Efficacy and safety of electrical acupoint stimulation for postoperative nausea and vomiting: A systematic review and meta-analysis

Liyue Lu; Chenlong Xie; Xing Li; Yalan Zhou; Zhiyu Yin; Pan Wei; Hao Gao; Jian Wang; Yue Yong; Jiangang Song

doi:10.1371/journal.pone.0285943

. 2023 May 31;18(5):e0285943. doi: 10.1371/journal.pone.0285943

Efficacy and safety of electrical acupoint stimulation for postoperative nausea and vomiting: A systematic review and meta-analysis

Liyue Lu ^1,^#, Chenlong Xie ^1,^#, Xing Li ^2,^‡, Yalan Zhou ^2,^‡, Zhiyu Yin ^2,^‡, Pan Wei ^2,^‡, Hao Gao ^2,^‡, Jian Wang ^2,^*, Yue Yong ^1,^2,^*, Jiangang Song ^1,^2,^*

Editor: Ahmed Mohamed Maged³

PMCID: PMC10231798 PMID: 37256901

Abstract

Background

Postoperative nausea and vomiting are typical postsurgical complications. Drug therapy is only partially effective. The goal of our meta-analysis is to systematically evaluate the efficacy and safety of electrical acupoint stimulation for postoperative nausea and vomiting and to score the quality of evidence supporting this concept.

Methods

PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov were searched from inception to March 19, 2020.

Results

Twenty-six studies (2064 patients) were included. Compared with control treatment, electrical acupoint stimulation reduced the incidence of postoperative nausea and vomiting (RR 0.49, 95% CI 0.41 to 0.57, P < 0.001), postoperative nausea (RR 0.55, 95% CI 0.47 to 0.64, P < 0.001) and postoperative vomiting (RR 0.56, 95% CI 0.45 to 0.70, P < 0.001). Electrical acupoint stimulation also reduced the number of patients requiring antiemetic rescue (RR 0.60, 95% CI 0.43 to 0.85, P = 0.004). No differences in adverse events were observed. Subgroup analysis showed that both electroacupuncture (RR 0.58, 95% CI 0.46 to 0.74, P < 0.001) and transcutaneous electrical acupoint stimulation (RR 0.44, 95% CI 0.34 to 0.58, P < 0.001) had significant effects. Electrical acupoint stimulation was effective whether administered preoperatively (RR 0.40, 95% CI 0.27 to 0.60, P < 0.001), postoperatively (RR 0.59, 95% CI 0.46 to 0.76, P < 0.001), or perioperatively (RR 0.50, 95% CI 0.37 to 0.67, P < 0.001). The quality of evidence was moderate to low.

Conclusions

Electrical acupoint stimulation probably reduce the incidence of postoperative nausea and vomiting, postoperative nausea, postoperative vomiting, and reduce the number of patients requiring antiemetic rescue, with few adverse events.

Introduction

Postoperative nausea and vomiting (PONV) are common postsurgical complications, and the incidence of PONV is approximately 20–30% [1], which increases up to 80% in high-risk patients without prophylactic antiemetic drugs [2]. Anesthetic factors, such as volatile anesthetics, opioids, type of surgery, and patient-related factors, are considered to have a key impact on the risk of PONV [3]. PONV not only reduces patient satisfaction after surgery but can also lead to serious postsurgical complications, such as electrolyte imbalance, aspiration of the gastric contents, increased intracranial pressure, aspiration pneumonia, suture dehiscence, and bleeding [4–11]. These factors ultimately prolong hospital stay and increase the cost of hospitalization [12].

PONV is triggered by several receptor systems, thus, preventing and treating PONV is a complex task [13, 14]. Antiemetic medications have widely been used to prevent PONV [15, 16]. They can be grouped into six different classes: 5-hydroxytryptamine 3 receptor antagonists, dopamine-2 receptor antagonists, neurokinin 1 receptor antagonists, corticosteroids, antihistamines, and anticholinergics [17–20]. Currently, most hospitals use antiemetic therapy involving a combination of these drugs [14]. Using dexamethasone in the beginning and 5-HT3 antagonist at the end based on Apfel Risk score is the best method to prevent PONV [14]. In addition, there are also pharmacological treatment modalities such as supplemental crystalloids [21], chewing gum [22], and ginger [13]. However, there is a complex and challenging aspect to pharmacological prophylaxis of PONV since it requires consideration of the individual patient’s PONV risk as well as the pharmacokinetics, efficacy, adverse effects profile, cost-effectiveness, and availability of antiemetic agents [14]. There are non‐pharmacologic approaches to PONV prevention as well. For example, acupuncture point stimulation [23, 24] and Morinda citrifolia Linn [25], etc. These nonpharmacological strategies offer attractive methods for managing PONV. In particular, acupoint stimulation shows promise for the management of PONV [16].

Some studies indicate that traditional Chinese medicine, especially acupoint stimulation, could be useful for prophylaxis and treatment of PONV [26, 27]. Electroacupuncture (EA) and transcutaneous electrical acupoint stimulation (TEAS) are commonly used interventions for acupoint stimulation [28, 29]. What EA and TEAS have in common is that they both apply electrical acupoint stimulation (EAS). A major difference between these interventions is that the former is invasive (involving needle insertion into the skin), whereas the latter is not. Clinically, both of these interventions are potential candidates for treating PONV [23, 30, 31]. EA and TEAS can be collectively called EAS, an effective and quantifiable modern version of manual acupuncture.

However, there is still insufficient evidence to demonstrate that electrical stimulation at acupuncture points has efficacy and safety for treating PONV. Hence, we systematically searched for published articles related to this treatment and conducted a systematic review of the evidence.

Methods

Our review was registered with PROSPERO (www.crd.york.ac.uk/PROSPERO) with the registration number CRD42020181386. This study was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses [32] and Assessing the methodological quality of systematic reviews (AMSTAR) guidelines [33].

Literature search

A comprehensive literature search was conducted of the major databases PubMed, EMBASE, Cochrane Library, Web of Science, and ClinicalTrials.gov from inception to March 19, 2020 without language restrictions. We used the following words: ("electroacupuncture [Mesh]" OR "electric stimulation therapy [Mesh]" OR "transcutaneous electric nerve stimulation [Mesh]" OR " electrical acupuncture" OR "electro-acupuncture" OR "TENS" OR "TEAS" OR "electroanalgesia*" OR "electric* stimulat*") AND ("surgical" OR "preoperative care" OR "procedure" OR "surgery" OR "preoperative") AND ("nause*" OR "vomit*" OR "emesis" OR "emeses" OR "emet*" OR "queas*"). Other databases use their own subtitles for individual searches individually to determine all eligible studies (S1 Table).

The control treatment (no acupuncture + active device, no acupuncture + inactive device, gel electrodes + inactive device, or usual care) as the control group: 1. No acupuncture + active device means the needles were bent to lay flat against the skin, or no needles were applied. Insulated wires from the activated stimulator box with a normal current output were attached to the needles or the inside of the arm covers. 2. No acupuncture + inactive device means the needles were bent to lay flat against the skin, or no needles were applied. Insulated wires from the inactivated stimulator box with no current output were attached to the needles or the inside of the arm covers. 3. Gel electrodes + inactive device means gel electrodes were placed on the acupoints and attached to a stimulator box with no current output.

Inclusion and exclusion criteria

The inclusion criteria were specified by the Population, Intervention, Control, Outcomes, and Study design (PICOS). The inclusion criteria were: 1. The review included emergency and elective surgery patients that underwent general anesthesia, regardless of age, sex, ethnicity, or surgery type. 2. The intervention measure in the treatment group was EAS (EA or TEAS). 3. the intervention measures in the control group were sham acupuncture, sham acupoint, sham electrical stimulation, or preoperative routine nursing. 4. Primary outcomes were the incidence of PONV, postoperative nausea (PON), or postoperative vomiting (POV). Secondary outcome measures were the numbers of patients requiring antiemetic rescue and adverse events. 5. The study was a randomized controlled trial (RCT) (blinded or non-blinded).

The exclusion criteria were as follows: 1. Patients undergoing cesarean section or abortion or those in the control group who received any electrical stimulation. 2. American Society of Anesthesiologists (ASA) ≥ III. 3. Literature with incorrect data or inaccessible data.

Study selection and data collection

Two researchers independently used EndNote (version X8.1, Clarivate Analytics, Philadelphia, United States) reference management software for literature classification, preparation, and removal of duplicates. Then, we excluded nonrelevant studies that did not meet the inclusion criteria after reading the title and abstract of each article. The articles that could not be excluded based on the title and abstract were retrieved for a full-text screening. If necessary, we acquired additional information from the trial authors by email or telephone.

A standardized data extraction list in an Excel spreadsheet (Microsoft Corporation, Redmond, Washington, United States) was used to collect information from the included studies: author, year, country, study design, sample size, age, types of surgery, intervention measures, duration and outcome indicators. This process was performed by two researchers independently and cross-checked after completion. When opinions differed, a third reviewer was consulted, and the case was reviewed for consensus.

Outcomes

The primary outcomes were the incidence of PONV, PON, or POV. The secondary outcome measures were the numbers of patients requiring antiemetic rescue and adverse events.

Risk of bias assessment

The risk of bias of the clinical trial was independently assessed by two reviewers using “The Cochrane Collaboration’s tool” [34], and any disagreements were solved by discussion. Furthermore, publication bias was evaluated by funnel plot analyses if sufficient studies were included.

The Grades of Recommendation Assessment Development and Evaluation

The quality of the evidence was assessed by the Grades of Recommendation Assessment Development and Evaluation (GRADE) system [35]. The GRADE system includes the risk of bias, inconsistency, indirectness, inaccuracy, and publication bias [36]. Bias risks included inappropriate randomization methods, allocation concealment, blindness, and excessive loss of follow-up data. The inconsistencies mainly involved different intervention or evaluation metrics. Indirectness covered direct and indirect comparisons of results between two groups. The inaccuracy was mainly judged by the width of the confidence intervals. Publication bias was due to unpublished studies (usually a negative result) by the investigator.

For each outcome, we initially awarded four points to each RCT and then downgraded the point total for defects regarding the 5 aspects. The quality of evidence was classified as A (high quality), B (medium quality), C (low quality), or D (very low quality) [37].

Statistical analysis

Statistical analyses were carried out using RevMan 5.4 (RevMan, the Cochrane Collaboration, Oxford, United Kingdom) software. We examined 5 outcomes, each as dichotomous variables. The differences in categorical outcomes between the EAS and control groups were reported as the relative risk (RR) with a 95% confidence interval (CI). Significant heterogeneity was considered when I² > 50% or P < 0.1, and a random-effects model was used for analysis [38]. Otherwise, a fixed-effects model was used.

If I² > 50% in a group of studies, suggesting there was high heterogeneity, then we used sensitivity analysis or subgroup analysis to investigate the possible reasons from both clinical and methodological perspectives [39].

Results

Study selection

A total of 864 articles were retrieved from the database search. By screening the article titles, abstracts, or both and removing duplicates, 794 records were excluded. Seventy full-text articles were included for rescreening. We excluded 3 reports published as abstracts, 15 articles lacking relevant data, 11 articles showing improper patients, 7 studies showing improper control groups, 2 studies without descriptions of acupoints, and 6 articles that were protocols. Finally, we included 26 studies [40–65]. A flowchart of the literature screening process is outlined in Fig 1.

Description of the included studies

Twenty-six studies [40–65] met our inclusion criteria and included work performed in 8 countries (United States of America, The United Kingdom, China, India, Malaysia, Turkey, Iran, and Denmark) with a total of 2,064 patients. Among them, 1,051 patients received EAS, and 1,013 patients served as controls. The surgical type included laparoscopy, lithotripsy, tonsillectomy, thyroidectomy, gynecological, thoracotomy, sinusotomy, craniotomy, and plastic surgery. Among the included RCTs that used EAS as an intervention measure, 8 trials [46–50, 54, 56, 57] including 545 patients performed EA and 18 trials [40–45, 51–53, 55, 58–65] including 1519 patients performed TEAS. The control patients received perioperative routine nursing in 7 trials [41, 43, 46, 49, 50, 54, 56], TEAS with an inactive device in 16 trials [40, 42, 44, 45, 51–53, 55, 58–65], an active device without needles in 2 trials [47, 48], and an inactive device without needles in 1 trial [57]. The time to first treatment was before surgery in 8 studies [41, 51, 54, 59, 61–63, 65], after surgery in 7 studies [40, 42–44, 47, 53, 57], and during surgery in 11 studies [45, 46, 48–50, 52, 55, 56, 58, 60, 64]. The duration of first treatment lasted from 10 minutes to 24 hours. Nausea and vomiting were measured by the frequency of PONV, PON, and POV as the primary outcome and the use of rescue antiemetic and adverse events as secondary outcomes. The safety assessment involved the incidence of adverse events. However, 14 (53.85%) studies [46–50, 52, 55, 57, 59–64] lacked data on adverse events. Table 1 and S2 Table shows the characteristics of the included literature.

Table 1. Characteristics of the included trials.

