; 95% CI, 0.27-0.95; P = .03). In the postoperative period, 3 patients required additional surgery for complications: 1 in the EA group for an anastomotic leak and 2 in the SA group for an anastomotic leak and surgical incision dehiscence.
Table 4. Morbidity.
| Outcome | Group, No. (%) | Effect size (95% CI)a | P value | |
|---|---|---|---|---|
| Electroacupuncture (n = 125) | Sham electroacupuncture (n = 123) | |||
| Readmission within 30 d after discharge | 2 (2)b | 1 (1)c | 1.95 (0.18-21.24) | .38 |
| Postoperative complications | ||||
| No complication | 107 (86) | 95 (77) | 0.63 (0.37-1.08) | .09 |
| Complicationd | 18 (14) | 28 (23) | ||
| Prolonged POI | 13 (10) | 25 (20) | 0.51 (0.27-0.95) | .03 |
| Adhesion ileus | 1 (1) | 1 (1) | 0.98 (0.06-15.56) | .50 |
| Anastomotic leakage | 1 (1) | 1 (1) | 0.98 (0.06-15.56) | .50 |
| Surgical incision dehiscence | 0 | 1 (1) | 1.01 (0.99-1.02) | .50 |
| Surgical incision infection | 2 (2) | 0 | 0.98 (0.96-1.01) | .25 |
| Hiccups | 0 | 2 (2) | 1.02 (0.99-1.04) | .25 |
| Intra-abdominal infection | 1 (1) | 0 | 0.99 (0.98-1.01) | .50 |
| Adverse eventse | .82 | |||
| Anyf | 8 (6) | 7 (6) | NA | NA |
| Serious | 0 | 0 | ||
| Hematoma | 5 (4) | 4 (3) | ||
| Sharp pain | 1 (1) | 1 (1) | ||
| Residual needling sensation after needle removal | 2 (2) | 2 (2) | ||
Abbreviations: NA, not applicable; POI, postoperative ileus.
Risk ratios for categorical outcomes.
Two intra-abdominal infections.
One chemotherapy.
Some patients experienced more than 1 complication.
Adverse events were counted by type rather than frequency in the same participant.
Adverse events of different types occurring in a single participant were defined as independent adverse events. An adverse event with multiple occurrences in a single participant was defined as 1 adverse event.
In the masked assessment, no between-group difference was found in the proportion of patients who guessed that they received acupuncture (eTable 5 in Supplement 2). Patients' expectations of electroacupuncture in the SA group were lower than those in the EA group (eTable 6 in Supplement 2).
Eight acupuncture-related AEs (6%) in the EA group and 7 AEs (6%) in the SA group were reported (Table 4). Treatment-related AEs were mild and transient. Three patients withdrew from the study because of AEs (1 patient in the EA group and 1 patient in the SA group) because of pain, and 1 patient withdrew because of residual needling sensation after needle removal. There were no serious AEs in either group.
Discussion
To our best knowledge, this was the first multicenter, randomized clinical trial comparing EA with SA in the treatment of postoperative ileus with the adoption of the ERAS protocol. Compared with SA, EA shortened the duration of POI and reduced the incidence of prolonged POI after laparoscopic resection of colorectal cancer without serious AEs. EA may provide a reasonable treatment option for patients after colorectal surgery to facilitate GI function recovery.
Acupuncture has been used extensively in perioperative medicine.25 Ng and colleagues26 found that EA reduced the time to first defecation (85.9 hours) as compared with SA (107.5 hours) after laparoscopic surgery in traditional nursing care. In a recently published acupuncture trial, Qiu et al27 reported that the time to first defecation was 4.2 days and 5.4 days in the EA and SA group, respectively, after pancreatectomy or gastrectomy without the ERAS protocol. The median (IQR) time to first defecation in this trial was 76.4 (67.6-96.8) hours in the EA group and 90.0 (73.6-100.3) hours in the SA group. In this trial, the difference in the time to first defecation was less than those in previously described studies that did not adopt the ERAS protocol. One possible reason is that laparoscopic resection, when combined with the ERAS protocol, greatly optimized postoperative outcomes in patients with colorectal cancer to such an extent that an additional intervention only added minimal benefits. Additionally, sham EA seems to have some benefits for postoperative recovery and thus led to smaller differences between groups. Sham control in the present trial was based on a validated method, which consists of using real acupuncture needles with superficial insertion at nonacupoints; this may still bear some placebo or small biological effects.28 It is intriguing that patients in the SA group had lower expectations than those in the EA group. Low expectations may create a nocebo effect, thereby counteracting the placebo effects. The results of this present trial are consistent with previous studies and added further evidence in supporting the use of acupuncture in the perioperative care of patients going through laparoscopic resection with the ERAS protocol.
