Acupuncture for the Postcholecystectomy Syndrome: A Systematic Review and Meta-Analysis

Background Postcholecystectomy syndrome (PCS) has become a common postoperative syndrome that requires systematic and comprehensive therapy to achieve adequate clinical control. Acupuncture and related therapies have shown clinical effects for PCS in many studies. However, systematic reviews/meta-analyses (SRs/MAs) for them are lacking. Objective To evaluate the efficacy and safety of acupuncture in the treatment of PCS using randomized controlled trials (RCTs). Methods Potentially eligible studies were searched in the following electronic databases up to 1 February 2020: PubMed, Embase, Cochrane Library, Web of Science (WoS), Chinese databases (Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), WanFang Database (WF), and China Science and Technology Journal Database (VIP)), and other sources (WHO ICTRP, ChiCTR, Clinical Trials, and Grey Literature Database). The RevMan 5.3 was employed for analyses. The Cochrane Collaboration' risk of bias tool was used to assess the risk of bias (ROB). The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess the quality of the evidence. Results A total of 14 RCTs with 1593 participants were included in this SR. MA showed that acupuncture in combination with conventional medicine (CM) did not show statistical differences in reduction in pain. However, acupuncture in combination with CM significantly reduced the incidence of postoperative nausea and vomiting (PONV) (RR, 0.71; 95% CI, 0.55–0.92) and improved gastrointestinal function recovery compared to the CM group. Acupuncture combined with traditional Chinese medicine and CM, and acupuncture as monotherapy may improve gastrointestinal function recovery with acceptable adverse events. Conclusion Acupuncture may be an effective and safe treatment for PCS. However, this study lacks conclusive evidence due to poor quality evidence, limited data, and clinical heterogeneity of acupuncture methods in the included studies.


Introduction
Cholecystectomy is one of the surgical procedures commonly performed to treat gallbladder disease [1]. Previous studies indicate that there are approximately 700,000 cases of cholecystectomy performed each year [2]. Cholecystectomy may sometimes fail to relieve symptoms and may contribute to adverse events [3]. Postcholecystectomy syndrome (PCS) develops weeks to months after cholecystectomy and describes the presence of symptoms including abdominal pain, vomiting, and gastrointestinal symptoms [4][5][6][7][8]. Meanwhile, with the advent of the laparoscopic era, the number of cholecystectomy surges and the number of PCS patients may also increase [9]. e incidence of PCS has been reported to be at least 15%, and the onset of symptoms ranges from days to years [8,10]. It seriously affects the quality of life of patients and also accelerates the deterioration of patients' diseases; so, the demand for treatment is increasing.
PCS management is challenging due to the different etiology of PCS symptoms, hence requiring specific treatment strategies. Conservative treatment and surgical therapy are the widely used treatment modalities for PCS [9]. Surgical treatment is recommended when conservative treatment is ineffective and the risk of reoperation is higher than that for the initial operation. And conservative treatment is still generally recommended. In China, acupuncture therapy (AT), an ancient conservative therapy, plays an important role in the treatment of PCS [11]. In traditional Chinese medicine (TCM), AT is used to regulate disharmony of the organ system and is theoretically used to resolve symptoms by stimulating acupuncture points related to the organs [12][13][14]. Meanwhile, acupuncture is effective and safe for pain [15][16][17], postoperative nausea and vomiting (PONV) [18,19], and gastrointestinal function [20,21]. Based on the evidence, the acupuncture method may be safe and effective for PCS.
However, to the best of our knowledge, there are no reported systematic reviews and meta-analysis of randomized controlled trials (RCTs) examining the efficacy and safety of acupuncture for PCS. erefore, this study is carried out to evaluate the current evidence on the efficacy and safety of acupuncture for PCS.
e Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach [22] was used to assess the quality of evidence level. We hope to provide evidence for clinical applications and references for future scientific and clinical research.