Author (year)	County	Study design	Surgery	Age (T/C)	Number of participants (T/C)	Intervention		Time point	Target outcomes	Adverse events
Author (year)	County	Study design	Surgery	Age (T/C)	Number of participants (T/C)	Treatment group	Control group	Time point	Target outcomes	Adverse events
Yeoh et al, 2016 [40]	Malaysia	RCT	LS	46.5±14.3/ 41.5±13.8	40/40	TEAS	Inactive device	24 h after surgery	1, 4, 5	No
Kabalak et al, 2005 [41]	Turkey	RCT	Tonsillectomy	6.9±3.6/6.7±3.8	30/30	TEAS	Usual care	5 min before induction	1, 5	Erythema
Zárate et al, 2001 [42]	USA	RCT	LC	42±16/39±14	110/56	TEAS	Inactive device	9 h after surgery	2, 3, 5	Erythema
Ye et al, 2008 [43]	China	RCT	Craniotomies	44.5±15/35.8±20.2	20/20	TEAS	Usual care	After surgery: 1 h per time, and 2 h intervals in 1 d	2, 3, 5	No
Chen et al, 1998 [44]	USA	RCT	AHS or myomectomy	43±13/45±12	25/25	TEAS	Inactive device	After surgery: 30 min per time, and 2–3 h intervals in 3 d	2, 3, 4, 5	Itching
Liu et al, 2008 [45]	China	RCT	LC	42±18/40±19	48/48	TEAS	Inactive device	30~60 min before the induction till the end of surgery	1, 2, 3, 4, 5	No
An et al, 2014 [46]	China	RCT	SC	40.7±12.1/39.1±10.9	41/40	EA	Usual care	From induction to the end of surgery	1	ND
Rusy et al, 2002 [47]	USA	RCT	Tonsillectomy	6.35±2.06/6.53±2.49	40/40	EA	No acupuncture with active device	20 min after surgery	1, 2, 3, 4	ND
Sahmeddini et al, 2010 [48]	Iran	RCT	Septoplasty	27±11/29±10	45/45	EA	No acupuncture with active device	5 min each before surgery and till the end of surgery	1	ND
El-Rakshy et al, 2009 [49]	UK	RCT	LC or AHS	> 18	44/58	EA	Usual care	During the period of induction	1	ND
Christensen et al, 1989 [50]	Denmark	RCT	AHS or ASO or tubal infertility	41.5/41.5	10/10	EA	Usual care	During the period of induction	2	ND
Zhang et al, 2014 [51]	China	RCT	ABS	35.0±7.6/34.3±9.1	33/32	TEAS	Inactive device	30 min before induction	2, 3, 5	Pruritus
Tu et al, 2018 [52]	China	RCT	VATSL	64.34±8.25/62.88±8.37	72/72	TEAS	Inactive device	throughout the surgery	1	ND
Tu et al, 2019 [53]	China	RCT	Ureteroscopic lithotripsy	64.32±10.21/62.14±11.34	60/60	TEAS	Inactive device	4,8,12 h postoperatively and three times on the next 2 d after surgery	1, 5	Itch
Li et al, 2017 [54]	China	RCT	GLS	35.2±6.1/34.4±9.1	20/20	EA	Usual care	30 min before surgery	2, 3, 5	Pain, bruising
Gu et al, 2019 [55]	China	RCT	Laparoscopic radical gastrectomy	57.59±7.32/56.67±6.23	58/59	TEAS	Inactive device	30 min before induction to 30 min after surgery: 30 min per time, and 3 times 1 day in 2d	1	ND
Amir et al, 2007 [56]	India	RCT	Middle ear surgery	17.95±8.25/21.1±7.48	20/20	EA	Usual care	20 min before induction till the end of surgery	1, 2, 3, 4, 5	Erythema
Chen et al, 2016 [57]	China	RCT	Lobectomy surgery	55.80±15.75/56.93±14.61	46/46	EA	No acupuncture with inactive device	after surgery: 30 min per time, and 2 times 1 day in 3d	2, 3	ND
Yang et al, 2015 [58]	China	RCT	GLS	37/35	50/50	TEAS	Inactive device	30 min before surgery and lasting to leave PACU	1, 2, 3, 4, 5	Redness, swelling, itching
Yu et al, 2020 [59]	China	RCT	GLS	48.5±16.2/45.9±17.5	30/30	TEAS	Inactive device	30 min before anesthesia	1, 4	ND
Liu et al, 2015 [60]	China	RCT	SC	42.1±10.83/43.8±11.47	44/44	TEAS	Inactive device	30 min before anesthesia and lasting to leave PACU	2, 3	ND
Chen et al, 2015 [61]	China	RCT	Thyroidectomy	41.9±9.9/41.4±9.8	29/30	TEAS	Inactive device	30 min before induction	1	ND
Chen Y et al, 2015 [62]	China	RCT	Thyroidectomy	37.5±8.5/40.2±7.8	41/42	TEAS	Inactive device	30 min before induction	1	ND
Yao et al, 2015 [63]	China	RCT	GLS	34.2±7.2/35.6±8.7	35/36	TEAS	Inactive device	30 min before induction	2, 3	ND
Zheng et al, 2008 [64]	China	RCT	Head and neck tumor surgery	54.7±10.2/53.6±9.5	30/30	TEAS	Inactive device	30 min in the first 2–4 h, then once more every 3 h, 3 times in total.	2, 3, 4	ND
wang et al, 2014 [65]	China	RCT	Sinusotomy	39.9/ 43.1	30/30	TEAS	Inactive device	30 min before anesthesia	1, 4	Pruritus

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Note: EA, electroacupuncture; TEAS, transcutaneous electrical acupoint stimulation; T, treated group (included EA and TEAS); C, control group; LC, laparoscopic cholecystectomy; LS, laparoscopic surgery; GLS, gynecological laparoscopic surgery; SC, supratentorial craniotomy; AHS, abdominal hysterectomy surgery; ABS, ambulatory breast surgery; ASO, hysterectomy, salpingo-oophorectomy; VATSL, video-assisted thoracic surgical lobectomy. * 1: postoperative nausea and vomiting; USA, United States of America; UK, The United Kingdom. 2: postoperative nausea; 3: postoperative vomiting; 4: number of patients requiring antiemetic rescue; 5: incidence of adverse effects. * ND = Not defined

Risk of bias within studies

All of the included trials mentioned randomization but 2 articles [43, 44] failed to report the method used to generate random sequences and were rated as unclear risk. For allocation concealment, 7 studies [48, 54, 57, 60–63] used a sealed envelope and 2 studies [52, 53] used central allocation and were considered low risk, whereas the others did not mention allocation concealment and were rated as unclear risk. For blinding, 16 studies [40–47, 49–51, 55, 56, 58, 59, 64] provided insufficient information or used methods that could allow the patients to be aware of their assigned groups and were rated as unclear risk. For blinding of the outcome measurers, 5 studies [43, 53, 57, 64, 65] were rated as unclear risk, 3 [53, 57, 64] of which were not blinded. Considering the specificity of EAS treatment, blinding might not be done for operators. The remaining 2 studies [43, 65] did not describe blinding in their design. In addition, due to incomplete outcome data reporting, 6 studies [43, 44, 48, 50, 56, 64] did not describe the loss rate of the follow-up population, and 2 studies [42, 55] did not describe the reasons for the loss in the follow-up. These were, therefore, classified as unclear risk. One study [41] was judged as high risk due to later changes in random enrollment personnel. For selective reporting, 1 trial [47] did not describe adverse events of therapy, but when asked, the authors indicated that no obvious adverse effects were noted during the study. In terms of other biases, for the purpose of treatment, 3 studies [41, 42, 45] were rated as high risk. Among them, 1 article [42] was rated as high risk due to the differences between the groups. Another article [45] was rated as high risk due to the inconsistency of the data between figures and text. The last article [41] was rated as high risk due to the late supplementation of patients (see S1 Fig).

Incidence of PONV

Sixteen of the studies [40, 41, 45–49, 52, 53, 55, 56, 58, 59, 61, 62, 65] included 1372 patients and measured and recorded the results of PONV after EAS. A fixed-effects model was used (P = 0.48; I² = 0%). The results indicated that participants who received EAS exhibited a significantly lower incidence of PONV than those in the control group (RR, 0.49; 95% CI, 0.41 to 0.57; P < 0.001) (Fig 2A). Sensitivity analysis of the outcomes showed that the heterogeneity was not significantly lower after any study was excluded (S3 Table).

Fig 2 — A: Forest plots comparing the incidence of postoperative nausea and vomiting between EAS and Control group. B: Forest plot comparing the incidence of nausea and vomiting after EAS treatment within 24 hours after surgery and other times after surgery.

According to the observation time, subgroup analysis showed that PONV within 24 h after surgery (RR, 0.51; 95% CI, 0.43 to 0.60; P < 0.001; I² = 0%) and at other times after surgery (RR, 0.40; 95% CI, 0.25 to 0.64; P = 0.001; I² = 30%) could be significantly reduced by EAS (Fig 2B).

The RCTs that recorded the incidence of PONV included several types of surgical procedures. To clarify the impact of the surgical procedure, we performed a subgroup analysis. Subgroup analysis showed that for laparoscopy (RR, 0.46; 95% CI, 0.36 to 0.60; P < 0.001; I² = 0%), thyroidectomy (RR, 0.40; 95% CI, 0.24 to 0.65; P = 0.0002; I² = 0%), and tonsillectomy (RR, 0.69; 95% CI, 0.53 to 0.90; P = 0.007; I² = 0%), EAS reduced the incidence of PONV (P < 0.001, S2A Fig).

In 25% (4/16) of the included studies, the control patients did not receive placebo targeting acupuncture points or electrical stimulation. Thus, we conducted a subgroup analysis. The results showed that with placebo (no acupuncture + active device, no acupuncture + inactive device, or gel electrodes + inactive device) (RR, 0.48; 95% CI, 0.40 to 0.57; P < 0.001; I² = 12%) or without placebo (usual care only) (RR, 0.53; 95% CI, 0.33 to 0.84; P = 0.007; I² = 0%), EAS reduced the incidence of PONV (P < 0.001, S2B Fig).

PONV within 24 h contained the maximum number of studies [40, 41, 45–47, 49, 56, 58, 59, 61, 62, 65]. We further used these studies to perform subgroup analysis based on different EAS therapies to determine whether EA or TEAS had the best treatment effect. A fixed-effects model was used (I² = 0%). The results showed that both EA (RR, 0.58; 95% CI, 0.46 to 0.74; P < 0.001) and TEAS (RR, 0.45; 95% CI, 0.34 to 0.58; P < 0.001) had significant therapeutic effects (P < 0.001, Fig 3A). However, there was no significant difference between the two types of treatment (RR, 0.51; 95% CI, 0.43 to 0.60; P = 0.13).

Fig 3 — A: Forest plots comparing the incidence of postoperative nausea and vomiting within 24 h between TEAS and EA. B: Forest plots comparing the incidence of postoperative nausea and vomiting within 24 h preoperatively, postoperatively, and perioperatively.

According to the starting and ending times of the first intervention, the studies were divided into three subgroups: preoperative intervention, postoperative intervention, and perioperative intervention groups. The results showed that preoperative interventions (RR, 0.43; 95% CI, 0.29 to 0.63; P < 0.001; I² = 0%), postoperative interventions (RR, 0.59; 95% CI, 0.46 to 0.76; P < 0.001; I² = 40%) and perioperative interventions (RR, 0.50; 95% CI, 0.37 to 0.67; P < 0.001; I² = 0%) all significantly reduced the incidence of PONV (Fig 3B). In this study, only 2 studies [40, 47] were in the postoperative group with a heterogeneity of 40%, and the other two groups had no heterogeneity (I² = 0%). It is possible that the intervention type and duration were different between the two postoperative studies.

Incidence of PON

Thirteen studies [43–45, 47, 50, 51, 54, 56–58, 60, 63, 64] involving 842 participants reported the incidence of PON. The results were analyzed using a fixed-effects model (P = 0.03; I² = 46%). The results showed that the incidence of PON was significantly lower in the EAS group than in the control group (RR, 0.53; 95% CI, 0.45 to 0.62; P < 0.001) (Fig 4).

When the trial by zheng [64] was excluded, the heterogeneity decreased to 7%, with no change in the results. The remaining trials revealed that EAS could reduce PON compared to the control group. The sources of heterogeneity that remained may have been due to the different types of surgery and durations of the interventions (S3 Table).

Incidence of POV

Twelve studies [43–45, 47, 51, 54, 56–58, 60, 63, 64] involving 822 participants reported the incidence of POV. The fixed-effects model analysis was conducted (P = 0.17; I² = 28%). The results demonstrated that the incidence of PON was significantly decreased in the EAS intervention group compared with the control group (RR, 0.56; 95% CI, 0.45 to 0.70; P < 0.001) (Fig 5).

Heterogeneity substantially disappeared when we excluded one study [47] (P = 0.54; I² = 0%), and the outcomes remained significant (RR, 0.49; 95% CI, 0.37 to 0.66; P < 0.001). It is possible that the intervention duration and type of operation were different (S3 Table).

Number of patients needing antiemetic rescue

Nine studies [40, 41, 44, 45, 47, 56, 58, 59, 64] reported the number of patients who required antiemetic rescue. We analyzed the results using a random-effects mode (P = 0.04; I² = 51%). The results showed that the need for rescue antiemetics was significantly lower in the EAS group than in the control groups (RR, 0.60; 95% CI, 0.43 to 0.85; P = 0.004) (S3 Fig).

Most of the heterogeneity was caused by one study [47]. After exclusion, heterogeneity decreased to I² = 33%, which may have been due to the type of surgery, the method, and the duration of the intervention (S3 Table).

Adverse events

Nine studies [41, 42, 44, 51, 53, 54, 56, 58] reported adverse reactions resulting from the treatment regimens. The heterogeneity test showed I² = 50%; P = 0.04, therefore, the fixed-effects model was used for analysis. There was no statistical significance between these two groups (RR, 0.94; 95% CI, 0.62 to 1.42; P = 0.78) (S4 Fig).

Sensitivity analysis of the outcomes showed that heterogeneity was not significantly lower after any study was excluded (S3 Table).

Publication bias

No obvious release bias was found through the inverted funnel chart (S5 Fig).

Sensitivity analysis

S3 Table describes the details of the sensitivity analyses by excluding one study at a time. S4 Table shows the results of sensitivity analysis by changing the effects model for outcome analysis.

GRADE evaluation

Based on the principles of the GRADE evaluation, we evaluated the quality of the evidence provided via the PONV, 24 h PONV, PON, POV, rescue antiemetic, and adverse events assessments. Table 2 shows that, except for rescue antiemetic assessments, which were classified as low-quality, the others were evaluated as moderate in quality.

Table 2. GRADE evaluation of evidence quality.

Outcomes Participants(studies)	Risk of bias	Inconsistency	Indirectness	Imprecision	Publication bias	Overall quality of evidence
PONV 1372(16 studies)	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	no publication bias²	⊕⊕⊕⊝ MODERATE^1,²
24h PONV 901(12 studies)	serious³	no serious inconsistency	no serious indirectness	no serious imprecision	no publication bias ²	⊕⊕⊕⊝ MODERATE²^,³
PON 842(13 studies)	serious⁴	no serious inconsistency	no serious indirectness	no serious imprecision	no publication bias ²	⊕⊕⊕⊝ MODERATE²^,⁴
POV 822(12 studies)	serious⁵	no serious inconsistency	no serious indirectness	no serious imprecision	no publication bias	⊕⊕⊕⊝ MODERATE⁵
Rescue Antiemetic 616(9 studies)	serious⁶	serious⁷	no serious indirectness	no serious imprecision	no publication bias	⊕⊕⊝⊝ LOW^6,⁷
Adverse Events 700(9 studies)	serious⁸	no serious inconsistency	no serious indirectness	no serious imprecision	no publication bias	⊕⊕⊕⊝ MODERATE⁸

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Note

¹ 11 studies were rated as unclear risk in allocation concealment; 2 studies were rated as hight-risk and 8 were rated as unclear in terms of other biases

² Funnel plot showed publication bias

³ 10 studies were rated as unclear risk in allocation concealment; 2 studies were rated as hight-risk and 5 were rated as unclear in terms of other biases

⁴ 2 studies were rated as unclear risk in random sequence generate; 8 studies were rated as unclear risk in allocation concealment; 4 studies applied a single-blind study design in blinding; 1 study was rated as hight-risk and 5 were rated as unclear in terms of other biases

⁵ 2 studies were rated as unclear risk in random sequence generate; 7 studies were rated as unclear risk in allocation concealment; 4 studies applied a single-blind study design in blinding; 1 study was rated as hight-risk and 4 were rated as unclear in terms of other biases

⁶ 1 study was rated as unclear risk in random sequence generate; 5 studies were rated as unclear risk in allocation concealment; 2 studies applied a single-blind study design in blinding; 2 study were rated as hight-risk and 2 were rated as unclear in terms of other biases

⁷ I square = 51%

⁸ 1 study was rated as unclear risk in random sequence generate; all studies were rated as unclear risk in allocation concealment; 2 studies applied a single-blind study design in blinding; 2 studies were rated as hight-risk and 3 were rated as unclear in terms of other biases.

Discussion

The results of this meta-analysis indicate that EAS significantly decreases the incidence of PONV, PON, and POV. Our results were consistent with the previous studies. A meta-analysis first published in 2004 was updated in 2015 and found that the effect of acupoint stimulation is comparable to antiemetics in preventing PONV [23]. But, this research only focused on evaluating the effect of PC6. Another meta-analysis indicated that additional effective meridian points in the treatment of PONV included BL10-11, BL18-26, SP4, SP6, ST34, ST36, ST44, and others [66], and thus PC6 may not be the only acupoint effective in treating PONV. We included studies looking at many acupuncture points, which are more comprehensive and practical for studying the efficacy of EAS. The acupoints should be selected for each patient according to their presenting symptoms and characteristics.