The development of postoperative complications is one of the main reasons for a longer hospital stay. In this trial, EA reduced the incidence of postoperative complications by 8%. Unfortunately, this benefit did not translate into decreased length of hospital stay. Notably, in the present trial, the incidence rate of prolonged POI was halved in the EA group compared with the SA group (RR, 0.51) and was lower than those previously reported with other interventions in the ERAS program.2 The incidence rate was also lower than acupuncture-related therapies that did not adopt the ERAS protocol.29 Meng et al29 reported that acupuncture could decrease the incidence of prolonged POI (inability to pass flatus or have a bowel movement by 96 hours after surgery) by 4.2%. Transcutaneous electrical acupoint stimulation decreased the risk of postoperative paralytic ileus (no flatus for >72 hours after surgery) by 32%.30 Differences between results of the present trial and the aforementioned studies are likely attributable to the enhanced benefits of EA when combined with the ERAS protocol. Our trial supports that EA, when combined with the ERAS protocol, confers faster postoperative recovery after laparoscopic resection of colorectal cancer.
Although EA was found to prevent postoperative nausea and vomiting,31 we did not find this association in our trial. We think this is again because the benefits of ERAS minimized the risks for postoperative nausea and vomiting to a degree, and EA only added little to no additional benefits. Similarly, EA was not superior to SA in alleviating postoperative pain or abdominal distension. With the use of multimodal analgesia, the severities of pain and abdominal distension in our cohort may have been less than those in other studies,32 thus making it difficult to discern differences between the EA and SA groups. Early ambulation after surgery was known to promote postoperative recovery.33 In the present trial, no difference was found between groups in the time to first ambulation. This indicates that the difference between groups in GI function or the duration of POI was not associated with the patients’ physical mobility.
The underlying mechanisms of POI are a complex interaction of inflammation and neural reflexes.3 Somatosensory autonomic reflexes allow EA to modulate body physiology at specific somatic tissues (acupoints).13 Growing evidence indicates that EA regulates the GI function by exciting the vagal nerve system and might produce an anti-inflammatory effect.34,35 EA at ST36 could restore impaired GI motility via the cholinergic pathway.36 In an experimental study, we discovered the complete EA anti-inflammatory signaling pathway in POI: EA excited the vagal nerve, which in turn suppresses intestinal manipulation-induced inflammation via activation of the α7 nicotinic acetylcholine receptor–mediated cholinergic anti-inflammatory pathway in macrophages.37 Meanwhile, another study showed that EA improved the GI tract transit function of POI by activating the vagal nerve directly but not regulating local inflammation.38 Nonetheless, the exact underlying mechanisms of acupuncture for POI warrant further investigation.
In contrast to pharmacologic interventions, acupuncture therapies rely on procedural expertise and are often complex and multifaceted,39 whereas the acupuncture protocols in perioperative studies are usually simpler, with few acupoints that can be applied clinically after simple training. These beneficial effects make acupuncture a promising approach in perioperative management.
Strengths and Limitations
The strengths of this trial lie in its multicenter, randomized controlled design and the fact that it was conducted in the new context of management of the perioperative period. Additionally, the acupuncturist had received unified standardized training to minimize heterogeneity among treatments of the same group. We assessed patient expectations and masked treatment groups, both of which were appropriate. With these rigorous methodologic designs, we believe that the results of this trial added new evidence supporting acupuncture effects in facilitating postoperative GI function recovery.
This trial has some limitations. First, this trial included only patients undergoing laparoscopic surgery; results may not be generalizable to patients undergoing the traditional open surgery. Second, the sham control with minimally invasive acupuncture at nonacupoints may have produced certain physiologic effects. The use of sham acupuncture may underestimate acupuncture’s treatment effect.40 Third, the existing definition of POI is ambiguous and thus heterogeneous among studies preventing accurate transverse comparisons. Fourth, the statistically significant expectancy scores limit the conclusions that can be drawn from the results. Fifth, the trial was performed in the setting characterized by a culture that believes in the benefit of acupuncture to a greater extent than many cultures. It is undeniable that the expectation of the outcome of treatment may vary between cultures and influence efficacy in different settings. The findings should take into account expectations and cultural factors and extrapolate cautiously to other populations and countries. Finally, although this study was conducted in the context of implementing the ERAS protocol, no formal compliance measurements were carried out. The lack of compliance details regarding the various study elements may have affected the comparison of findings.