Methods
is systematic review had been registered with PROSPERO under registration number CRD42019129287 and the protocol published [23]. e study was performed based on the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines [24] and A Measure Tool to Assess Systematic Reviews-2 (AMSTAR-2) [25]. e following search terms were used: (1) clinical condition: postcholecystectomy syndrome, cholecystectomy, cholecystotomy, and cystectomy; (2) acupuncture terms: acupuncture therapy, acupuncture-moxibustion, meridian, electro-acupuncture, acupoint, acupuncture points, acupressure-acupuncture therapy, warm needling, moxa needle, acupuncture plus moxibustion, moxibustion with warming needle, auricular acupuncture, auricular needle, ear acupuncture, moxibustion, and abdomen acupuncture; and (3) study type (randomized controlled trial). We used "and" and "or" to connect the search terms. e search strategy for PubMed is shown in Table 1 as an example.

Type of Study.
We included RCTs that evaluated the safety and efficacy of AT for PCS. Parallel and crossover studies were included. Nonrandomized clinical studies, quasi-RCTs, cluster RCTs, and case reports were excluded.

Types of Participants.
We included patients with PCS above the age of 18 years, regardless of race, gender, and region. We considered actual clinical conditions; however, there were no exact diagnostic criteria for PCS, but the diagnosis was confirmed based on surgery history and associated symptoms (pain, PONV, and gastrointestinal symptoms).  [26] and PONV incidence [27] were analyzed.

Study Selection and Data Extraction.
All reviewers had previous professional training on study selection and data extraction. After the elimination of duplicate studies and uploading of eligible RCTs into NoteExpress, two researchers (QX and HY) independently screened the titles, abstracts, and keywords to identify studies that potentially met the inclusion criteria. Disagreements were resolved through a discussion between the two researchers. However, if the discussion did not resolve the disagreement, a third researcher (LZ or FL) was consulted to assist in making the final decision. Details of the selection procedure for studies are shown in a PRISMA flowchart ( Figure 1).
Data extraction was independently conducted by two authors (QX and HY) using standardized tabulation. e extracted information included the first author, publication date, country, sample size, mean age, gender, details of the treatment group and control group, outcome, conclusion, and acupuncture details. In case of a disagreement, a 3 rd party's opinion was sought to assist in making the final decision. e primary authors were contacted if any missing or additional information was needed.

Quality Assessment.
Two authors (ZY and GX) independently assessed the risk of bias (ROB) of the included studies using the Cochrane Handbook for Systematic Reviews of Interventions [29,30]. e following 7 items were assessed: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data, selective reporting, and other sources of bias. Each item was evaluated and categorized as "low risk," "unclear," and "high risk," e arbiter (FL) solved any disagreement between the two reviewers.
2.5. Statistical Analysis. We used endpoint scores or prepost differences as outcome measures for each included study. Review Manager (RevMan) Version 5.3 software (Cochrane, London, UK) suggested by Cochrane Collaboration was used for quantitative synthesis. For the meta-analyses, the fixed-effects model by the Mantel-Haenszel method was used; otherwise, the random-effects model adopted by the DerSimonian-Laired method was used. e I 2 statistic was used to measure the heterogeneity among the studies. We considered that there was no heterogeneity when p > 0.1 and I 2 < 50%, and all data were analyzed with 95% CIs. e dichotomous data were analyzed by risk ratios (RR), while for continuous data, the standard mean differences (SMD) were used. e subgroup was adopted on the condition of high data heterogeneity. Funnel plots were used to measure publication bias when the number of included studies was more than 10. If the funnel chart was evenly distributed, there was no reporting of bias.

Quality of Evidence.
e GRADE approach [22] was used by the reviewers to assess the quality of evidence of the obtained outcome indicators from five items of research limitations, inconsistency, indirectness, inaccuracy, and publication bias. e quality of evidence was rated as "very low," "low," "moderate," or "high" based on GRADE rating standards. e quality of the evidence "high" indicates that future research is very unlikely to change existing evidence; "moderate" indicates that future research may change the results; being "low" level indicates that future research is likely to have an important impact on existing evidence and is likely to change the evaluation results; and "very low" indicates that we are highly uncertain about the existing evidence.

