Efficacy of electroacupuncture in improving postoperative ileus in patients receiving colorectal surgery: a systematic review and meta-analysis

Background: This meta-analysis aimed to evaluate the efficacy and safety of electroacupuncture (EA) in improving postoperative ileus after colorectal surgery. Methods: Electronic databases (e.g. Medline) were screened to identify randomized controlled trials that focused on the association between EA and postoperative ileus. Time to first flatus served as the primary outcome, while the secondary outcomes included time required for the recovery of other gastrointestinal functions (e.g. bowel sound recovery), time to tolerability of liquid/solid food, postoperative pain scores, risk of overall complications, and hospital length of stay. Results: Our meta-analysis focusing on 16 studies with a total of 1562 patients demonstrated positive associations of EA with shorter times to the first flatus [mean difference (MD): −10.1 h, P<0.00001, n=1562], first defecation (MD: −11.77 h, P<0.00001, n=1231), bowel sound recovery (MD: −10.76 h, P<0.00001, n=670), tolerability of liquid (MD: −16.44 h, P=0.0002, n=243), and solid food (MD: −17.21 h, P=0.005, n=582) than those who received standard care. The use of EA was also correlated with a lower risk of overall complications (risk ratio:0.71, P=0.04, n=1011), shorter hospital length of stay (MD: −1.22 days, P=0.0001, n=988), and a lower pain score on postoperative days two (standardized MD: −0.87, P=0.009, n=665) and three (standardized MD: −0.45, P<0.00001, n=795), without a difference in time to first ambulation. Conclusion: Our findings showed an association between EA and enhanced gastrointestinal functional recovery and reduced pain severity following colorectal surgery, highlighting the potential benefits of incorporating EA into perioperative care to enhance recovery outcomes in this setting.


Introduction
Colorectal cancer (CRC) is a highly prevalent malignancy worldwide, accounting for 9.4% of all cancer incidences in men and 10.1% in women [1] .More importantly, the total number of fatalities from rectal and colon cancers is speculated to increase by 60 and 71.5%, respectively [2] .Although surgical treatment remains the primary curative approach, various operation-related factors, including anesthesia, surgical trauma, inflammatory reactions, and the use of opioids, can impair postoperative gastrointestinal motility [3] .In particular, 10-30% of patients undergoing colorectal surgery reported the occurrence of postoperative ileus (POI) [3,4] characterized by a range of symptoms, including abdominal distension, pain, delayed passage of gas and stool, nausea, vomiting, and an inability to tolerate oral intake [5] .Despite the typical resolution of POI within 5 days following open abdominal surgery and within three days following laparoscopic surgery [6] , its occasional presentation as a prolonged and recurrent disorder may lead to severe morbidities including electrolyte imbalances, dehydration, and sepsis [7] .Given the global burden of CRC and the high incidence of POI following surgical interventions, appropriate implementation of preventive strategies, close monitoring, and timely interventions for POI are crucial for minimizing associated morbidities and improving patient recovery.
Acupuncture, a traditional Chinese medicine technique originating in East Asia that has been practiced for centuries, involves the stimulation of specific acupoints to alleviate various gastrointestinal symptoms [8] .In recent years, acupuncture has gained popularity as a nonpharmacological and minimally invasive therapeutic option for various gastrointestinal disorders, including abdominal distension, pain, constipation, nausea, and vomiting [9][10][11] .Several meta-analyses have shown the effectiveness of acupuncture and related techniques, such as electroacupuncture (EA) or transcutaneous acupoint electrical stimulation (TEAS), in improving POI among patients undergoing abdominal surgery [12][13][14] .However, the significant heterogeneity within these meta-analyses raises concerns regarding the robustness and generalizability of the evidence generated.
EA is a contemporary clinical approach that integrates traditional acupuncture techniques with the precise application of stabilized electrical stimulation, enabling objective, and quantifiable adjustments of stimulation frequency and intensity [15] .This unique characteristic has garnered considerable attention, focusing on EA as a potential therapeutic intervention for patients with CRC who develop POI [16] .Therefore, the primary objective of this systematic review and meta-analysis was to examine the reliability and validity of currently available evidence supporting the use of EA to improve POI among patients with CRC.