Conclusions
In conclusion, this randomized clinical trial demonstrated that EA shortened the duration of POI and decreased the risks of prolonged POI after laparoscopic surgery for colorectal cancer with the ERAS protocol. These data affirm and expand the evidence that the effect of EA remained in the ERAS setting. EA may be considered as a compelling adjunct to the ERAS protocol to promote postoperative recovery in colorectal cancer.
Trial Protocol
eFigure. Locations of Acupoints and Nonacupoints
eTable 1. Location of Acupoints for EA Group
eTable 2. Location of Nonacupoints for SA Group
eTable 3. Expenses
eTable 4. Number of Episodes of Postoperative Nausea and Vomiting
eTable 5. Blinding Assessment
eTable 6. Credibility and Expectancy Scores
Data Sharing Statement
References
- 1.Lassen K, Soop M, Nygren J, et al. ; Enhanced Recovery After Surgery (ERAS) Group . Consensus review of optimal perioperative care in colorectal surgery: Enhanced Recovery After Surgery (ERAS) group recommendations. Arch Surg. 2009;144(10):961-969. doi: 10.1001/archsurg.2009.170 [DOI] [PubMed] [Google Scholar]
- 2.Peters EG, Smeets BJJ, Nors J, et al. Perioperative lipid-enriched enteral nutrition versus standard care in patients undergoing elective colorectal surgery (SANICS II): a multicentre, double-blind, randomised controlled trial. Lancet Gastroenterol Hepatol. 2018;3(4):242-251. doi: 10.1016/S2468-1253(18)30031-1 [DOI] [PubMed] [Google Scholar]
- 3.Sommer NP, Schneider R, Wehner S, Kalff JC, Vilz TO. State-of-the-art colorectal disease: postoperative ileus. Int J Colorectal Dis. 2021;36(9):2017-2025. doi: 10.1007/s00384-021-03939-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Iyer S, Saunders WB, Stemkowski S. Economic burden of postoperative ileus associated with colectomy in the US. J Manag Care Pharm. 2009;15(6):485-494. doi: 10.18553/jmcp.2009.15.6.485 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Hamel JF, Sabbagh C, Alves A, Regimbeau JM, Vignaud T, Venara A. Comparison of treatment to improve gastrointestinal functions after colorectal surgery within enhanced recovery programmes: a systematic review and meta-analysis. Sci Rep. 2021;11(1):7423. doi: 10.1038/s41598-021-86699-w [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Gustafsson UO, Scott MJ, Hubner M, et al. Guidelines for perioperative care in elective colorectal surgery: Enhanced Recovery After Surgery (ERAS) society recommendations: 2018. World J Surg. 2019;43(3):659-695. doi: 10.1007/s00268-018-4844-y [DOI] [PubMed] [Google Scholar]
- 7.Keller DS, Flores-Gonzalez JR, Ibarra S, Mahmood A, Haas EM. Is there value in alvimopan in minimally invasive colorectal surgery? Am J Surg. 2016;212(5):851-856. doi: 10.1016/j.amjsurg.2016.02.016 [DOI] [PubMed] [Google Scholar]
- 8.Short V, Herbert G, Perry R, et al. Chewing gum for postoperative recovery of gastrointestinal function. Cochrane Database Syst Rev. 2015;(2):CD006506. doi: 10.1002/14651858.CD006506.pub3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Güngördük K, Özdemir İA, Güngördük Ö, Gülseren V, Gokçü M, Sancı M. Effects of coffee consumption on gut recovery after surgery of gynecological cancer patients: a randomized controlled trial. Am J Obstet Gynecol. 2017;216(2):145.e1-145.e7. doi: 10.1016/j.ajog.2016.10.019 [DOI] [PubMed] [Google Scholar]
- 10.Boeckxstaens GE, de Jonge WJ. Neuroimmune mechanisms in postoperative ileus. Gut. 2009;58(9):1300-1311. doi: 10.1136/gut.2008.169250 [DOI] [PubMed] [Google Scholar]
- 11.Mao JJ, Pillai GG, Andrade CJ, et al. Integrative oncology: addressing the global challenges of cancer prevention and treatment. CA Cancer J Clin. 2022;72(2):144-164. doi: 10.3322/caac.21706 [DOI] [PubMed] [Google Scholar]
- 12.Yang JW, Wang LQ, Zou X, et al. Effect of acupuncture for postprandial distress syndrome: a randomized clinical trial. Ann Intern Med. 2020;172(12):777-785. doi: 10.7326/M19-2880 [DOI] [PubMed] [Google Scholar]