Subgroup analysis showed that EAS, whether applied as a preoperative intervention, postoperative intervention, or perioperative intervention, had a significant effect. To the best of our knowledge, no meta-analysis has been conducted on this topic. However, one RCT showed that EA on PC6 is effective in the prevention of PONV, and pre-operative acupuncture is more effective than post-operative acupuncture. There are two possible reasons for the disparity in results. Firstly, meta-analysis can only show that the three types of treatment timing are effective because they were not directly compared in the included studies by us. Secondly, the previous meta-analysis indicated that the antiemetic effect of acupuncture require treatment of awake rather than anesthetized patients [67]. Third, during surgery, the needle cannot be well protected, and the overall effect may be minimized. For safety reasons, it is ideal to provide acupuncture to conscious patients before surgery because most of the acupuncture points are located around the nerves, and deep punctures on unconscious patients may damage nerves.

Another subgroup analysis demonstrated that both EA and TEAS had good therapeutic effects compared with the control group. As far as we know, no similar study comparing the efficacy of EA and TEAS for PONV. However, a meta-analysis indicated that acupuncture therapy can reduce the risk of PONV in abdominal operation. Another meta-analysis suggested that TEAS was effective in preventing PONV [68]. Those results were consistent with the results obtained in our study. The addition of EAS treatment can reduce the workload of doctors, allowing doctors to treat multiple patients at once, and mass production also makes the parameters used in treatment more accurate. EAS is divided into EA and TEAS. EA combines a pulsating electrical current with acupuncture to enhance acupoint stimulation, which is a more effective method for administering acupuncture [28]. The advantages of EA are that it preserves the therapeutic effect of traditional acupuncture based on increasing EAS and combines electro with physical stimulation generated by acupuncture at acupuncture points. However, these advantages also mean that this process of acupuncture requires professional acupuncturists to only use invasive needles. In addition, some patients who are sensitive to needles may experience syncope during treatment and may have complications, such as subcutaneous bleeding, persistent acid bloating, and a burning sensation at the acupuncture site. TEAS has advantages: there is no intrusive behavior and patients’ acceptance is higher. TEAS also has disadvantages: only electrical stimulation can be applied and there is a lack of physical stimulation of needle penetration into the skin. Additionally, TEAS may cause minor allergies, such as skin flushing. Compared with EA, TEAS treatment is safer, more effective, and worthy of clinical promotion.

We have found that for laparoscopy, thyroidectomy, and tonsillectomy, EAS reduced the incidence of PONV. Similar findings have also been reported. Studies on the preventive and therapeutic effects of acupuncture on PONV for specific types of surgeries, and the findings all indicate that acupuncture is an effective and safe therapy for PONV [69, 70].

In our meta-analysis, we included more patients and RCTs. In addition to the inclusion of TEAS, RCTs evaluating the effectiveness of EA in the treatment of PONV were also added. Thus, our study provides a more comprehensive analysis than the 2020 TEAS meta-analysis [68]. Furthermore, we used the Quality Evaluation Tool approach to rate the quality of evidence to provide more reliable conclusions. In addition, we conducted a subgroup analysis to compare the pros and cons of EA and TEAS and distinguish the role of EAS in different types of procedures.

The quality of the RCTs included in this review was assessed by the GRADE system [35]. GRADE clearly differentiates the quality of each RCT from the overall strength of the evidence, making the accuracy of the analysis results clearer [71, 72]. Grading the strength of the evidence using the GRADE approach is becoming an important, recommended step in a comprehensive evidence evaluation and could increase the transparency of the clinical decision-making processes, especially when the quality of the evidence is poor or unclear [71, 73]. AMSTAR is a measurement tool created to assess the methodological quality of systematic reviews [74]. It is a reliable, valid, and critical assessment tool developed by AMSTAR in 2017 [75]. According to the GRADE criteria and AMSTAR 2 system, the quality of evidence was moderate for all outcomes, except the rescue antiemetic requirement (low-quality evidence). Therefore, the results lower our confidence in clinical decisions. Fortunately, the methodological quality was high. Incorporating all the evaluation results reported in the study, some studies may have a certain degree of bias. However, no obvious release bias was found through the inverted funnel chart.

Moreover, regarding adverse events, there was no significant difference between the EAS group and the control group. This result indicated that EAS is not related to any serious adverse events, although some patients may present minor hemorrhage or pain at the insertion site of the needle, or redness and itching may appear on the skin where the surface electrode was applied. The safety data available were limited, as 14 (53.85%) studies did not report any side effects of EAS.

Apfel and his colleagues developed a data-based assessment tool to predict the risk of PONV [76]. The tool assigns one point for each known risk factor (gender, smoking status, history of PONV or motion sickness, and use of opioids for postoperative pain) [77]. They found that the presence of 1, 2, 3, and 4 of these risk factors increased the incidence of PONV by 21%, 39%, 61%, and 79%, respectively [76]. The tool classifies patients with 0–1, 2, or 3-plus risk factors into “low,” “medium,” and “high” risk categories, respectively. In 2020, the Fourth Consensus Guidelines for the Management of PONV concluded that “multimodal PONV prophylaxis in patients with 1 or 2 risk factors, in an attempt to reduce risk of inadequate prophylaxis” [14]. Two antiemetics are recommended for PONV prophylaxis in patients at medium risk and 3–4 antiemetics in patients at high risk [14]. In order to evaluate whether EAS is useful for patients with “low,” “medium,” or “high” risk of PONV, RCTs in which participants were stratified by Apfel score should be done.However, only one article mentioned the Apfel scoring system during patient inclusion among the included studies. It specifies the inclusion of patients with an Apfel score ≥ 2 including patients with a medium-high risk for PONV [40]. While none of the other 25 studies had that inclusion criterion. Thus, we could not conduct a subgroup analysis based on Apfel scores. We agree that the Apfel scoring system is very important. If these RCTs included Apfel scores in their inclusion criteria or stratified randomized groups of patients based on the Apfel scoring system, higher-quality results would have been obtained.

Opioids have been identified as an independent risk factor for the development of PONV [77]. The mechanism of action of EAS may involve the regulation of endogenous opioid release and other neurotransmitters [78]. Evidence has shown that EA treatment might lead to better analgesia and reduce opioid use [79]. This is a possible mechanism of how EAS reduces PONV.

We excluded patients who underwent cesarean section or abortion, because the abortion patients may have had pregnancy vomiting. Similarly, cesarean patients might be administered oxytocin. Oxytocin causes emesis. We only included patients who underwent general anesthesia, whereas most cesarean patients do not use this type of anesthesia.

Our review has several limitations. First, most of the included studies had small sample sizes, and the event rates of several outcomes were low. This limitation may lead to imprecise evidence. Additionally, using GRADE, we judged the quality of the evidence in the review to be only moderate or low. The GRADE evidence quality of the pooled results lowers our confidence in the utility of the evidence to guide clinical decisions. Third, some design flaws are obvious. For example, there are many types of surgery included in the literature. The results of the analysis of all surgical studies are more likely to lead to bias. And some results that were significant for the evaluation of PONV were not included (the frequency of PONV). Cause only one of the 26 studies included in our meta-analysis recorded the frequency of PONV. Fourth, no clear comparison with already recommended pharmacological treatment group. Fifth, no obvious risk assessment or use of the scoring system to stratify the included studies. In addition, a certain degree of heterogeneity was observed in this meta-analysis. We tried to reduce heterogeneity through subgroup and sensitivity analyses, but it has not yet been completely resolved.

Conclusion

Our analysis showed that EAS can decrease the incidence of PONV, PON, and POV, as well as the number of patients requiring antiemetic rescue, and does not increase adverse events in patients undergoing elective surgery under general anesthesia. According to the GRADE criteria, the quality of evidence was moderate for all outcomes, except the rescue antiemetic requirement (low-quality evidence). These findings suggest that EAS may be considered an effective and safe treatment for PONV and that the EAS approach may be promising to promote the recovery of patients after surgery. The reliability of these results for PONV needs to be further explored, and the quantity and quality of the included studies need to be improved.

Supporting information

S1 Checklist. PRISMA 2009 checklist.

(DOC)

Click here for additional data file.^{(65.5KB, doc)}

S1 Fig. Risk of bias summary: Review authors’ judgments of each included trial.

(TIF)

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S2 Fig. Subgroup analyses about postoperative nausea and vomiting.

A: Forest plots of types of surgical procedures. B: Forest plot of EAS vs. placebo.

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S3 Fig. Forest plots of the numbers of patients needing antiemetic rescue in EAS vs control.

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S4 Fig. Forest plots of the adverse events in EAS vs control.

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S5 Fig. Funnel plot for the assessment of publication bias for postoperative nausea and vomiting.

A: Funnel plot for postoperative nausea and vomiting. B: Funnel plot for postoperative nausea. C: Funnel plot for postoperative vomiting.

(TIF)

Click here for additional data file.^{(1.1MB, tif)}

S1 Table. Search strategy.

(DOCX)

Click here for additional data file.^{(28.9KB, docx)}

S2 Table. Details of the included trials for treatments methods.

(DOCX)

Click here for additional data file.^{(47KB, docx)}

S3 Table. Sensitivity analyses by excluding one study at a time.

(DOCX)

Click here for additional data file.^{(96KB, docx)}

S4 Table. Sensitivity analysis by changing the effects model for outcome analysis.

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Click here for additional data file.^{(22.1KB, docx)}

S5 Table. AMSTAR 2: A critical appraisal tool for systematic reviews.

(DOCX)

Click here for additional data file.^{(35.5KB, docx)}

S1 Raw data

(RAR)

Click here for additional data file.^{(75.2KB, rar)}

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

This work was supported by the National Natural Science Foundation of China [81774108, 81703898, 81973652].

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PLoS One. doi: 10.1371/journal.pone.0285943.r001

Decision Letter 0

Elisa Panada

9 Feb 2022

PONE-D-21-05426

Efficacy and safety of electrical acupoint stimulation for postoperative nausea and vomiting: A systematic review and meta-analysis

PLOS ONE

Dear Dr. Song,

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**********

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Reviewer #1: PONE-D-21-05426

Efficacy and safety of electrical acupoint stimulation for postoperative nausea and

vomiting: A systematic review and meta-analysis

Thank you for the opportunity to review this submission to the journal. I have a small nuber of comments.

The submission is similar to the meta-analysis of Chen (Chen J, Tu Q, Miao S, Zhou Z, Hu S. Transcutaneous electrical acupoint stimulation for preventing postoperative nausea and vomiting after general anesthesia: a meta-analysis of randomized controlled trials. International Journal of Surgery. 2020 Jan 1;73:57-64.) but has a more up to date search (up to March 2020 vs July 2019) and as expected has more publications under analysis. I would have expected all of the studies included by Chen to be included in this submission but they are not – approximately half are included. What is the difference in the inclusion/exclusion criteria.

After a brief search of the literature there were a number of publications that seem eligible for analysis such as those below. The second was published online in February 2020 and seems eligible.

H. Wang, Y. Xie, Q. Zhang, N. Xu, H. Zhong, H. Dong, L. Liu, T. Jiang, Q. Wang, L. Xiong, Transcutaneous electric acupoint stimulation reduces intra-operative remifentanil consumption and alleviates postoperative side-effects in patients undergoing sinusotomy: a prospective, randomized, placebo-controlled trial, BJA: British Journal of Anaesthesia, Volume 112, Issue 6, June 2014, Pages 1075–1082, https://doi.org/10.1093/bja/aeu001

Chen J, Zhang Y, Li X, Wan Y, Ji X, Wang W, Kang X, Yan W, Fan Z. Efficacy of transcutaneous electrical acupoint stimulation combined with general anesthesia for sedation and postoperative analgesia in minimally invasive lung cancer surgery: A randomized, double‐blind, placebo‐controlled trial. Thoracic cancer. 2020 Apr;11(4):928-34.

The findings are similar to that of Chen in terms of effect on PONV, nausea, vomiting and anti-emetic use. I would be interested to know what the authors suggestion is as to the proposed mechanism of effect. Is it simply an indirect effect through better analgesia and downstream opioid sparing which is emetogenic itself. Is it possible to deduce this from the data by comparing studies in which opioid consumption was measured.

Lastly is the anti-emetic effect more or less pronounced if anti-emetics are administered prophylactically. This would require an assessment of the anti-emetic interventions in the controls. I am not clear from the description of studies how the control groups were managed in terms of prophylaxis against PONV. It should be stated whether PONV prophylaxis was administered in the controls. Which studies were head to head RCTs of electroacupuncture vs anti-emetics and what was the meta-analytic result of these?

Figures 2 and 3 are very blurred and hard to read in the main body of the document.

Reviewer #2: The paper entitled Efficacy and safety of electrical acupoint stimulation for postoperative nausea and vomiting: A systematic review and meta-analysis is well designed and well performed meta-analysis. The methods used here are appropriate, the manuscript is clear, well-organized. Only minor remarks are listed below:

- avoid using abbreviations in the abstract (TEAS)

- lines 74 and 77: repetition

-line 80: why not sufficiently comprehensive? Explain.

- line 84: meanwhile is not the appropriate word.

- line 172: one category (3 articles) is missing

- line 183: 7 or 8 trials?

- lines 233 AND 237: figure numbering to be corrected

Reviewer #3: Comments to the authors:

1. English language still needs some refinement and editing.

2. Abbreviation used in the manuscript should have full forms at the time of first mentioning.

3. Some details should be discussed about assessment and severity of PONV using Apfel scoring system.

4. Not only the therapeutic measures, also commonly adopted preventive measures should also me mentioned.

5. Many comments made about EAS are not supported by reference, which should be.

6. Role of EAS outside China is questionable and thus not widely used, as claimed here, even now.

7. Uniqueness of your meta-analysis compared to previous ones should be mentioned in the result and discussion sections, not in the introduction section.

8. Did you use any filter during your literature search?

9. What do you mean by “sham” treatment in the control group?

10. Why were cesarean section and abortion excluded?

11. Regarding the analysis of incidence of PONV, what was used in the control group? Also, you have mentioned incidence with EAS than presenting data separately on EA and TEAS.

12. Did you do any subgroup analysis here between different types of surgery or not? Also was the anesthesia technique used standard in all the studies?

13. What do you mean by “EAS plus other treatments”? What are the other components of the other treatments? From the data I can see the additional other treatment did not decrease the incidence, rather increased the incidence of PONV a bit compared to only EAS. Why so?

14. In remaining 20% studies where you have mentioned that they received some treatment than placebo in the control arm, what are those interventions used?

15. Apart from the incidence, did you do any analysis of frequency of PONV or not?

16. Regarding timing of intervention used, not finding any difference between pre and postoperative EAS means, it does not have any better preemptive effect. Am I right? How do you explain this?

17. Targeted and comparative literature review is missing.

Strengths:

• Very relevant topic chosen for meta-analysis.

• Extensive literature search used.

• Extensive statistical analysis and subgroup analysis and multiple outcomes measured.

Weakness:

• English language used is very lucid, has several grammatical mistakes and lacked scientific tone.

• Some design flaws are quite obvious.

• No clarity on control or sham treatment group.

• No clear comparison with already recommended pharmacological treatment group.

• No obvious risk assessment or use of scoring system.

• Several repetitions of statistical methods in the methodology and result section. Especially the result section is confusing.

• The literature review is incomplete without targeted comparative analysis.

Verdict: Good intent of analyzing the efficacy of non-pharmacological measure in very relevant PONV which is still an intriguing issue despite abundance of antiemetics. But the manuscript still needs several modifications, refinement before I can accept it.

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Pradipta Bhakta

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PLoS One. 2023 May 31;18(5):e0285943. doi: 10.1371/journal.pone.0285943.r002

Author response to Decision Letter 0

7 Apr 2022

General comments:

We thank the editor and reviewers for their helpful suggestions and we have addressed all the points raised in our revised manuscript, and the revisions are outlined below. In addition to addressing these comments, we have also carefully reviewed the manuscript throughout to ensure clarity and reduce redundancy and repetition, and comply with Nature Communications style and formatting.