Methods
The study protocol can be accessed from the PROSPERO International prospective register of the systematic review database.This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA, Supplemental Digital Contents 3 and 4, http://links.lww.com/JS9/B234,http:// links.lww.com/JS9/B235) [17]and AMSTAR (Supplemental Digital Content 2, http://links.lww.com/JS9/B233)(Assessing the methodological quality of systematic reviews) [18] guidelines when reporting its findings.

Search strategies and data sources
A comprehensive literature search was conducted to identify randomized controlled trials (RCTs) that investigated the effectiveness of EA in improving postoperative gastrointestinal motility disorders in patients undergoing colorectal surgery.The search encompassed major databases, including PubMed, MEDLINE, Embase, and the Cochrane CENTRAL register of controlled trials, spanning from their inception dates until 8 June 2023.A search of the ClinicalTrials.gov database was also performed to ensure the inclusion of ongoing or unpublished studies.The search strategy employed a combination of keywords and medical subject headings (e.g.MeSH terms in Medline), including the following keywords: (ʻAcupunctureʼ or ʻElectroacupuncture therapyʼ or ʻElectroacupunctureʼ or ʻElectro acupuncturingʼ or ʻLaser acu-punctureʼ or ʻElectro needle acupunctureʼ or ʻElectro auricular acupunctureʼ) and (ʻcolorectal cancerʼ or ʻcolorectal carcinomaʼ or ʻcolon adenocarcinomaʼ or ʻcolorectal tumorʼ or ʻcolonic neoplasmʼ or ʻrectal cancerʼ or ʻrectosigmoid tumorʼ or ʻsigmoid colon tumorʼ) and (ʻpostoperative ileusʼ or ʻpostoperative bowel dysfunctionʼ or ʻpostoperative gastrointestinal dysfunctionʼ or ʻparalytic ileusʼ).Furthermore, to prevent the omission of relevant studies, Google Scholar, the China National Knowledge Infrastructure (CNKI) database, Chongqing VIP Database (CQVIP), Chinese Biomedical Literature Database (CBM), and the Wanfang Database were also searched.To identify additional studies, the reference lists of the published systematic reviews and included RCTs were screened.No restrictions were placed on the language, sample size, publication date, or country of origin.

Inclusion criteria and study selection
The following PICOS criteria were used to screen eligible trials: The following criteria were used to exclude ineligible studies: (a) studies that included patients receiving both colorectal and other gastrointestinal surgeries (e.g.gastrectomy); (b) acupuncture-related therapy was also used in the control group; (c) studies that focused on manual acupuncture or TEAS; and (d) full-text or POI-related outcomes were unavailable.
Following the removal of duplicate records, potentially eligible studies underwent a screening process conducted by two independent reviewers who evaluated the titles and abstracts.Full-text articles were obtained and reviewed by the same reviewers to determine the inclusion criteria.In cases of disagreement, a third reviewer was consulted to facilitate discussion and reach consensus.

Data extraction
The data extraction process was conducted independently by two reviewers who extracted relevant information using a standardized data extraction form.The extracted data included the first author's name, publication year, baseline characteristics of participants (e.g.age), size of the study population, surgical techniques (e.g.laparoscopy or laparotomy), details of the EA procedure, interventions in controls (e.g.sham acupuncture or standard care), and country.Outcomes, including time to first flatus (TFF), time to bowel sound recovery (TBSR), time to first

HIGHLIGHTS
• The efficacy of electroacupuncture (EA) for postoperative ileus was investigated.• Sixteen trials with 1578 patients receiving colorectal surgery were meta-analyzed.• EA was linked to shorter times to first flatus/defecation and bowel sound recovery.• EA correlated with reduced time to food tolerance and pain score on days 2 and 3. • EA was associated with a lower risk of complications and a shorter hospital stay.defecation (TFD), time to liquid/semiliquid/solid food intake, postoperative pain score, postoperative overall complications, and hospital length of stay (LOS) were also retrieved.In cases of divergent opinions, a third reviewer made a final decision to resolve any discrepancies.