Effects of Intervention.
e summaries for all comparison results and GRADE analyses are shown in Table 4.
ere was great heterogeneity, and we had performed a subgroup analysis based on the type of acupuncture.

Reduction in Pain
Intensity. Based on the existing strong correlation between the pain assessment scales, the visual analogue scale (VAS), or other scales, results were all converted to the 11-point digital rating scale (0 points for no pain, and 10 points for the most severe pain) [45].
Erden et al. [31] used CM and tramadol and reported no statistically significant difference between AT + CM with tramadol and CM with tramadol (n � 60; SMD, −0.50; 95% CI, −1.02 to 0.01; p � 0.06). e study further reported that the application of acupuncture did not cause any change in the consumption of tramadol. We carried out sensitivity analysis, and the study was excluded and the meta-analysis repeated. e results indicated that there was a significant difference between AT + CM and CM (n � 212; SMD, 2.25; 95% CI, 0.68-3.82; p � 0.005). e quality of evidence for the outcome was "low." (2) AT versus CM. ere was no significant difference between AT and CM (n � 60; SMD, −0.21; 95% CI −0.72 to 0.30; p � 0.42; Figure 3(b)). Wang [41] reported that there was no significant difference between acupuncture and CM combined with morphine. e quality of evidence for this outcome was "moderate".

POVN Incidence.
e POVN effect is defined as the ratio of the number of people showing POVN after treatment to the total number of people in the treatment group.

3.5.
Heterogeneity. Acupuncture methods, techniques, acupoints, depth of insertion, acupuncture doses, acupuncture operators, acupuncture retention duration, and treatment sessions among other factors were varied, which may lead to high clinical heterogeneity; hence, subgroup analysis was performed. Meanwhile, medication therapy showed heterogeneity on accounts of different types of drugs and dosages. However, since most of the studies did not provide adequate CM information, we did not accomplish the subgroup analyses. Finally, we found that the subgroup according to the type of acupuncture could better illustrate the heterogeneity. And we also tried to perform sensitivity analysis by excluding studies that were "high risk;" however, very few articles were included leading to high risk of bias.

Reporting Bias.
Since the number of included studies did not exceed 10, funnel plots were not used to measure publication bias.

Quality of Evidence.
e GRADE approach was used to evaluate the quality of the evidence of the included studies, and the analyses are presented in Table 4. Outcomes were the reduction in pain intensity, POVN incidence, 1 st defecation time, 1 st flatus time, and 1 st bowel sounds time. A total of 13 outcomes were applied to the RCTs. e quality of the evidence for the overall outcomes was acceptable. e results showed that there was 1 (1/13, 7.7%) outcome with very low quality evidence, 6 (6/13, 46.15%) with low quality evidence, 3 (6/13, 46.15%) with moderate quality evidence, and none with high quality evidence. However, it is difficult for therapists and patients to use blinding for acupuncture.    erefore, future research should pay more attention to the above aspects and avoid the risk of prejudice or revise evaluation tools to make them more suitable for acupuncture, Chinese medicine therapy, or other conservative treatment.