Editor and Reviewer comments:

Reviewer #1: Efficacy and safety of electrical acupoint stimulation for postoperative nausea and vomiting: A systematic review and meta-analysis

Thank you for the opportunity to review this submission to the journal. I have a small number of comments.

1. The submission is similar to the meta-analysis of Chen (Chen J, Tu Q, Miao S, Zhou Z, Hu S. Transcutaneous electrical acupoint stimulation for preventing postoperative nausea and vomiting after general anesthesia: a meta-analysis of randomized controlled trials. International Journal of Surgery. 2020 Jan 1; 73: 57-64.) but has a more up to date search (up to March 2020 vs July 2019) and as expected has more publications under analysis. I would have expected all of the studies included by Chen to be included in this submission but they are not – approximately half are included. What is the difference in the inclusion/exclusion criteria.

Reply：We appreciate your professional question. Due to the influence of anesthetic factors, type of surgery, and patient-related factors on PONV [1], we added 2 exclusion criteria compared to Chen's study: (1) Exclusion of patients with ASA ≥ III; (2) Excluding patients in the control group who received any electrical stimulation. That is why only about half of the studies included by Chen were included in our study. We’re sorry that the inaccurate description in the manuscript may lead to misunderstanding. We have revised the inclusion and exclusion criteria in the method accordingly (line 99 to 110). The reasons for excluding these articles are listed in the following table:

Thank you again for your helpful question.

[1] Apfel CC, Roewer N. Risk assessment of postoperative nausea and vomiting. Int Anesthesiol Clin. 2003;41(4):13-32. Epub 2003/10/24. doi: 10.1097/00004311-200341040-00004.

2. After a brief search of the literature there were a number of publications that seem eligible for analysis such as those below. The second was published online in February 2020 and seems eligible.

Replay: Thank you very much for this comment. Regarding the first literature (H. Wang, Y. Xie et al, 2014), we are very sorry that we excluded it by mistake. After rechecking and finding this to be an oversight on our part, we have revised all results and figures in the full paper. We are so sorry for our mistake.

Regarding the second study (Chen J, Zhang Y et al, 2020), we excluded it because patients in the sham-TEAS group received 4 mA stimulation. Our exclusion criteria included the control group receiving electrical stimulation.

Again, we thank the reviewer for pointing out this literature omission.

3. The findings are similar to that of Chen in terms of effect on PONV, nausea, vomiting and anti-emetic use. I would be interested to know what the authors suggestion is as to the proposed mechanism of effect. Is it simply an indirect effect through better analgesia and downstream opioid sparing which is emetogenic itself. Is it possible to deduce this from the data by comparing studies in which opioid consumption was measured.

Replay: Thanks for your suggestion. In deed, opioids have been long identified as an independent risk factor for the development of PONV [2]. And evidences showed that EA treatment might lead to better analgesia and reducing opioid use. This is a possible mechanism of how EAS reduced PONV. However, it is hard to drop this conclusion because the amount of medication used was not explicitly given in a large part of the included literature. So we are sorry that can only add some discussion about the possible mechanism (line 405 to 409).

[2] Apfel CC, Laara E, Koivuranta M, Greim CA, Roewer N. A simplified risk score for predicting postoperative nausea and vomiting: conclusions from cross-validations between two centers. Anesthesiology. 1999;91(3):693–700. doi: 10.1097/00000542-199909000-00022.

4. Lastly is the anti-emetic effect more or less pronounced if anti-emetics are administered prophylactically. This would require an assessment of the anti-emetic interventions in the controls. I am not clear from the description of studies how the control groups were managed in terms of prophylaxis against PONV. It should be stated whether PONV prophylaxis was administered in the controls. Which studies were head to head RCTs of electroacupuncture vs anti-emetics and what was the meta-analytic result of these?

Replay: Thanks for your question. In the included studies, the control and treatment groups were consistent in their use of antiemetic prophylaxis. The prophylactic use of antiemetics is a routine practice after surgery even in the control group. In the literature we included, 7 explicitly stated the use of prophylactic antiemetics in the postoperative period, 4 stated that antiemetics were not used in the postoperative period, and the remaining 15 were not explicitly described in the literature.

And there were no head to head RCTs of electroacupuncture vs anti-emetics in our included studies.

5. Figures 2 and 3 are very blurred and hard to read in the main body of the document.

Replay: Thank you for pointing this out. We have re-uploaded the Figures in high resolution.

- avoid using abbreviations in the abstract (TEAS)

Replay: We appreciate this valuable advice. We deleted all the abbreviations in the abstract.

- lines 74 and 77: repetition

Replay: We apologize for this oversight. This section has been modified to address this point (line 73 to 76).

-line 80: why not sufficiently comprehensive? Explain.

Replay: We are sorry that we didn’t describe this clearly. In our meta-analysis, we included more patients and RCTs. In addition to the inclusion of TEAS, RCTs evaluating the effectiveness of EA in the treatment of PONV were also added. What EA and TEAS have in common is that they both treat diseases by electrical acupoint stimulation. Thus, our study involves a more comprehensive analysis than the 2020 TEAS meta-analysis. We have moved this paragraph from the Introduction to the Discussion and modified the related description in the Discussion and changed the inappropriate statement (line 414 to 418).

- line 84: meanwhile is not the appropriate word.

Replay: We are sorry for the improper use of word. We moved this part to the Discussion and have revised the text (line 418).

- line 172: one category (3 articles) is missing

Replay: Thank you very much for pointing it out. In study selection, we added a category to describe three reports as published in abstract form (line 166).

- line 183: 7 or 8 trials?

Replay: Thank you for your great patience in listing the problems that exist with the manuscript. Here are 8 trials, we have added a Reference in the text (line 185).

- lines 233 AND 237: figure numbering to be corrected

Replay: Thank you for pointed out our mistake. We have modified the numbering of the figures (line 231 to 236).

Thank you again for your careful work.

Reviewer #3: Comments to the authors:

1. English language still needs some refinement and editing.

Replay: We thank the reviewer for the comment. The English language has been revised by an expert who is a native speaker.

2. Abbreviation used in the manuscript should have full forms at the time of first mentioning.

Replay: Thank you for pointing this out. We carefully reviewed the revision and made modifications. All of the abbreviations have full forms at the time of first mentioning now.

3. Some details should be discussed about assessment and severity of PONV using Apfel scoring system.

Replay: Thank you very much for your advice. We have added a paragraph in the discussion to describe in detail the assessment and severity of PONV using Apfel scoring system (line 397 to 409).

4. Not only the therapeutic measures, also commonly adopted preventive measures should also me mentioned.

Replay: Thank you so much. Routine use of 5-HT₃ receptor antagonists after surgery is the most common preventive measure. To address this point we added a sentence on the commonly adopted preventive measures in the clinic to the introduction (lines 60 to 65).

5. Many comments made about EAS are not supported by reference, which should be.

Replay: We agree with the reviewer and the reference has been added to the introduction. Thank you again for your helpful point.

6. Role of EAS outside China is questionable and thus not widely used, as claimed here, even now.

Replay: Thank you for pointing this out. we have removed this description from the introduction. We included 26 studies in 8 countries, so EA is described as increasingly popular in clinical.

7. Uniqueness of your meta-analysis compared to previous ones should be mentioned in the result and discussion sections, not in the introduction section.

Replay: Thanks for the suggestion and we have moved this part from Introduction to the Discussion section (line 410 to 421).

8. Did you use any filter during your literature search?

Replay: No, we did not use any filters when searching the literature. Thank you for your question.

9. What do you mean by “sham” treatment in the control group?

Replay: Compared to the treatment group, sham treatment in the control group included use of an inactive device, no needles with active device, patient-controlled analgesia + inactivated device, patient-controlled analgesia + usual care, which we corrected an inappropriate description in Table I and described the detail in the text (line 182 to 184; line 345 to 347).

10. Why were cesarean section and abortion excluded?

Replay: Thanks for your question. This is because the abortion patient may have pregnancy vomiting. Similarly, cesarean patients will use oxytocin. The oxytocin cause emesis-producing. And we included patients with general anesthesia, whereas most cesarean patients do not use this type of anesthesia. We describe this in Discussion to make this issue transparent (line 422 to 425).

11. Regarding the analysis of incidence of PONV, what was used in the control group? Also, you have mentioned incidence with EAS than presenting data separately on EA and TEAS.

Replay: Thank you for asking. The control group included in our study included: use of an inactive device, no needles with active device, no needles with inactive device, patient-controlled analgesia+ inactivated device, patient-controlled analgesia+ usual care. We have now revised this description in the text somewhat to be clearer (line 182 to 184; line 345 to 347). Our aim was to study the role of EAS, therefore, in describing the incidence of PONV, we used EAS as an overall intervention. In the fourth paragraph of the chapter, we did a subgroup analysis to determine whether EA or TEAS had treatment effect. The results showed that both EA and TEAS had significant therapeutic effects.

12. Did you do any subgroup analysis here between different types of surgery or not? Also was the anesthesia technique used standard in all the studies?

Replay: Thank you for your question. First, in our analysis, the surgical types, include laparoscopy, lithotripsy, tonsillectomy, thyroidectomy, gynecological, thoracotomy, craniotomy and plastic surgery. Thus, subgroup analysis according to surgery types will result in a small number of literature grouping.

Second, general anesthesia and standard anesthetic techniques was used in all the studies.

Replay: Sorry for the undefined description. "EAS plus other treatments" means that there were other interventions in the treatment group in addition to EAS. Other treatments included the use of PCA in 6 articles and Dexameth in 1 article. Among these 7 studies, these other treatments were also applied in the control group. The variable between two groups in one article was the presence or absence of EAS. We have added an explanation in the "Incidence of PONV" section of our article.

14. In remaining 20% studies where you have mentioned that they received some treatment than placebo in the control arm, what are those interventions used?

Replay: Thank you for your helpful question. As for the control group, some studies used placebo treatment while others did not. Control patients in studies with no placebo treatment were given usual care, while those in studies with placebo treatment recieved either non-electric acupuncture or electrical stimulation to sham acupuncture points besides usual care. We have modified our text in the third part of the Result in order to clarify this point (line 231 to 236).

15. Apart from the incidence, did you do any analysis of frequency of PONV or not?

Replay: Thank you for your question. We did not do the analysis of frequency of PONV. This is an uncountable component due to the inclusion of very few studies documenting the PONV frequency. In deed, studies including PONV frequencies would make our analysis more credible.

16. Regarding timing of intervention used, not finding any difference between pre and postoperative EAS means, it does not have any better preemptive effect. Am I right? How do you explain this?

Replay: Thank you for your questions. Unfortunately, we cannot draw that conclusion, using the results obtained in our meta-analysis. Our analysis did not compare the effects of preoperative, intraoperative and postoperative EAS application. Because they are not in the same study. So we were unable to conclude which group had the best efficacy. And there are few such studies at present. In order to get this data, RCTs with higher quality are needed.

17. Targeted and comparative literature review is missing.

Replay: We sincerely appreciate the reviewer's insights. In the Discussion section, we have added a paragraph discussing the development of studies for meta-analysis related to our topic (line 411 to 422).

Strengths:

• Very relevant topic chosen for meta-analysis.

• Extensive literature search used.

• Extensive statistical analysis and subgroup analysis and multiple outcomes measured.

Weakness:

• English language used is very lucid, has several grammatical mistakes and lacked scientific tone.

• Some design flaws are quite obvious.

• No clarity on control or sham treatment group.

• No clear comparison with already recommended pharmacological treatment group.

• No obvious risk assessment or use of scoring system.

• Several repetitions of statistical methods in the methodology and result section. Especially the result section is confusing.

• The literature review is incomplete without targeted comparative analysis.

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(27.6KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0285943.r003

Decision Letter 1

Pradipta Bhakta

26 May 2022

PONE-D-21-05426R1

Efficacy and safety of electrical acupoint stimulation for postoperative nausea and vomiting: A systematic review and meta-analysis

PLOS ONE

Dear Dr. Song,

Please submit your revised manuscript by Jul 04 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Pradipta Bhakta

Guest Editor

PLOS ONE

Additional Editor Comments (if provided):

Comments to the authors:

1. My initial Question: English language still needs some refinement and editing.

Authors’ Reply: We thank the reviewer for the comment. The English language has been revised by an expert who is a native speaker.

My Reply: But I can see there are still many mistakes. Even your reply to my questions has several linguistic and grammatical mistakes. Either you take help from language expert or journal’s service.

2. My initial Question: Abbreviation used in the manuscript should have full forms at the time of first mentioning.

Authors’ Reply: Thank you for pointing this out. We carefully reviewed the revision and made modifications. All of the abbreviations have full forms at the time of first mentioning now.

My Reply: Still many abbreviations are not mentioned in full form initially. Make sure when you reply that you have corrected, you have really address them.

3. My initial Question: Some details should be discussed about assessment and severity of PONV using Apfel scoring system.

Authors’ Reply: Thank you very much for your advice. We have added a paragraph in the discussion to describe in detail the assessment and severity of PONV using Apfel scoring system (line 397 to 409).

My Reply: It should be done in the introduction or methodology, than in the discussion section. In the discussion section, regarding Apfel scoring, you only mentioned general part. Neither have discussed the pros and cons of that, nor have stressed why your own scoring system is superior to that one.

4. My initial Question: Not only the therapeutic measures, also commonly adopted preventive measures should also be mentioned.

Authors’ Reply: Thank you so much. Routine use of 5-HT₃ receptor antagonists after surgery is the most common preventive measure. To address this point we added a sentence on the commonly adopted preventive measures in the clinic to the introduction (lines 60 to 65).

My Reply: Do you think pharmacological mean is the only preventive measure, and nothing else need to be discussed here? Even your comment about routine use of 5-HT3 antagonist is not supported by evidence. You should know that drugs are not only the preventive and therapeutic means for managing PONV.

5. My initial Question: Many comments made about EAS are not supported by reference, which should be.

Authors’ Reply: We agree with the reviewer and the reference has been added to the introduction. Thank you again for your helpful point.

My Reply: Still I can see many comments are not supported by reference. Again, make sure what you reply here, actually you have done that in modified manuscript. No expert comment should be made in the manuscript without citing reference.

6. My initial Question: Role of EAS outside China is questionable and thus not widely used, as claimed here, even now.

Authors’ Reply: Thank you for pointing this out. we have removed this description from the introduction. We included 26 studies in 8 countries, so EA is described as increasingly popular in clinical.

My Reply: Use of EA in 8 countries does not mean universal acceptance. Moreover, can I know which are these 8 countries?

7. My initial Question: Uniqueness of your meta-analysis compared to previous ones should be mentioned in the result and discussion sections, not in the introduction section.

Authors’ Reply: Thanks for the suggestion and we have moved this part from Introduction to the Discussion section (line 410 to 421).

My Reply: Accepted.

8. My initial Question: Did you use any filter during your literature search?

Authors’ Reply: No, we did not use any filters when searching the literature. Thank you for your question.

My Reply: Then how you analysed the searched studies? Did you use only inclusion criteria then?

9. My initial Question: What do you mean by “sham” treatment in the control group?

Authors’ Reply: Compared to the treatment group, sham treatment in the control group included use of an inactive device, no needles with active device, patient-controlled analgesia + inactivated device, patient-controlled analgesia + usual care, which we corrected an inappropriate description in Table I and described the detail in the text (line 182 to 184; line 345 to 347).

My Reply: What do you mean by “inactive device”? Is it dry needling? That is also a treatment, isn’t it?