- 13.Liu S, Wang Z, Su Y, et al. A neuroanatomical basis for electroacupuncture to drive the vagal-adrenal axis. Nature. 2021;598(7882):641-645. doi: 10.1038/s41586-021-04001-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Yang NN, Ye Y, Tian ZX, et al. Effects of electroacupuncture on the intestinal motility and local inflammation are modulated by acupoint selection and stimulation frequency in postoperative ileus mice. Neurogastroenterol Motil. 2020;32(5):e13808. doi: 10.1111/nmo.13808 [DOI] [PubMed] [Google Scholar]
- 15.Liu YH, Dong GT, Ye Y, et al. Effectiveness of acupuncture for early recovery of bowel function in cancer: a systematic review and meta-analysis. Evid Based Complement Alternat Med. 2017;2017:2504021. doi: 10.1155/2017/2504021 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Liu Y, May BH, Zhang AL, et al. Acupuncture and related therapies for treatment of postoperative ileus in colorectal cancer: a systematic review and meta-analysis of randomized controlled trials. Evid Based Complement Alternat Med. 2018;2018:3178472. doi: 10.1155/2018/3178472 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Chen KB, Huang Y, Jin XL, Chen GF. Electroacupuncture or transcutaneous electroacupuncture for postoperative ileus after abdominal surgery: A systematic review and meta-analysis. Int J Surg. 2019;70:93-101. doi: 10.1016/j.ijsu.2019.08.034 [DOI] [PubMed] [Google Scholar]
- 18.Mazzotta E, Villalobos-Hernandez EC, Fiorda-Diaz J, Harzman A, Christofi FL. Postoperative ileus and postoperative gastrointestinal tract dysfunction: pathogenic mechanisms and novel treatment strategies beyond colorectal enhanced recovery after surgery protocols. Front Pharmacol. 2020;11:583422. doi: 10.3389/fphar.2020.583422 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Zhou K, Fang J, Wang X, et al. Characterization of de qi with electroacupuncture at acupoints with different properties. J Altern Complement Med. 2011;17(11):1007-1013. doi: 10.1089/acm.2010.0652 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Tu JF, Yang JW, Shi GX, et al. Efficacy of intensive acupuncture vs sham acupuncture in knee osteoarthritis: a randomized controlled trial. Arthritis Rheumatol. 2021;73(3):448-458. doi: 10.1002/art.41584 [DOI] [PubMed] [Google Scholar]
- 21.Chinese Society of Surgery; Chinese Society of Anesthesiology . Consensus on ERAS and guidelines for pathway management in China. Chin J Anesthesiol. 2018;38(1):8-13. [Google Scholar]
- 22.Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240(2):205-213. doi: 10.1097/01.sla.0000133083.54934.ae [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Vather R, Trivedi S, Bissett I. Defining postoperative ileus: results of a systematic review and global survey. J Gastrointest Surg. 2013;17(5):962-972. doi: 10.1007/s11605-013-2148-y [DOI] [PubMed] [Google Scholar]
- 24.Sparreboom CL, van Groningen JT, Lingsma HF, et al. ; Dutch ColoRectal Audit group . Different risk factors for early and late colorectal anastomotic leakage in a nationwide audit. Dis Colon Rectum. 2018;61(11):1258-1266. doi: 10.1097/DCR.0000000000001202 [DOI] [PubMed] [Google Scholar]
- 25.Lu Z, Dong H, Wang Q, Xiong L. Perioperative acupuncture modulation: more than anaesthesia. Br J Anaesth. 2015;115(2):183-193. doi: 10.1093/bja/aev227 [DOI] [PubMed] [Google Scholar]
- 26.Ng SSM, Leung WW, Mak TWC, et al. Electroacupuncture reduces duration of postoperative ileus after laparoscopic surgery for colorectal cancer. Gastroenterology. 2013;144(2):307-313.e1. doi: 10.1053/j.gastro.2012.10.050 [DOI] [PubMed] [Google Scholar]