Outcomes and definitions
TFF, defined in accordance with the individual studies, was the primary endpoint of the current meta-analysis.Additionally, several secondary outcomes were evaluated, including TBSR, TFD, time to initiate intake of liquid or solid food, postoperative pain scores, postoperative complications, and hospital LOS.In cases where pain scores were measured at multiple time points, data were gathered from the first three postoperative days.

Quality of included studies
The methodological quality of the included trials was assessed by two reviewers using the Cochrane Risk of bias (ROB) tool.The RoB2 framework encompasses diverse domains crucial for the examination of potential biases, namely, the randomization process, deviations from intended interventions, missing outcome data, measurement of outcomes, selection of reported results, and overall bias.Any disagreements between the two reviewers were discussed, and if unresolved, a third reviewer was involved in the discussion until consensus was reached.

Certainty of evidence
The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was employed to evaluate the overall quality of the evidence in this study.The GRADE guidelines examine five domains: risk of bias, inconsistency, indirectness, imprecision, and potential publication bias.These domains collectively contribute to the assessment of evidence quality and are classified into four levels: high, moderate, low, and very low.To ensure objectivity and reliability, two researchers independently conducted the evaluation, whereas a third researcher reviewed the assessment process.Any discrepancies or disagreements were resolved through thorough discussion and consultation with professional specialists.
heterogeneity was considered significant.Given the variation in clinical settings, a random effects model was used.To investigate the sources of heterogeneity, subgroup analyses based on the type of surgery (laparoscopy vs. laparotomy), type of control group (sham-EA vs. standard care), position of acupoint (ST36-based EA vs. others), and time of EA (preoperative vs. postoperative) were conducted to analyze the primary outcome.A sensitivity analysis was performed by sequentially excluding each RCT to assess the robustness of the results.When at least 10 trials or data sets were included, a funnel plot was used to detect potential publication bias when at least ten trials or datasets were included.Statistical significance was set at a P-value of less than 0.05.

Search results
Of the initial 534 records obtained from the four electronic databases, 162 were eliminated because of duplications.Among the remaining 372 records, 334 were considered ineligible based on the assessment of their titles and abstracts.Subsequently, following a thorough full-text screening of the remaining 38 trials, an additional 30 reports were excluded, resulting in eight RCTs that met the eligibility criteria for inclusion in the present study (Fig. 1).Furthermore, during the examination of other databases, such as CNKI, an additional eight RCTs were identified.Overall, a total of 16 RCTs (n = 1562 patients) conducted in China published between 2013 and 2023 were included in the analysis [16,[20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] .

Characteristics of studies
The characteristics of the studies included in this meta-analysis are summarized in Table 1.Baseline patient characteristics, including age and sex, were available for 15 studies.Participants in the EA group were aged 49-67, while those in the control group were aged 51-69.The proportion ranged from 47.5 to 64.6%.However, one study did not provide any relevant information [32] .

Subgroup analysis of the primary outcome
Table 3 summarizes the findings of the subgroup analysis.Subgroup analysis based on the type of surgery (laparoscopy vs. open surgery), type of control group (standard care vs. sham EA), position of acupoint (ST36 vs. other acupoints), and time of EA (postoperative vs. preoperative) demonstrated no influence of these variables on the primary outcome (TFF).

Certainty of evidence
Supplemental Table 1 (Supplemental Digital Content 1, http:// links.lww.com/JS9/B232)summarizes the certainty of evidence across different outcomes.A high level of certainty was assigned to four outcomes (TFF, TBSR, time to tolerability of liquid, and time to tolerability of semiliquid food), indicating their robustness and reliability.Four other outcomes had a moderate level of certainty (i.e.TFD, time to first ambulation, time to tolerability of solid food, and postoperative complications), whereas the other four outcomes (i.e.postoperative pain on days 1, 2, and 3, as well as hospital LOS) had a low level of certainty.