10. My initial Question: Why were cesarean section and abortion excluded?

Authors’ Reply: Thanks for your question. This is because the abortion patient may have pregnancy vomiting. Similarly, cesarean patients will use oxytocin. The oxytocin cause emesis-producing. And we included patients with general anesthesia, whereas most cesarean patients do not use this type of anesthesia. We describe this in Discussion to make this issue transparent (line 422 to 425).

My Reply: Accepted.

11. My initial Question: Regarding the analysis of incidence of PONV, what was used in the control group? Also, you have mentioned incidence with EAS than presenting data separately on EA and TEAS.

Authors’ Reply: Thank you for asking. The control group included in our study included: use of an inactive device, no needles with active device, no needles with inactive device, patient-controlled analgesia+ inactivated device, patient-controlled analgesia+ usual care. We have now revised this description in the text somewhat to be clearer (line 182 to 184; line 345 to 347). Our aim was to study the role of EAS, therefore, in describing the incidence of PONV, we used EAS as an overall intervention. In the fourth paragraph of the chapter, we did a subgroup analysis to determine whether EA or TEAS had treatment effect. The results showed that both EA and TEAS had significant therapeutic effects.

My Reply: I am still very confused about inactive device with needle. Can you clarify this a bit more?

12. My initial Question: Did you do any subgroup analysis here between different types of surgery or not? Also was the anesthesia technique used standard in all the studies?

Authors’ Reply: Thank you for your question. First, in our analysis, the surgical types, include laparoscopy, lithotripsy, tonsillectomy, thyroidectomy, gynecological, thoracotomy, craniotomy and plastic surgery. Thus, subgroup analysis according to surgery types will result in a small number of literature grouping.

Second, general anesthesia and standard anesthetic techniques was used in all the studies.

My Reply: Lithotripsy, thyroidectomy, thoracotomy, craniotomy, and plastic surgeries are not unique to have high PONV. I agree, that tonsillectomy, gynecological surgeries, laparoscopy are. But why squint surgery was omitted which is a prototype surgery to study PONV?

13. My initial Question: What do you mean by “EAS plus other treatments”? What are the other components of the other treatments? From the data I can see the additional other treatment did not decrease the incidence, rather increased the incidence of PONV a bit compared to only EAS. Why so?

Authors’ Reply: Sorry for the undefined description. "EAS plus other treatments" means that there were other interventions in the treatment group in addition to EAS. Other treatments included the use of PCA in 6 articles and Dexameth in 1 article. Among these 7 studies, these other treatments were also applied in the control group. The variable between two groups in one article was the presence or absence of EAS. We have added an explanation in the "Incidence of PONV" section of our article.

My Reply: Is PCA a treatment option for managing PONV? Dexamethasone has only preventive role in PONV, it is not a therapeutic option. I am really now confused about your open unfiltered search method.

14. My initial Question: In remaining 20% studies where you have mentioned that they received some treatment than placebo in the control arm, what are those interventions used?

Authors’ Reply: Thank you for your helpful question. As for the control group, some studies used placebo treatment while others did not. Control patients in studies with no placebo treatment were given usual care, while those in studies with placebo treatment recieved either non-electric acupuncture or electrical stimulation to sham acupuncture points besides usual care. We have modified our text in the third part of the Result in order to clarify this point (line 231 to 236).

My Reply: Can placebo be called as a treatment option? I am more confused now.

15. My initial Question: Apart from the incidence, did you do any analysis of frequency of PONV or not?

Authors’ Reply: Thank you for your question. We did not do the analysis of frequency of PONV. This is an uncountable component due to the inclusion of very few studies documenting the PONV frequency. Indeed, studies including PONV frequencies would make our analysis more credible.

My Reply: Even if you have not done initially, you need to do it now as this is very important, and this you too have agreed.

16. My initial Question: Regarding timing of intervention used, not finding any difference between pre and postoperative EAS means, it does not have any better pre-emptive effect. Am I right? How do you explain this?

Authors’ Reply: Thank you for your questions. Unfortunately, we cannot draw that conclusion, using the results obtained in our meta-analysis. Our analysis did not compare the effects of preoperative, intraoperative and postoperative EAS application. Because they are not in the same study. So we were unable to conclude which group had the best efficacy. And there are few such studies at present. In order to get this data, RCTs with higher quality are needed.

My Reply: When you did mention that you have done some subgroup analysis and that is the strength of your meta-analysis compared to the 2020 one, then you need to do this.

17. My initial Question: Targeted and comparative literature review is missing.

Authors’ Reply: We sincerely appreciate the reviewer's insights. In the Discussion section, we have added a paragraph discussing the development of studies for meta-analysis related to our topic (line 411 to 422).

My Reply: Targeted literature review does not only mean history of meta-analysis related to your topic and where yours one differ with previous one. This mean analysing the previous literature related to PONV, related to your areas of PONV topic and meta-analysis, and finally where they differed, why they differed from yours meta-analysis. Also, why yours one is unique and what new you have found from them. You have to defend your findings, and negate the differing findings of others.

Strengths:

• Very relevant topic chosen for meta-analysis.

• Extensive literature search used.

• Extensive statistical analysis and subgroup analysis and multiple outcomes measured.

My question: Why no comment here?

Weakness:

• English language used is very lucid, has several grammatical mistakes and lacked scientific tone.

• Some design flaws are quite obvious.

• No clarity on control or sham treatment group.

• No clear comparison with already recommended pharmacological treatment group.

• No obvious risk assessment or use of scoring system.

• Several repetitions of statistical methods in the methodology and result section. Especially the result section is confusing.

• The literature review is incomplete without targeted comparative analysis.

My question: Why no comment here?

My New Verdict: Although authors have tried to address the issues I have raised, but unfortunately, many issues still remain unaddressed even though authors have mentioned that they have done. Again considering the importance of the topic and the maturation of the manuscript, I want to give the authors another chance to readdress my points carefully. They should make sure that they have corrected the issues when they mention that they have done. Also they need to do some important subgroup analysis, PONV incidence comparison and should rewrite the literature review and analytic discussion section in a more scientific and argumentative way. If they come up with valid answers to my renewed points and reorganise their manuscript accordingly, I can give another re-look to the manuscript.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

PLoS One. 2023 May 31;18(5):e0285943. doi: 10.1371/journal.pone.0285943.r004

Author response to Decision Letter 1

17 Jul 2022

Dear editor:

On behalf of my co-authors, thank you for giving us another chance to revise our article and improve its quality. We have read the comments carefully by you and other reviewers, and revisions have been done by now. Also, we have tried our best to revise our manuscript according to the comments. Attached please find the revised version, which we would like to submit for your kind consideration. Here, we would like to explain the changes briefly as follows:

1. Initial Question: English language still needs some refinement and editing.

My Reply: We thank the reviewer for the comment. The English language has been revised by an expert who is a native speaker.

Reviewers’ Reply: But I can see there are still many mistakes. Even your reply to my questions has several linguistic and grammatical mistakes. Either you take help from language expert or journal’s service.

My New Response: We apologize for the linguistic problems in the previous revision and my replies. We worked on the manuscript for a long time, and the repeated addition and removal of sentences obviously led to the previous polishing no longer being applicable. We now have asked American Journal Experts to help us with the language editing in this revision (certificate enclosed). We hope that the language in the current version of the manuscript is acceptable.

2. Initial Question: Abbreviation used in the manuscript should have full forms at the time of first mentioning.

My Reply: Thank you for pointing this out. We carefully reviewed the revision and made modifications. All of the abbreviations have full forms at the time of first mentioning now.

Reviewers’ Reply: Still many abbreviations are not mentioned in full form initially. Make sure when you reply that you have corrected, you have really address them.

My New Response: We apologize for the abbreviation issue. In this revision, all abbreviations were carefully checked to ensure that they are defined at first use. In addition, we have removed abbreviations that appear only once in our study and replaced them with the full wording. In addition, the abbreviations and their meanings are listed in the following table. Thank you for pointing this out.

Abbreviation Full words Location

PONV Postoperative nausea and vomiting line 51

EA Electroacupuncture line 75

TEAS transcutaneous electrical acupoint stimulation line 76

EAS electrical acupoint stimulation line 78

AMSTAR Assessing the methodological quality of systematic reviews line 94

PON postoperative nausea line 114

POV postoperative vomiting line 114

RCT randomized controlled trials line 115

ASA American Society of Anesthesiologists line 117

GRADE the Grades of Recommendation Assessment Development and Evaluation line 149

RR relative risk line 164

CI confidence interval line 164

3. Initial Question: Some details should be discussed about assessment and severity of PONV using Apfel scoring system.

My Reply: Thank you very much for your advice. We have added a paragraph in the discussion to describe in detail the assessment and severity of PONV using Apfel scoring system (line 397 to 409).

Reviewers’ Reply: It should be done in the introduction or methodology, than in the discussion section. In the discussion section, regarding Apfel scoring, you only mentioned general part. Neither have discussed the pros and cons of that, nor have stressed why your own scoring system is superior to that one.

My New Response: Thank you so much for your questions regarding the scoring system. We apologize for not explaining more clearly why we did not use the Apfel scoring as the main observation in the previous version. The Apfel score is used to predict the risk of PONV but it does not show whether PONV occurred[1]. Our primary outcome index is the incidence of PONV, an objective indicator. Among the included studies, only one article used the Apfel scoring system. It specifies the inclusion of patients with an Apfel score ≥ 2 (the maximum score with this system is 4)[2]. This was done to include people with a high risk for PONV, while none of the other 25 studies had that inclusion criterion. Therefore, based on the current evidence base, we could not include Apfel scores in our analysis. However, we agree that the Apfel scoring system is very important. If these RCTs included Apfel scores in their inclusion criteria or stratified randomized groups of patients based on the Apfel scoring system, higher quality results would have been obtained. We have modified the discussion about Apfel scoring accordingly (lines 414 to 425).

When you mentioned our “scoring system”, were you referring to the GRADE system? GRADE is a well-established system used to assess the quality of evidence derived from RCTs. It classifies the evidence quality as A (high quality), B (medium quality), C (low quality), or D (very low quality)[3]. Its use is an important, highly recommended step in any comprehensive evidence evaluation and could increase the transparency of the decision-making process [4, 5]. If we misunderstood your question about scoring, please correct us. Thank you again for your helpful suggestion.

4. Initial Question: Not only the therapeutic measures, also commonly adopted preventive measures should also be mentioned.

My Reply: Thank you so much. Routine use of 5-HT₃ receptor antagonists after surgery is the most common preventive measure. To address this point we added a sentence on the commonly adopted preventive measures in the clinic to the introduction (lines 60 to 65).

Reviewers’ Reply: Do you think pharmacological mean is the only preventive measure, and nothing else need to be discussed here? Even your comment about routine use of 5-HT3 antagonist is not supported by evidence. You should know that drugs are not only the preventive and therapeutic means for managing PONV.

My New Response: We apologize for the insufficient clarity in our initial submission. As you mentioned, pharmacological treatment is not the only preventive and therapeutic means for managing PONV. We have added text describing nonpharmacological approaches to PONV prevention in the introduction (lines 68 to 72). To provide a better and more comprehensive description of the prevention and treatment of PONV, we have revised a paragraph in the introduction (lines 60 to 73). Thank you again for your helpful suggestion.

5. Initial Question: Many comments made about EAS are not supported by reference, which should be.

My Reply: We agree with the reviewer and the reference has been added to the introduction. Thank you again for your helpful point.

Reviewers’ Reply: Still I can see many comments are not supported by reference. Again, make sure what you reply here, actually you have done that in modified manuscript. No expert comment should be made in the manuscript without citing reference.

My New Response: Thank you very much for your careful review. We have carefully checked our manuscript and added 8 references (lines 59, 61, 62, 65, 77, 374 and 409). We hope there is no omission in the revised manuscript.

6. Initial Question: Role of EAS outside China is questionable and thus not widely used, as claimed here, even now.

My Reply: Thank you for pointing this out. we have removed this description from the introduction. We included 26 studies in 8 countries, so EA is described as increasingly popular in clinical.

Reviewers’ Reply: Use of EA in 8 countries does not mean universal acceptance. Moreover, can I know which are these 8 countries?

My New Response: The 26 studies included in our research were conducted in 8 countries: USA, The United Kingdom, China, India, Malaysia, Turkey, Iran, and Denmark. Table 1 lists the countries for each RCT in our manuscript. As you said, the use of EA in 8 countries does not mean universal acceptance. To make this clearer, we listed the names of these 8 countries in the results (lines 186 to 187). RCTs with higher quality and larger sample sizes need to be performed to promote the usage of EA worldwide. Thank you so much for the suggestion.

7. Initial Question: Uniqueness of your meta-analysis compared to previous ones should be mentioned in the result and discussion sections, not in the introduction section.

My Reply: Thanks for the suggestion and we have moved this part from Introduction to the Discussion section (line 410 to 421).

Reviewers’ Reply: Accepted.

My New Response: Thank you for accepting our reply.

8. Initial Question: Did you use any filter during your literature search?

My Reply: No, we did not use any filters when searching the literature. Thank you for your question.

Reviewers’ Reply: Then how you analysed the searched studies? Did you use only inclusion criteria then?

My New Response: We apologize for not answering your question clearly. We added more details to our search process, including the literature search strategy, inclusion criteria, and exclusion criteria.

In the first step, using the literature search strategy, we retrieved a total of 864 articles from the databases. In the second step, two researchers independently used EndNote reference management software for literature management. By screening the titles, abstracts, or both and removing duplicates, 794 records were excluded. In the third step, after reading the full articles, we excluded 44 RCTs that met the exclusion criteria. Finally, we included 26 studies.

Literature search strategy (Take PubMed as an example)

#1 Postoperative Nausea and Vomiting [Mesh]

#2 (“post operative” OR “postoperati*” OR “perioperati*” OR “peri-operative” OR “surger*” OR “surgical*” OR “postsurg*” OR “intraoperative” OR “anesthe*” OR “anaesthe*” OR “postanesthe*” OR “postanaesthe*” OR “anaesthetic recovery”)

#3 (“nause*” OR “vomit*” OR “emesis” OR “emeses” OR “emet*” OR “queasiness” OR “queasy”)

#4 #2 AND #3

#5 #1 OR #4

#6 Electroacupuncture [Mesh]

#7 electric*

#8 (acupuncture OR needle OR acupoint OR point OR stimulat*)

#9 #7 AND #8

#10 #6 OR #9

#11 Transcutaneous Electric Nerve Stimulation [Mesh]

#12 (“Transcutaneous Electrical Acupoint Stimulation” OR “TENS” OR “TEAS” OR “TNS” OR “ENS” OR “TES” OR “Transcutaneous electric* nerve stimulation” OR “transcutaneous nerve stimulation” OR “transcutaneous electric*” OR “transcutaneous electric* stimulation” OR “electric* nerve therap*” OR “electroanalgesi*” OR “electro-analgesi*” OR “Percutaneous Electric*” OR “Percutaneous Neuromodulation therap*” OR “Electroanalgesia*” OR “nerve stimulat*” OR “neuro-modulation” OR “neuromodulation” OR “neuromusc* electric*”)

#13 #11 OR #12

#14 Electric Stimulation Therapy [Mesh]

#15 (“Electric Stimulation Therapy” OR “Electric* Stimulation” OR “electrotherap*” OR “electrostimul*” OR “electromyostimulation” OR “Interferential Current Electrotherapy” OR “Therapeutic Electric* stimulat*” OR “Electric* stimulat* therap*”)

#16 #14 OR #15

#17 (“random* controlled trial” OR “random*” OR “placebo”)]

#18 #10 OR #13 OR #16

#19 #5 AND #18 AND #17

The inclusion criteria were:

1). Patients who underwent surgery, regardless of age, sex, ethnicity or surgery type

2). The intervention measures in the treatment group was EAS (EA or TEAS).