Discussion
In the current study, we conducted a systematic review and meta-analysis of 14 RCTs with 1593 participants to evaluate the efficacy and safety of acupuncture for PCS. e outcomes assessment of this review are summarized in 3 aspects: the change of pain before and after treatment, the incidence of POVN, and the recovery of gastrointestinal function (first defecation time, 1 st flatus time, and 1 st bowel sounds time).
ere were significant differences between acupuncture and CM in the POVN and the recovery of gastrointestinal function. However, acupuncture plus CM with single CM did not show statistical differences in reduction of pain.
When acupuncture was added to CM, our results indicated no significant reductions in pain intensity between CM and CM + acupuncture. A previous study [31] reported no significant difference in pain intensity between acupuncture + CM (tramadol) and CM (tramadol). However, the quality of evidence for this study was "low"; hence, we disputed these results. No significant differences in pain were reported between acupuncture and CM (morphine). However, only one trial [41] evaluated the differences in pain efficacy between acupuncture and CM. erefore, the results concerning the efficacy of acupuncture as monotherapy for pain reduction in PCS should be interpreted with caution.
Even though the quality of the evidence for the outcome was moderate, 3 studies [34][35][36] showed significant differences between AT + CM and CM in POVN. No significant differences in efficacy were reported between AT and CM. In addition, AT + TCM + CM showed no significant differences from CM.
In recovery of gastrointestinal function, AT + CM VS CM, AT VS CM, and AT + TCM + CM VS CM showed significant differences. However, this review reported significant differences between acupuncture and CM, and the quality of the evidence for the outcome was moderate. In addition, the results indicated that acupuncture might improve first defecation time and 1 st flatus time; however, due to the limited number of studies included, these results require further investigations. e significant differences in efficacy reported between AT + TCM + CM and CM were not conclusive due to the low level of evidence and the limited number of studies included.
Only 4 RCTs (28.57%) reported safety data for acupuncture, and there was no reported evidence of association of acupuncture with any serious adverse events. erefore, this review could not draw any firm conclusions on the safety of acupuncture for PCS. is review has several limitations. (1) Despite our efforts to reduce bias and the inclusion of grey literature, we are not        Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, and in duplicate) and any processes for obtaining and confirming data from investigators 3-4

Data items 11
List and define all variables for which data were sought (e.g., PICOS and funding sources) and any assumptions and simplifications made 3-4

Risk of bias in individual studies 12
Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis e low methodological quality of some RCTs remains a challenge. However, many studies showed performance bias since acupuncture was difficult to blind. e low methodological quality of some RCTs may cause overestimation of the effects of acupuncture on PCS. (4) In some studies, significant heterogeneity was reported for several outcomes. ese may have been caused by a number of factors such as age, gender, and surgical methods among other factors of the recruited PCS patients. In addition, acupuncture clinical trials involve many factors that may lead to heterogeneity, such as acupoint selection, depth of insertion, deqi, needle stimulation, needle retention duration, number of treatment sessions, frequency of treatment, and duration. Even though the treatment method used in the control group is CM, the differences in dosage and dosage forms may have caused heterogeneity. (5) e quality of various outcomes evidence included mainly low and moderate quality evidence. erefore, future research may have a significant impact on existing evidence and may change the evaluation results.
We provide prospects and suggestions for future research. Previous research reveals that PCS lacks a widely accepted diagnostic standard. Future research must standardize and generalize acupuncture treatment for PCS. It is important to consider possible clinical heterogeneity due to inconsistencies in the types of acupuncture, acupoint selection, acupuncture retention time, stimulation intensity, and course. In this review, most of the included studies used the ST 36 and PC 6 acupoints. e most frequent needle retention time was 30 minutes, and the number of treatments was 6 times. e treatment time was once a day. According to the current RCTs included in this review, the methodological quality and evidence quality was not high. erefore, in future, a multicentered, large sample, high quality RCT should be conducted in full compliance with the Consolidated Standards of Reporting Trials (CONSORT) [46], Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) [47], and Cochrane Handbook for Systematic Reviews of Interventions to control the methodological quality.

Conclusion
e results of this SR/MA indicated that acupuncture may improve the overall symptoms of PCS. e reported acupuncture-related adverse events are mild and acceptable. However, due to limited data, heterogeneity of acupuncture methods among the RCTs and the low methodological quality of some of the RCTs, there is a need for additional and well-designed RCTs with larger sample sizes to be performed to confirm these results.

Appendix (A). Full-Text Articles Excluded with Reasons
Full-text articles excluded with reasons are given in Table 6.

Data Availability
No data were used to support this study.

Conflicts of Interest
e authors declare that they have no conflicts of interest.

Risk of bias within studies 19
Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12) 5 Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot

5-8
Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency 5-8 Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15) 8 Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, metaregression (see Item 16)) 5-8

Summary of evidence 24
Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers) Evidence-Based Complementary and Alternative Medicine