Discussion
The current meta-analysis, focusing on 16 studies with a total of 1562 patients demonstrated several positive outcomes associated with the use of EA in patients undergoing colorectal surgeries.First, patients who received EA had shorter gastrointestinal functional recovery times, including TFF, TFD, and TBSR, than those who received standard care.Consistently, patients undergoing EA showed shorter times to tolerability of liquid, semiliquid, and solid food intake.Despite the lack of difference in time to first ambulation between the EA and control groups, the former exhibited a trend of reduced postoperative pain on day one and experienced significantly less severe pain on days two and three compared to the controls.Furthermore, our results demonstrated the association of EA with a lower risk of overall complications and a shorter hospital LOS.These findings highlight the potential benefits of incorporating EA into perioperative care to enhance recovery.POI, which is characterized by the temporary cessation of bowel movement, is a prevalent postoperative complication, particularly following open abdominal surgery.Its etiology is believed to be an interplay between sympathetic input, mediator release, the inflammatory cascade, and analgesic impact [36] .Although there is no ideal treatment modality for POI, previous studies have provided compelling evidence supporting the effectiveness of EA in alleviating POI and its associated symptoms [13,14] .EA is a therapeutic approach that involves the insertion of fine needles into acupoints followed by the application of low-level electrical currents to achieve therapeutic outcomes by synergistically combining the stimulatory effects of acupuncture and electrostimulation.Compared with conventional acupuncture, one distinct advantage of EA is its ability to stimulate acupoints with precise modulation of frequency and intensity, thereby allowing for accurate and quantifiable adjustments [25] .Furthermore, EA triggers analgesic effects by activating a range of bioactive substances through peripheral, spinal, and supraspinal mechanisms [37] .Previous investigations have demonstrated an association of acupoints ST36 and SP6 with the cAMP-CREB pathway and the mRNA expression profile in the brainstem of morphine-tolerant mice [38] .Moreover, EA exhibits anti-inflammatory effects by suppressing the expression of adenosine and substance P, which contribute to inflammatory pain [39] .Furthermore, EA activates the cholinergic anti-inflammatory pathway, leading to a reduction in the release of proinflammatory cytokines, including TNF-α, IL-1β, and IL-10, thereby mitigating postoperative inflammatory responses and diminishing the incidence of unexplained fever in patients receiving craniotomy [40] .
One previous meta-analysis, including an article published before 2017, reported a correlation between acupuncture and related therapies with enhanced gastrointestinal recovery after colorectal surgery, as reflected by a shorter TFF (i.e.− 15.79 h) compared to the control group [41] .However, the strength of the evidence of this analysis was limited by the inclusion of only four RCTs.Two other meta-analyses, which included patients undergoing various abdominal surgeries, also found a shorter TFF with the use of mixed acupuncture techniques (i.e.EA, TEA, or manual acupuncture) than with the control group.Nevertheless, the significance of their findings was impaired by high heterogeneity (I 2 = 94% and I 2 = 90%, respectively) [13,14] probably due to the inclusion of different acupuncture techniques  and various surgical procedures.Additionally, as only a small subset of studies (i.e. three and five RCTs, respectively) in those meta-analyses focused on laparoscopic procedures, their findings [13,14] may not be applicable to real-world scenarios, considering the increasing popularity of laparoscopic procedures in current clinical practice [42][43][44] .Our meta-analysis of 1552 patients found a significant association between EA and a shorter TFF (i.e.− 10.1 h) compared to standard care.The relatively low heterogeneity (51%) in our analysis may be attributed to the precise application of stabilized electrical stimulation during the EA procedure and the inclusion of patients specifically undergoing colorectal surgery.In addition, a substantial number of studies in our meta-analysis that included patients undergoing laparoscopic colorectal surgery (i.e.nine RCTs) may provide updated information for clinical practice.
Our current meta-analysis revealed a lower pain score on postoperative days two and three in patients who received EA than in the control group, despite only borderline significance on day one.Nevertheless, our finding of a borderline reduction in pain score on postoperative day one aligned with that of a previous study that demonstrated the effectiveness of TEAS for pain alleviation at short-term time points (i.e. 4 h, 12 h, and 24 h) following laparoscopy [12] .Our inclusion of studies that involved both open laparotomy and laparoscopic procedures may have hampered the significance of our findings.Considering the association between the development of POI and aggravation of postoperative pain [45] , our findings of a shorter TFF (i.e.lower risk of POI) in patients receiving EA may partly explain their lower pain scores observed on days two and three than those in the controls.
According to the traditional meridian theory in traditional Chinese medicine, specific anatomical locations along the meridians, known as acupoints, are believed to have a direct influence on internal organs.Zusanli (ST36) is an acupoint located along the stomach meridian of the foot-yangming meridian channel.A previous RCT has demonstrated that not only could EA at ST36 alleviate inflammatory reactions, but it could also attenuate intraabdominal pressure in septic patients [46] .Similarly, several animal studies have shown the effectiveness of EA in improving gastrointestinal motility [46][47][48] .These findings, therefore, suggest that EA at ST36 has therapeutic potential for preventing POI and optimizing gastrointestinal function.
This study had several limitations that should be acknowledged.First, the fact that all 16 included RCTs were conducted in China may limit the extrapolation of the findings to other populations of different ethnic and geographic backgrounds, as well as healthcare settings.Second, the wide variation in sample size (i.e. from 19 to 125 in the EA group and from 20 to 123 in the control group) may have impaired the statistical power and precision of the results.Third, although we found a significant positive effect of EA on the alleviation of POI regardless of the choice of acupoints, the majority of studies focused on acupoint ST36 alone or in combination with other acupoints, and only a few studies explored other acupoints.Therefore, the impact of EA on different acupoints cannot be differentiated.Fourth, the difference in the timing of EA administration among the studies (i.e.preoperative or postoperative) may be a potential confounder that could influence the outcomes.Finally, the finding of some concerns in our assessment of the risk of bias in the majority of studies suggested the presence of methodological limitations that may impact the reliability and validity of our results.Furthermore, the extended publication period of the included studies (i.e. from 2013 to 2023) could introduce potential biases associated with changes in clinical practice and advancements in surgical techniques over time.
In conclusion, the current meta-analysis of 16 studies involving 1562 patients demonstrated a positive association between the use of EA and enhanced gastrointestinal recovery (e.g.time to first flatus), shortened time to tolerability of liquid/food, reduced postoperative pain on day two and three, as well as a lower risk of complications and shorter hospital stays compared to patients receiving standard care.Although our findings support the multifaceted advantages of EA in optimizing the recovery trajectory in patients undergoing colorectal surgery, the inclusion of only Asian studies warrants further large-scale investigations to elucidate the benefits of EA in patients with different ethnic and geographical backgrounds.
(P) participants: adults receiving colorectal surgery regardless of the surgical techniques (e.g.laparoscopy or laparotomy); (I) interventions: the use of EA with or without other adjunct therapies to improve POI; (C) comparisons: sham acupuncture or standard care; (O) Outcomes: POI-related outcomes were available [for example, time to first flatus (TFF)]; and (S) study design: only RCTs were included.