3). The control group could be sham acupuncture, placebo acupuncture, no treatment, nonacupoint acupuncture, no electrical stimulation or perioperative routine nursing.

4). The outcomes were the incidence of PONV, PON or POV.

5). To reduce the risk of bias and enhance the accuracy of the conclusions, only studies that had a randomized controlled trials (RCT) design were included.

The exclusion criteria were as follows:

1). Patients undergoing cesarean section or abortion.

2). American Society of Anesthesiologists ≥ III.

3). Patients in the control group who received any electrical stimulation.

4). Unpublished reports or reports published as abstracts only.

9. Initial Question: What do you mean by “sham” treatment in the control group?

My Reply: Compared to the treatment group, sham treatment in the control group included use of an inactive device, no needles with active device, patient-controlled analgesia + inactivated device, patient-controlled analgesia + usual care, which we corrected an inappropriate description in Table I and described the detail in the text (line 182 to 184; line 345 to 347).

Reviewers’ Reply: What do you mean by “inactive device”? Is it dry needling? That is also a treatment, isn’t it?

My New Response: We apologize for not clearly describing the different kinds of control treatments. The control treatments include the following four types:

When the treatment is EA, the control treatment includes: no needles + active device; no needles + inactive device or usual care,

When the treatment is TEAS, the control treatment includes: gel electrodes + inactive device or usual care,

� no needles + active device: The needles were bent to lay flat against the skin, or no needles were applied. Insulated wires from the activated stimulator box with a normal current output were attached to the needles or the inside of the arm covers.

� no needles + inactive device: The needles were bent to lay flat against the skin, or no needles were applied. Insulated wires from the inactivated stimulator box with no current output were attached to the needles or the inside of the arm covers.

� gel electrodes + inactive device: Gel electrodes were placed on the acupoints and attached to a stimulator box with no current output.

Therefore, “no needles + inactive device” is not a dry needling. It has no acupoint stimulation effect. It is a type of placebo. We performed subgroup analysis. The results showed that regardless of what was used as the control, placebo or usual care, EAS showed a significant role in reducing the incidence of PONV (lines 255 to 260). Therefore, we think “no needles + inactive device” should not be counted as a treatment, but only as a kind of psychological comfort.

10. Initial Question: Why were cesarean section and abortion excluded?

My Reply: Thanks for your question. This is because the abortion patient may have pregnancy vomiting. Similarly, cesarean patients will use oxytocin. The oxytocin cause emesis-producing. And we included patients with general anesthesia, whereas most cesarean patients do not use this type of anesthesia. We describe this in Discussion to make this issue transparent (line 422 to 425).

Reviewers’ Reply: Accepted.

My New Response: It’s very kind of you to accept our answer. Thank you so much.

11. Initial Question: Regarding the analysis of incidence of PONV, what was used in the control group? Also, you have mentioned incidence with EAS than presenting data separately on EA and TEAS.

My Reply: Thank you for asking. The control group included in our study included: use of an inactive device, no needles with active device, no needles with inactive device, patient-controlled analgesia+ inactivated device, patient-controlled analgesia+ usual care. We have now revised this description in the text somewhat to be clearer (line 182 to 184; line 345 to 347). Our aim was to study the role of EAS, therefore, in describing the incidence of PONV, we used EAS as an overall intervention. In the fourth paragraph of the chapter, we did a subgroup analysis to determine whether EA or TEAS had treatment effect. The results showed that both EA and TEAS had significant therapeutic effects.

Reviewers’ Reply: I am still very confused about inactive device with needle. Can you clarify this a bit more?

My New Response: We apologize for the confusion. In the answer to Question 9, we described all of the controls. The "inactive device with needle" you mentioned here should correspond to "no needle + inactive device", which means that the needles were bent to lay flat against the skin or no needles were applied and insulated wires from the activated stimulator box with no current output were attached to the needles or the insides of arm covers[6, 7].

We have revised this description in the text to make this more clear (lines 361 to 369).

12. Initial Question: Did you do any subgroup analysis here between different types of surgery or not? Also was the anesthesia technique used standard in all the studies?

My Reply: Thank you for your question. First, in our analysis, the surgical types, include laparoscopy, lithotripsy, tonsillectomy, thyroidectomy, gynecological, thoracotomy, craniotomy and plastic surgery. Thus, subgroup analysis according to surgery types will result in a small number of literature grouping.

Second, general anesthesia and standard anesthetic techniques was used in all the studies.

Reviewers’ Reply: Lithotripsy, thyroidectomy, thoracotomy, craniotomy, and plastic surgeries are not unique to have high PONV. I agree, that tonsillectomy, gynecological surgeries, laparoscopy are. But why squint surgery was omitted which is a prototype surgery to study PONV?

My New Response: Thank you for your professional question. Indeed, PONV is the most frequent complication in patients undergoing strabismus surgery[8]. We did not intentionally exclude squint surgery. A search of the literature revealed that these RCTs meeting the inclusion and exclusion criteria did not include squint surgery.

13. Initial Question: What do you mean by “EAS plus other treatments”? What are the other components of the other treatments? From the data I can see the additional other treatment did not decrease the incidence, rather increased the incidence of PONV a bit compared to only EAS. Why so?

My Reply: Sorry for the undefined description. "EAS plus other treatments" means that there were other interventions in the treatment group in addition to EAS. Other treatments included the use of PCA in 6 articles and Dexameth in 1 article. Among these 7 studies, these other treatments were also applied in the control group. The variable between two groups in one article was the presence or absence of EAS. We have added an explanation in the "Incidence of PONV" section of our article.

Reviewers’ Reply: Is PCA a treatment option for managing PONV? Dexamethasone has only preventive role in PONV, it is not a therapeutic option. I am really now confused about your open unfiltered search method.

My New Response: Thank you for raising this question. We defined PCA and dexamethasone as “other treatments” inappropriately. PCA is not a treatment option for managing PONV. It is a pain relief method given for postoperative analgesia. PCA is routinely used for postoperative analgesia in some countries. In addition, as you stated, dexamethasone is used as routine prophylaxis, not as a treatment. Six studies explicitly emphasized the use of PCA because all six studies were also about postoperative recovery or postoperative analgesia. One study explicitly emphasized the use of dexamethasone because it focused on the efficacy of dexamethasone and TEAS. Among these 7 studies, PCA/dexamethasone was also applied in the control group. Therefore, neither PCA nor dexamethasone is a specific treatment modality for PONV and is part of the standardized treatment regimen for both groups of patients. The attached table shows the 7 studies that emphasized the usage of PCA/dexamethasone. To remove the ambiguity, we have deleted the "EAS plus other treatments" from the table and text and removed the subgroup analysis of this topic from the results. Thank you again for the helpful feedback and comments on the manuscript.

Author (year) Title of the paper.

El-Rakshy et al, 2009 Effect of intraoperative electroacupuncture on postoperative pain, analgesic requirements, nausea and sedation: a randomised controlled trial.

Gu et al, 2019 The effect of pre-treatment with transcutaneous electrical acupoint stimulation on the quality of recovery after ambulatory breast surgery: a prospective, randomised controlled trial.

Chen et al, 2015 ranscutaneous electric acupoint stimulation alleviates remifentanil-induced hyperalgesia in patients undergoing thyroidectomy: a randomized controlled trial.

Ye et al, 2008 Pain management using Han's acupoint nerve stimulator combined with patient-controlled analgesia following neurosurgery: A randomized case control study

Chen et al, 1998 The effect of location of transcutaneous electrical nerve stimulation on postoperative opioid analgesic requirement: acupoint versus nonacupoint stimulation.

Zheng et al, 2008 Effect of transcutaneous electrical acupoint stimulation on nausea and vomiting induced by patient controlled intravenous analgesia with tramadol.

Yang et al, 2015 Dexamethasone alone vs in combination with transcutaneous electrical acupoint stimulation or tropisetron for prevention of postoperative nausea and vomiting in gynaecological patients undergoing laparoscopic surgery.

14. Initial Question: In remaining 20% studies where you have mentioned that they received some treatment than placebo in the control arm, what are those interventions used?

My Reply: Thank you for your helpful question. As for the control group, some studies used placebo treatment while others did not. Control patients in studies with no placebo treatment were given usual care, while those in studies with placebo treatment recieved either non-electric acupuncture or electrical stimulation to sham acupuncture points besides usual care. We have modified our text in the third part of the Result in order to clarify this point (line 231 to 236).

Reviewers’ Reply: Can placebo be called as a treatment option? I am more confused now.

My New Response: Except for usual care, the other control treatments can be considered a placebo. We performed subgroup analysis. The results showed that regardless of what was used as the control, placebo or usual care, EAS showed a significant role in reducing the incidence of PONV (lines 255 to 260). We think a placebo should not be counted as a treatment but only as a kind of psychological comfort.

The control treatments include the following four types:

When the treatment is EA, the control treatment includes: no needles + active device, no needles + inactive device or usual care.

When the treatment is TEAS, the control treatment includes: gel electrodes + inactive device and usual care.

15. Initial Question: Apart from the incidence, did you do any analysis of frequency of PONV or not?

My Reply: Thank you for your question. We did not do the analysis of frequency of PONV. This is an uncountable component due to the inclusion of very few studies documenting the PONV frequency. Indeed, studies including PONV frequencies would make our analysis more credible.

Reviewers’ Reply: Even if you have not done initially, you need to do it now as this is very important, and this you too have agreed.

My New Response: We apologize for not explaining more clearly why we did not perform an analysis of the frequency of PONV in the previous version of our manuscript. Only one of the 26 studies included in our meta-analysis recorded the frequency of PONV (please see the table below). Therefore, there was insufficient data to conduct a meta-analysis of the frequency of PONV. We have included the lack of data about the frequency of PONV as a limitation of this study (Discussion section lines 473 to 475). We hope this explains why we did not analyze the frequency of PONV.

Author (year) Number of participants

（TEAS / Control） Frequency of PONV

Yeoh et al, 2016 40/40 No record

Kabalak et al, 2005 30/30 TEAS group: 2 times;

Control group: 4 times

Zárate et al, 2001 110/56 No record

Ye et al, 2008 20/20 No record

Chen et al, 1998 25/25 No record

Liu et al, 2008 48/48 No record

An et al, 2014 41/40 No record

Rusy et al, 2002 40/40 No record

Sahmeddini et al, 2010 45/45 No record

El-Rakshy et al, 2009 44/58 No record

Christensen et al, 1989 10/10 No record

Zhang et al, 2014 33/32 No record

Tu et al, 2018 72/72 No record

Tu et al, 2019 60/60 No record

Li et al, 2017 20/20 No record

Gu et al, 2019 58/59 No record

Amir et al, 2007 20/20 No record

Chen et al, 2016 46/46 No record

Yang et al, 2015 50/50 No record

Yu et al, 2020 30/30 No record

Liu et al, 2015 44/44 No record

Chen et al, 2015 29/30 No record

Chen Y et al, 2015 41/42 No record

Yao et al, 2015 35/36 No record

Zheng et al, 2008 30/30 No record

wang et al, 2014 30/30 No record

16. Initial Question: Regarding timing of intervention used, not finding any difference between pre and postoperative EAS means, it does not have any better pre-emptive effect. Am I right? How do you explain this?

My Reply: Thank you for your questions. Unfortunately, we cannot draw that conclusion, using the results obtained in our meta-analysis. Our analysis did not compare the effects of preoperative, intraoperative and postoperative EAS application. Because they are not in the same study. So we were unable to conclude which group had the best efficacy. And there are few such studies at present. In order to get this data, RCTs with higher quality are needed.

Reviewers’ Reply: When you did mention that you have done some subgroup analysis and that is the strength of your meta-analysis compared to the 2020 one, then you need to do this.

My New Response: We apologize for the unclear explanation in the previous version. To reduce the incidence of PONV, the subgroup analysis showed that EAS, whether applied as a preoperative intervention, postoperative intervention or perioperative intervention, had a significant effect. We can only show that the three types of treatment timing are effective because they were not directly compared in any of the studies.

The sentence “Similarly, no significant subgroup differences were observed among the three types of treatment timing (RR, 0.51; 95% CI, 0.43 to 0.60; P = 0.33)” in the original text means that there was no significant difference in heterogeneity among the three subgroups. We apologize for the confusion. To avoid any further ambiguity, we have removed this sentence.

17. Initial Question: Targeted and comparative literature review is missing.

My Reply: We sincerely appreciate the reviewer's insights. In the Discussion section, we have added a paragraph discussing the development of studies for meta-analysis related to our topic (line 411 to 422).

Reviewers’ Reply: Targeted literature review does not only mean history of meta-analysis related to your topic and where yours one differ with previous one. This mean analysing the previous literature related to PONV, related to your areas of PONV topic and meta-analysis, and finally where they differed, why they differed from yours meta-analysis. Also, why yours one is unique and what new you have found from them. You have to defend your findings, and negate the differing findings of others.

My New Response: Thank you for the specific suggestion. we rewrote the literature review and analytic discussion section. We have added the targeted and comparative literature to the discussion accordingly (lines 438 to 464).

Thank you for giving us your constructive comments. We think that the revised manuscript has become more convincing.

Strengths:

• Very relevant topic chosen for meta-analysis.

• Extensive literature search used.

• Extensive statistical analysis and subgroup analysis and multiple outcomes measured.

Reviewers’ question: Why no comment here?

My New Response: We apologize for not responding to this comment last time. Thank you very much for your positive appraisal of the manuscript.

Weakness:

• English language used is very lucid, has several grammatical mistakes and lacked scientific tone.

• Some design flaws are quite obvious.

• No clarity on control or sham treatment group.

• No clear comparison with already recommended pharmacological treatment group.

• No obvious risk assessment or use of scoring system.

• Several repetitions of statistical methods in the methodology and result section. Especially the result section is confusing.

• The literature review is incomplete without targeted comparative analysis.

Reviewers’ question: Why no comment here?

My New Response: We apologize for not replying to your comments. Thank you for the reviewer’s careful reading of our manuscript. In light of all the above issues, we have carefully revised the document item by item.

Reviewers’ question: Why no comment here?

My New Response: We appreciate the reviewer’s succinct and accurate summary of our manuscript. Thank you for the kind statements. In light of your questions, we have carefully revised the document item by item. Thank you for taking the time to review our manuscript again. We hope that the current version of our manuscript reaches the standard for acceptance.

Reviewers’ Verdict: Although authors have tried to address the issues I have raised, but unfortunately, many issues still remain unaddressed even though authors have mentioned that they have done. Again considering the importance of the topic and the maturation of the manuscript, I want to give the authors another chance to readdress my points carefully. They should make sure that they have corrected the issues when they mention that they have done. Also they need to do some important subgroup analysis, PONV incidence comparison and should rewrite the literature review and analytic discussion section in a more scientific and argumentative way. If they come up with valid answers to my renewed points and reorganise their manuscript accordingly, I can give another re-look to the manuscript.

My New Response: Thank you for taking the time to read our revision and giving us your constructive comments. We have made the corresponding changes in the revised manuscript, and we think that the revised manuscript has become more rigorous and convincing. In the answer to the fifteenth question, we explained why we did not analyze the frequency of PONV. In addition, we rewrote the literature review and analytic discussion section. Thank you again for giving us the opportunity to have our manuscript reconsidered. We earnestly appreciate the reviewers’ hard work and hope that the corrections will meet with approval. Should you have any questions, please contact us without hesitation.