- 27.Qiu G, Huang T, Lu Y, et al. Perioperative electroacupuncture can accelerate the recovery of gastrointestinal function in cancer patients undergoing pancreatectomy or gastrectomy: a randomized controlled trial. Evid Based Complement Alternat Med. 2021;2021:5594263. doi: 10.1155/2021/5594263 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Lund I, Lundeberg T. Are minimal, superficial, or sham acupuncture procedures acceptable as inert placebo controls? Acupunct Med. 2006;24(1):13-15. doi: 10.1136/aim.24.1.13 [DOI] [PubMed] [Google Scholar]
- 29.Meng ZQ, Garcia MK, Chiang JS, et al. Electro-acupuncture to prevent prolonged postoperative ileus: a randomized clinical trial. World J Gastroenterol. 2010;16(1):104-111. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Gao W, Li W, Yan Y, et al. Transcutaneous electrical acupoint stimulation applied in lower limbs decreases the incidence of paralytic ileus after colorectal surgery: a multicenter randomized controlled trial. Surgery. 2021;170(6):1618-1626. doi: 10.1016/j.surg.2021.08.007 [DOI] [PubMed] [Google Scholar]
- 31.Frey UH, Scharmann P, Löhlein C, Peters J. P6 acustimulation effectively decreases postoperative nausea and vomiting in high-risk patients. Br J Anaesth. 2009;102(5):620-625. doi: 10.1093/bja/aep014 [DOI] [PubMed] [Google Scholar]
- 32.Deng G, Wong WD, Guillem J, et al. A phase II, randomized, controlled trial of acupuncture for reduction of postcolectomy ileus. Ann Surg Oncol. 2013;20(4):1164-1169. doi: 10.1245/s10434-012-2759-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Fiore JF Jr, Castelino T, Pecorelli N, et al. Ensuring early mobilization within an enhanced recovery program for colorectal surgery: a randomized controlled trial. Ann Surg. 2017;266(2):223-231. doi: 10.1097/SLA.0000000000002114 [DOI] [PubMed] [Google Scholar]
- 34.Villegas-Bastida A, Torres-Rosas R, Arriaga-Pizano LA, Flores-Estrada J, Gustavo-Acosta A, Moreno-Eutimio MA. Electrical stimulation at the ST36 acupoint protects against sepsis lethality and reduces serum TNF levels through vagus nerve– and catecholamine-dependent mechanisms. Evid Based Complement Alternat Med. 2014;2014:451674. doi: 10.1155/2014/451674 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Wang H, Wang L, Shi X, et al. Electroacupuncture at Zusanli prevents severe scalds-induced gut ischemia and paralysis by activating the cholinergic pathway. Evid Based Complement Alternat Med. 2015;2015:787393. doi: 10.1155/2015/787393 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Luo D, Liu S, Xie X, Hou X. Electroacupuncture at acupoint ST-36 promotes contractility of distal colon via a cholinergic pathway in conscious rats. Dig Dis Sci. 2008;53(3):689-693. doi: 10.1007/s10620-007-9929-7 [DOI] [PubMed] [Google Scholar]
- 37.Yang NN, Yang JW, Ye Y, et al. Electroacupuncture ameliorates intestinal inflammation by activating α7nAChR-mediated JAK2/STAT3 signaling pathway in postoperative ileus. Theranostics. 2021;11(9):4078-4089. doi: 10.7150/thno.52574 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Fang JF, Fang JQ, Shao XM, et al. Electroacupuncture treatment partly promotes the recovery time of postoperative ileus by activating the vagus nerve but not regulating local inflammation. Sci Rep. 2017;7:39801. doi: 10.1038/srep39801 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Zhang YQ, Jiao RM, Witt CM, et al. How to design high quality acupuncture trials-a consensus informed by evidence. BMJ. 2022;376:e067476. doi: 10.1136/bmj-2021-067476 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Fei YT, Cao HJ, Xia RY, et al. Methodological challenges in design and conduct of randomised controlled trials in acupuncture. BMJ. 2022;376:e064345. doi: 10.1136/bmj-2021-064345 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol
eFigure. Locations of Acupoints and Nonacupoints
eTable 1. Location of Acupoints for EA Group
eTable 2. Location of Nonacupoints for SA Group
eTable 3. Expenses
eTable 4. Number of Episodes of Postoperative Nausea and Vomiting
eTable 5. Blinding Assessment
eTable 6. Credibility and Expectancy Scores
Data Sharing Statement