Figure 1 .
Figure 1.Flowchart for inclusion and exclusion of studies.

Figure 2
Figure 2 summarizes the results of the risk of bias assessment.Of the 16 studies, 13 were categorized as 'having concernsʼ over

Figure 2 .
Figure 2. The risks of bias of individual studies.

Figure 3 .
Figure 3. Forest plot showing the association of electroacupuncture (EA) use with the time to first flatus (n = 1562).IV, inverse variance; CI, confidence interval; SD, standard deviation.

Figure 4 .
Figure 4. Forest plot demonstrating the correlation between electroacupuncture (EA) use and the time to first defecation (h).IV, inverse variance; CI, confidence interval; SD, standard deviation.

Figure 5 .
Figure 5. Forest plot showing the association of electroacupuncture (EA) use with bowel sound recovery time (h).IV, inverse variance; CI, confidence interval; SD, standard deviation.

Figure 7 .
Figure 7. Forest plot showing the associations of electroacupuncture (EA) use with the time to tolerability of (A) liquid; (B) semiliquid; and (C) solid food.CI, confidence interval; IV, inverse variance; SD, standard deviation.

Figure 8 .
Figure 8. Forest plot showing the association between electroacupuncture (EA) use and the risks of postoperative complications.CI, confidence interval; IV, inverse variance; SD, standard deviation.

Figure 9 .
Figure 9. Forest plot showing the association of electroacupuncture (EA) use with length of postoperative hospital stay (days).CI, confidence interval; IV, inverse variance; SD, standard deviation.