Reference

1. Apfel CC, Greim CA, Haubitz I, Goepfert C, Usadel J, Sefrin P, et al. A risk score to predict the probability of postoperative vomiting in adults. Acta anaesthesiologica Scandinavica. 1998;42(5):495-501. Epub 1998/05/30. doi: 10.1111/j.1399-6576.1998.tb05157.x. PubMed PMID: 9605363.

2. Yeoh AH, Tang SS, Abdul Manap N, Wan Mat WR, Said S, Che Hassan MR, et al. Effectiveness of P6 acupoint electrical stimulation in preventing postoperativenausea and vomiting following laparoscopic surgery. Turkish journal of medical sciences. 2016;46(3):620-5. Epub 2016/08/12. doi: 10.3906/sag-1502-56. PubMed PMID: 27513234.

3. Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. Journal of clinical epidemiology. 2011;64(4):401-6. Epub 2011/01/07. doi: 10.1016/j.jclinepi.2010.07.015. PubMed PMID: 21208779.

4. Alonso-Coello P, Schünemann HJ, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, et al. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 1: Introduction. BMJ (Clinical research ed). 2016;353:i2016. Epub 2016/06/30. doi: 10.1136/bmj.i2016. PubMed PMID: 27353417.

5. Xin Z, Xue-Ting L, De-Ying K. GRADE in Systematic Reviews of Acupuncture for Stroke Rehabilitation: Recommendations based on High-Quality Evidence. Scientific reports. 2015;5:16582. Epub 2015/11/13. doi: 10.1038/srep16582. PubMed PMID: 26560971; PubMed Central PMCID: PMCPMC4642304.

6. Rusy LM, Hoffman GM, Weisman SJ. Electroacupuncture prophylaxis of postoperative nausea and vomiting following pediatric tonsillectomy with or without adenoidectomy. Anesthesiology. 2002;96(2):300-5. Epub 2002/01/31. doi: 10.1097/00000542-200202000-00013. PubMed PMID: 11818760.

7. Sahmeddini MA, Farbood A, Ghafaripuor S. Electro-acupuncture for pain relief after nasal septoplasty: a randomized controlled study. Journal of alternative and complementary medicine (New York, NY). 2010;16(1):53-7. Epub 2009/12/17. doi: 10.1089/acm.2009.0288. PubMed PMID: 20001536.

8. Sayed JA, MA FR, MO MA. Comparison of dexamethasone or intravenous fluids or combination of both on postoperative nausea, vomiting and pain in pediatric strabismus surgery. Journal of clinical anesthesia. 2016;34:136-42. Epub 2016/10/01. doi: 10.1016/j.jclinane.2016.03.049. PubMed PMID: 27687360.

Attachment

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PLoS One. doi: 10.1371/journal.pone.0285943.r005

Decision Letter 2

Huijuan Cao

24 Nov 2022

PONE-D-21-05426R2Efficacy and safety of electrical acupoint stimulation for postoperative nausea and vomiting: A systematic review and meta-analysisPLOS ONE

Dear Dr. Song,

Please submit your revised manuscript by Jan 08 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Huijuan Cao, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments:

The English of this article needs to be further improved. Professional language polishing team can be considered for assistance

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #3: All comments have been addressed

Reviewer #4: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #3: Partly

Reviewer #4: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #3: Yes

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #3: Yes

Reviewer #4: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #3: No

Reviewer #4: Yes

**********

6. Review Comments to the Author

Reviewer #3: My Comments to the authors’ revised version:

1. My initial Question: English language still needs some refinement and editing.

Authors’ Repeat Response: We apologize for the linguistic problems in the previous revision and my replies. We worked on the manuscript for a long time, and the repeated addition and removal of sentences obviously led to the previous polishing no longer being applicable. We now have asked American Journal Experts to help us with the language editing in this revision (certificate enclosed). We hope that the language in the current version of the manuscript is acceptable.

My repeat response: I can still see several grammatical mistake, mistakes in sentence organisation as well as use of punctuation. I cannot do English editing repeatedly, and neither have time to do that. I leave this to the handling editor. If done properly, then OK for me.

2. My initial Question: Abbreviation used in the manuscript should have full forms at the time of first mentioning.

Authors’ Repeat Response: We apologize for the abbreviation issue. In this revision, all abbreviations were carefully checked to ensure that they are defined at first use. In addition, we have removed abbreviations that appear only once in our study and replaced them with the full wording. In addition, the abbreviations and their meanings are listed in the following table. Thank you for pointing this out.

My repeat response: Accepted if all corrected.

3. My initial Question: Some details should be discussed about assessment and severity of PONV using Apfel scoring system.

Authors’ Repeat Response: Thank you so much for your questions regarding the scoring system. We apologize for not explaining more clearly why we did not use the Apfel scoring as the main observation in the previous version. The Apfel score is used to predict the risk of PONV but it does not show whether PONV occurred[1]. Our primary outcome index is the incidence of PONV, an objective indicator. Among the included studies, only one article used the Apfel scoring system. It specifies the inclusion of patients with an Apfel score ≥ 2 (the maximum score with this system is 4)[2]. This was done to include people with a high risk for PONV, while none of the other 25 studies had that inclusion criterion. Therefore, based on the current evidence base, we could not include Apfel scores in our analysis. However, we agree that the Apfel scoring system is very important. If these RCTs included Apfel scores in their inclusion criteria or stratified randomized groups of patients based on the Apfel scoring system, higher quality results would have been obtained. We have modified the discussion about Apfel scoring accordingly (lines 414 to 425).

My repeat response: Agree that Apfel scoring system identifies the at risk patients preoperatively, but it does predict the PONV as well. Although you have again mentioned the risk of PONV, but there is no mention how to evaluate and stratify those risks. This is confusing.

4. My initial Question: Not only the therapeutic measures, also commonly adopted preventive measures should also be mentioned.

Authors’ Repeat Response: We apologize for the insufficient clarity in our initial submission. As you mentioned, pharmacological treatment is not the only preventive and therapeutic means for managing PONV. We have added text describing nonpharmacological approaches to PONV prevention in the introduction (lines 68 to 72). To provide a better and more comprehensive description of the prevention and treatment of PONV, we have revised a paragraph in the introduction (lines 60 to 73). Thank you again for your helpful suggestion.

My repeat response: Good for this acknowledgement. What I wanted to mean is that along with non-pharmacological means and modification of patient’s factors as well as the anaesthesia technique, using dexamethasone in the beginning and 5-HT3 antagonist at the end based on Apfel Risk score is the best method to prevent PONV. This should be clearly mentioned. Again in the non-pharmacological means you have mentioned crystalloids, chewing gum, ginger etc. These are indeed pharmacological means. Pharmacological means doesn’t have to me classic antiemetic medicine, but can be traditional medicines as well including IV fluids.

5. My initial Question: Many comments made about EAS are not supported by reference, which should be.

Authors’ Repeat Response: Thank you very much for your careful review. We have carefully checked our manuscript and added 8 references (lines 59, 61, 62, 65, 77, 374 and 409). We hope there is no omission in the revised manuscript.

My repeat response: Accepted.

6. My initial Question: Role of EAS outside China is questionable and thus not widely used, as claimed here, even now.

Authors’ Repeat Response: The 26 studies included in our research were conducted in 8 countries: USA, The United Kingdom, China, India, Malaysia, Turkey, Iran, and Denmark. Table 1 lists the countries for each RCT in our manuscript. As you said, the use of EA in 8 countries does not mean universal acceptance. To make this clearer, we listed the names of these 8 countries in the results (lines 186 to 187). RCTs with higher quality and larger sample sizes need to be performed to promote the usage of EA worldwide. Thank you so much for the suggestion.

My repeat response: Accepted.

7. My initial Question: Uniqueness of your meta-analysis compared to previous ones should be mentioned in the result and discussion sections, not in the introduction section.

Authors’ Reply: Thanks for the suggestion and we have moved this part from Introduction to the Discussion section (line 410 to 421).

My Response: Accepted.

8. My initial Question: Did you use any filter during your literature search?

Authors’ Repeat Response: We apologize for not answering your question clearly. We added more details to our search process, including the literature search strategy, inclusion criteria, and exclusion criteria. In the first step, using the literature search strategy, we retrieved a total of 864 articles from the databases. In the second step, two researchers independently used EndNote reference management software for literature management. By screening the titles, abstracts, or both and removing duplicates, 794 records were excluded. In the third step, after reading the full articles, we excluded 44 RCTs that met the exclusion criteria. Finally, we included 26 studies.

My repeat response: Accepted. The sentence of the inclusion and exclusion criteria should be revamped and organised to make it look more scientific.

9. My initial Question: What do you mean by “sham” treatment in the control group?

Authors’ Repeat Response: We apologize for not clearly describing the different kinds of control treatments. The control treatments include the following four types: When the treatment is EA, the control treatment includes: no needles + active device; no needles + inactive device or usual care, When the treatment is TEAS, the control treatment includes: gel electrodes + inactive device or usual care, no needles + active device: The needles were bent to lay flat against the skin, or no needles were applied. Insulated wires from the activated stimulator box with a normal current output were attached to the needles or the inside of the arm covers. no needles + inactive device: The needles were bent to lay flat against the skin, or no needles were applied. Insulated wires from the inactivated stimulator box with no current output were attached to the needles or the inside of the arm covers. gel electrodes + inactive device: Gel electrodes were placed on the acupoints and attached to a stimulator box with no current output. Therefore, “no needles + inactive device” is not a dry needling. It has no acupoint stimulation effect. It is a type of placebo. We performed subgroup analysis. The results showed that regardless of what was used as the control, placebo or usual care, EAS showed a significant role in reducing the incidence of PONV (lines 255 to 260). Therefore, we think “no needles + inactive device” should not be counted as a treatment, but only as a kind of psychological comfort.

My repeat response: I am a bit confused here. What did you exactly mean by “active” and “inactive” device with or without needle? In these complex and mixed methodology how did you do the double blinding?

10. My initial Question: Why were cesarean section and abortion excluded?

Authors’ Repeat Response: It’s very kind of you to accept our answer. Thank you so much.

11. My initial Question: Regarding the analysis of incidence of PONV, what was used in the control group? Also, you have mentioned incidence with EAS than presenting data separately on EA and TEAS.

Authors’ Repeat Response: We apologize for the confusion. In the answer to Question 9, we described all of the controls. The "inactive device with needle" you mentioned here should correspond to "no needle + inactive device", which means that the needles were bent to lay flat against the skin or no needles were applied and insulated wires from the activated stimulator box with no current output were attached to the needles or the insides of arm covers [6, 7]. We have revised this description in the text to make this more clear (lines 361 to 369).

My repeat response: What is the active device without needle then?

12. My initial Question: Did you do any subgroup analysis here between different types of surgery or not? Also was the anesthesia technique used standard in all the studies?

Authors’ Repeat Response: Thank you for your professional question. Indeed, PONV is the most frequent complication in patients undergoing strabismus surgery[8]. We did not intentionally exclude squint surgery. A search of the literature revealed that these RCTs meeting the inclusion and exclusion criteria did not include squint surgery.

My repeat response: Surprising, but accepted.

Authors’ Repeat Response: Thank you for raising this question. We defined PCA and dexamethasone as “other treatments” inappropriately. PCA is not a treatment option for managing PONV. It is a pain relief method given for postoperative analgesia. PCA is routinely used for postoperative analgesia in some countries. In addition, as you stated, dexamethasone is used as routine prophylaxis, not as a treatment. Six studies explicitly emphasized the use of PCA because all six studies were also about postoperative recovery or postoperative analgesia. One study explicitly emphasized the use of dexamethasone because it focused on the efficacy of dexamethasone and TEAS. Among these 7 studies, PCA/dexamethasone was also applied in the control group. Therefore, neither PCA nor dexamethasone is a specific treatment modality for PONV and is part of the standardized treatment regimen for both groups of patients. The attached table shows the 7 studies that emphasized the usage of PCA/dexamethasone. To remove the ambiguity, we have deleted the "EAS plus other treatments" from the table and text and removed the subgroup analysis of this topic from the results. Thank you again for the helpful feedback and comments on the manuscript.

My repeat response: Partially agree. Even though your included studies have used PCA for postoperative analgesia (possibly opioid), it should not be included as measure for PONV, rather will be a proponent of causing PONV. Yes, I agree that prophylactic dexamethasone can really have in impact on the incidence of PONV and thus should be included in the meta-analysis.

14. My initial Question: In remaining 20% studies where you have mentioned that they received some treatment than placebo in the control arm, what are those interventions used?

Authors’ Repeat Response: Except for usual care, the other control treatments can be considered a placebo. We performed subgroup analysis. The results showed that regardless of what was used as the control, placebo or usual care, EAS showed a significant role in reducing the incidence of PONV (lines 255 to 260). We think a placebo should not be counted as a treatment but only as a kind of psychological comfort.

The control treatments include the following four types:

When the treatment is EA: the control treatment included no needles + active device, no needles + inactive device or usual care.

When the treatment is TEAS: the control treatment included gel electrodes + inactive device and usual care.

My repeat response: Although I agree ultimately, but I am not convinced with your explanation that placebo can be a treatment option. Usually placebo means no treatment. Control group can have usual care when you are comparing with a new care like EAS and TEAS.

15. My initial Question: Apart from the incidence, did you do any analysis of frequency of PONV or not?

Authors’ Repeat Response: We apologize for not explaining more clearly why we did not perform an analysis of the frequency of PONV in the previous version of our manuscript. Only one of the 26 studies included in our meta-analysis recorded the frequency of PONV (please see the table below). Therefore, there was insufficient data to conduct a meta-analysis of the frequency of PONV. We have included the lack of data about the frequency of PONV as a limitation of this study (Discussion section lines 473 to 475). We hope this explains why we did not analyze the frequency of PONV.

My repeat response: Although not fully happy, but agree.

Authors’ Repeat Response: We apologize for the unclear explanation in the previous version. To reduce the incidence of PONV, the subgroup analysis showed that EAS, whether applied as a preoperative intervention, postoperative intervention or perioperative intervention, had a significant effect. We can only show that the three types of treatment timing are effective because they were not directly compared in any of the studies.

My repeat response: Accepted.

17. My initial Question: Targeted and comparative literature review is missing.

Authors’ Repeat Response: Thank you for the specific suggestion. we rewrote the literature review and analytic discussion section. We have added the targeted and comparative literature to the discussion accordingly (lines 438 to 464). Thank you for giving us your constructive comments. We think that the revised manuscript has become more convincing.

My repeat response: Again I am unable to see targeted comparative literature review. For your every outcome measures you should mention some previous literature whether it is matching or you have found a new one. If not matching, why so. Simple descriptive literature review is unnecessary here.

General discussion on PONV and its etiology are immaterial here as this is very well-known. Keep the literature review pertaining to your topic of interest.

Weakness:

• English language used is very lucid, has several grammatical mistakes and lacked scientific tone.

• Some design flaws are quite obvious.

• No clarity on control or sham treatment group.

• No clear comparison with already recommended pharmacological treatment group.

• No obvious risk assessment or use of scoring system.

• Several repetitions of statistical methods in the methodology and result section. Especially the result section is confusing.

• The literature review is incomplete without targeted comparative analysis.

Authors’ Reply: We apologize for not replying to your comments. Thank you for the reviewer’s careful reading of our manuscript. In light of all the above issues, we have carefully revised the document item by item.

My repeat response: Your all loopholes and gaps need to be highlighted in the limitation section clearly.

Discussion should be started with findings of your meta-analysis than the group description. The description of groups with active or inactive with or without needles should come in the methodology or literature search section, not in the first paragraph of discussion.

My Initial impression: Good intent of analyzing the efficacy of non-pharmacological measures in very relevant PONV topic which is still an intriguing issue despite abundance of availability of antiemetics. But the manuscript still needs several modifications, refinement before I can accept it.

Authors’ Reply: Thank you for taking the time to read our revision and giving us your constructive comments. We have made the corresponding changes in the revised manuscript, and we think that the revised manuscript has become more rigorous and convincing. In the answer to the fifteenth question, we explained why we did not analyze the frequency of PONV. In addition, we rewrote the literature review and analytic discussion section. Thank you again for giving us the opportunity to have our manuscript reconsidered. We earnestly appreciate the reviewers’ hard work and hope that the corrections will meet with approval. Should you have any questions, please contact us without hesitation.

My Renewed Impression: Although the manuscript has matured much, but still there are areas which need to be improved further including the English language as well as targeted comparative literature review. I shall like to give authors another chance to improve the manuscript as it is improving in right direction. If they come up with clear explanations on the points I have raised and modify the manuscript accordingly I will give another look.

Reviewer #4: 1. Please describe the treatment methods, including the treatment site, treatment schedule, electrical stimulation intensity, evaluation schedule, and the results of RCTs included in this study in more detail.

2. Please provide the literature search strategy of each electronic database as a additional file in a supporting information.

3. Although the quality of evidence was moderate to low, the conclusion in the abstract section is too positive. Please revise it.

4. The authors provided reference 32 and 33 as the basis for the sentence “ EAS is becoming increasingly popular in clinical practice due to its repeatability and standardization of frequency, intensity and duration “ in the introduction section ( page 4, line 82-83). I wonder how this sentence relates to reference 32 and 33.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #3: Yes: Pradipta Bhakta

Reviewer #4: No

**********

PLoS One. 2023 May 31;18(5):e0285943. doi: 10.1371/journal.pone.0285943.r006

Author response to Decision Letter 2

4 Jan 2023

Dear Editors and Reviewers:

Thank you very much again for giving us another chance to revise our article. And We are very grateful for your valuable suggestions and comments of the paper that are very helpful for us to improve our work. We have tried our best to revise our manuscript according to the comments. We are very happy that the reviewers accepted our explanation to some questions. We are now removing the questions that were accepted last time, leaving the questions that still need to be answered. We hope that your suggestions and comments could be perfectly addressed and the revised manuscript could meet the requirements for publication.

Attached please find the revised version, which we would like to submit for your kind consideration. We below present our responses and indicate where new information can be found in the original manuscript.

1. Initial Question: English language still needs some refinement and editing.

My Reply: We thank the reviewer for the comment. The English language has been revised by an expert who is a native speaker.

My last Response: We apologize for the linguistic problems in the previous revision and my replies. We worked on the manuscript for a long time, and the repeated addition and removal of sentences obviously led to the previous polishing no longer being applicable. We now have asked American Journal Experts to help us with the language editing in this revision (certificate enclosed). We hope that the language in the current version of the manuscript is acceptable.

Reviewers’ repeat response: I can still see several grammatical mistake, mistakes in sentence organisation as well as use of punctuation. I cannot do English editing repeatedly, and neither have time to do that. I leave this to the handling editor. If done properly, then OK for me.

My New Response: We thank you for the patience and suggestion. We have seriously revised our manuscript again. This has been done to the best of our abilities. We will appreciate if editor could help us to improve our manuscript writing.

3. Initial Question: Some details should be discussed about assessment and severity of PONV using Apfel scoring system.

My Reply: Thank you very much for your advice. We have added a paragraph in the discussion to describe in detail the assessment and severity of PONV using Apfel scoring system (line 397 to 409).

My last Response: Thank you so much for your questions regarding the scoring system. We apologize for not explaining more clearly why we did not use the Apfel scoring as the main observation in the previous version. The Apfel score is used to predict the risk of PONV but it does not show whether PONV occurred[1]. Our primary outcome index is the incidence of PONV, an objective indicator. Among the included studies, only one article used the Apfel scoring system. It specifies the inclusion of patients with an Apfel score ≥ 2 (the maximum score with this system is 4)[2]. This was done to include people with a high risk for PONV, while none of the other 25 studies had that inclusion criterion. Therefore, based on the current evidence base, we could not include Apfel scores in our analysis. However, we agree that the Apfel scoring system is very important. If these RCTs included Apfel scores in their inclusion criteria or stratified randomized groups of patients based on the Apfel scoring system, higher quality results would have been obtained. We have modified the discussion about Apfel scoring accordingly (lines 414 to 425).

Reviewers’ repeat response: Agree that Apfel scoring system identifies the at risk patients preoperatively, but it does predict the PONV as well. Although you have again mentioned the risk of PONV, but there is no mention how to evaluate and stratify those risks. This is confusing.

My New Response: Thank you again for your questions regarding the scoring system. In order to evaluate whether EAS is useful for patients with “low,” “medium,” or “high” risk of PONV, RCTs in which participants were stratified by Apfel score should be done. However, only one article mentioned the Apfel scoring system during patient inclusion among the included studies. It specifies the inclusion of patients with an Apfel score ≥ 2 (the maximum score with this system is 4) including patients with a medium-high risk for PONV [2]. This was done to include people with a medium or high risk for PONV, while none of the other 25 studies had that inclusion criterion. Thus, we could not conduct a subgroup analysis based on Apfel scores. We have added the discussion of how to evaluate and stratify the risk of PONV (Discussion section lines 454 to 468). And we have included the lack of scoring system as a limitation of this study (Discussion section lines 488 to 489).

4. Initial Question: Not only the therapeutic measures, also commonly adopted preventive measures should also be mentioned.

My last Response: We apologize for the insufficient clarity in our initial submission. As you mentioned, pharmacological treatment is not the only preventive and therapeutic means for managing PONV. We have added text describing nonpharmacological approaches to PONV prevention in the introduction (lines 68 to 72). To provide a better and more comprehensive description of the prevention and treatment of PONV, we have revised a paragraph in the introduction (lines 60 to 73). Thank you again for your helpful suggestion.

Reviewers’ repeat response: Good for this acknowledgement. What I wanted to mean is that along with non-pharmacological means and modification of patient’s factors as well as the anaesthesia technique, using dexamethasone in the beginning and 5-HT3 antagonist at the end based on Apfel Risk score is the best method to prevent PONV. This should be clearly mentioned. Again in the non-pharmacological means you have mentioned crystalloids, chewing gum, ginger etc. These are indeed pharmacological means. Pharmacological means doesn’t have to me classic antiemetic medicine, but can be traditional medicines as well including IV fluids.

My New Response: Thank you very much for your precious reminding. According to your indication, we add the following sentence to the introduction section: Using dexamethasone in the beginning and 5-HT3 antagonist at the end based on Apfel Risk score is the best method to prevent PONV (Lines 64 to 66). As you pointed out, crystalloids, chewing gum, ginger are indeed pharmacological means. We made the correction (Lines 65 to 67; Lines 70 to 72).

8. Initial Question: Did you use any filter during your literature search?

My Reply: No, we did not use any filters when searching the literature. Thank you for your question.

Reviewers’ Reply: Then how you analysed the searched studies? Did you use only inclusion criteria then?

My last Response: We apologize for not answering your question clearly. We added more details to our search process, including the literature search strategy, inclusion criteria, and exclusion criteria.

Literature search strategy (Take PubMed as an example)

#1 Postoperative Nausea and Vomiting [Mesh]

#3 (“nause*” OR “vomit*” OR “emesis” OR “emeses” OR “emet*” OR “queasiness” OR “queasy”)

#4 #2 AND #3

#5 #1 OR #4

#6 Electroacupuncture [Mesh]

#7 electric*

#8 (acupuncture OR needle OR acupoint OR point OR stimulat*)

#9 #7 AND #8

#10 #6 OR #9

#11 Transcutaneous Electric Nerve Stimulation [Mesh]

#13 #11 OR #12

#14 Electric Stimulation Therapy [Mesh]

#16 #14 OR #15

#17 (“random* controlled trial” OR “random*” OR “placebo”)]

#18 #10 OR #13 OR #16

#19 #5 AND #18 AND #17

The inclusion criteria were:

1). Patients who underwent surgery, regardless of age, sex, ethnicity or surgery type

2). The intervention measures in the treatment group was EAS (EA or TEAS).

3). The control group could be sham acupuncture, placebo acupuncture, no treatment, nonacupoint acupuncture, no electrical stimulation or perioperative routine nursing.

4). The outcomes were the incidence of PONV, PON or POV.

5). To reduce the risk of bias and enhance the accuracy of the conclusions, only studies that had a randomized controlled trials (RCT) design were included.

The exclusion criteria were as follows:

1). Patients undergoing cesarean section or abortion.

2). American Society of Anesthesiologists ≥ III.

3). Patients in the control group who received any electrical stimulation.

4). Unpublished reports or reports published as abstracts only.

Reviewers’ repeat response: Accepted. The sentence of the inclusion and exclusion criteria should be revamped and organised to make it look more scientific.

My New Response: Thank you for your kind accepting and your suggestion. We have revamped and organized the inclusion and exclusion criteria (Lines 119 to 130).

The inclusion criteria were:

1. The review included emergency and elective surgery patients that underwent general anesthesia, regardless of age, sex, ethnicity, or surgery type.

2. The intervention measure in the treatment group was EAS (EA or TEAS).

3. the intervention measures in the control group were sham acupuncture, sham acupoint, sham electrical stimulation, or preoperative routine nursing.

4. Primary outcomes were the incidence of PONV, postoperative nausea (PON) or postoperative vomiting (POV). Secondary outcome measures were the numbers of patients requiring antiemetic rescue and adverse events.

5. The study was a randomized controlled trial (RCT) (blinded or non-blinded).

The exclusion criteria were as follows:

1. Patients undergoing cesarean section or abortion or those in the control group who received any electrical stimulation.

2. American Society of Anesthesiologists (ASA) ≥ III.

3. Literature with incorrect data or inaccessible data.

9. Initial Question: What do you mean by “sham” treatment in the control group?

Reviewers’ Reply: What do you mean by “inactive device”? Is it dry needling? That is also a treatment, isn’t it?

My New Response: We apologize for not clearly describing the different kinds of control treatments. The control treatments include the following four types:

When the treatment is EA, the control treatment includes: no needles + active device; no needles + inactive device or usual care,

When the treatment is TEAS, the control treatment includes: gel electrodes + inactive device or usual care,

� gel electrodes + inactive device: Gel electrodes were placed on the acupoints and attached to a stimulator box with no current output.

Reviewers’ repeat response: I am a bit confused here. What did you exactly mean by “active” and “inactive” device with or without needle? In these complex and mixed methodology how did you do the double blinding?

My New Response: For the control treatments part, we are sorry for our confusing descriptions. Now, we have organized our mind so that we can be much easier to explain. In order to avoid any ambiguity, we rename “no needles” into “no acupuncture” (Lines: 106 to 107, 110, 216, and 271 to 272). The details of changes are as follows:

1. “active device” means Insulated wires from the activated stimulator box with a normal current output;

2. “Inactive device” means Insulated wires from the inactivated stimulator box with no current output (for example, the output wires of the stimulator were broken)

3. No needles essentially mean no acupuncture, include the following two types:

� with needle: The needles were bent to lay flat against the skin;

� without needle: the wire of the stimulator is pasted over the hand without needle and stimulation;

For the blinding part, we evaluated the reasonableness of the blinding method from the description of the 26 included studies. If the blinding was unclear, we marked it in yellow in our evaluation. If the blinding was not appropriate, we mark red in the evaluation (see S1 Fig). We apologize for not clearly describing the blinding. We think part of the articles are possible to be double blind, for the patients and outcome assessor. Considering the specificity of EAS treatment, blinding might not be done for operators (Lines 232 to 233).

11. Initial Question: Regarding the analysis of incidence of PONV, what was used in the control group? Also, you have mentioned incidence with EAS than presenting data separately on EA and TEAS.

Reviewers’ Reply: I am still very confused about inactive device with needle. Can you clarify this a bit more?

My Last Response: We apologize for the confusion. In the answer to Question 9, we described all of the controls. The "inactive device with needle" you mentioned here should correspond to "no needle + inactive device", which means that the needles were bent to lay flat against the skin or no needles were applied and insulated wires from the activated stimulator box with no current output were attached to the needles or the insides of arm covers[6, 7].

We have revised this description in the text to make this more clear (lines 361 to 369).

Reviewers’ repeat response: What is the active device without needle then?

My New Response: Thank you for your question. We are sorry for the unclear explanation. Active device without needle means no acupuncture, the activated stimulator box with a normal current output and the wire of the stimulator is pasted over the hand, without needle and stimulation. Hopefully our pictures will explain this.

My Last Response: Thank you for raising this question. We defined PCA and dexamethasone as “other treatments” inappropriately. PCA is not a treatment option for managing PONV. It is a pain relief method given for postoperative analgesia. PCA is routinely used for postoperative analgesia in some countries. In addition, as you stated, dexamethasone is used as routine prophylaxis, not as a treatment. Six studies explicitly emphasized the use of PCA because all six studies were also about postoperative recovery or postoperative analgesia. One study explicitly emphasized the use of dexamethasone because it focused on the efficacy of dexamethasone and TEAS. Among these 7 studies, PCA/dexamethasone was also applied in the control group. Therefore, neither PCA nor dexamethasone is a specific treatment modality for PONV and is part of the standardized treatment regimen for both groups of patients. The attached table shows the 7 studies that emphasized the usage of PCA/dexamethasone. To remove the ambiguity, we have deleted the "EAS plus other treatments" from the table and text and removed the subgroup analysis of this topic from the results. Thank you again for the helpful feedback and comments on the manuscript.

Author (year) Title of the paper.

El-Rakshy et al, 2009 Effect of intraoperative electroacupuncture on postoperative pain, analgesic requirements, nausea and sedation: a randomised controlled trial.

Gu et al, 2019 The effect of pre-treatment with transcutaneous electrical acupoint stimulation on the quality of recovery after ambulatory breast surgery: a prospective, randomised controlled trial.

Chen et al, 2015 ranscutaneous electric acupoint stimulation alleviates remifentanil-induced hyperalgesia in patients undergoing thyroidectomy: a randomized controlled trial.

Ye et al, 2008 Pain management using Han's acupoint nerve stimulator combined with patient-controlled analgesia following neurosurgery: A randomized case control study

Chen et al, 1998 The effect of location of transcutaneous electrical nerve stimulation on postoperative opioid analgesic requirement: acupoint versus nonacupoint stimulation.

Zheng et al, 2008 Effect of transcutaneous electrical acupoint stimulation on nausea and vomiting induced by patient controlled intravenous analgesia with tramadol.

Reviewers’ repeat response: Partially agree. Even though your included studies have used PCA for postoperative analgesia (possibly opioid), it should not be included as measure for PONV, rather will be a proponent of causing PONV. Yes, I agree that prophylactic dexamethasone can really have in impact on the incidence of PONV and thus should be included in the meta-analysis.

My New Response: Thank you so much for your agreement.

17. Initial Question: Targeted and comparative literature review is missing.

My Last Response: Thank you for the specific suggestion. we rewrote the literature review and analytic discussion section. We have added the targeted and comparative literature to the discussion accordingly (lines 438 to 464).

Thank you for giving us your constructive comments. We think that the revised manuscript has become more convincing.

Reviewers’ repeat response: Again I am unable to see targeted comparative literature review. For your every outcome measures you should mention some previous literature whether it is matching or you have found a new one. If not matching, why so. Simple descriptive literature review is unnecessary here.

General discussion on PONV and its etiology are immaterial here as this is very well-known. Keep the literature review pertaining to your topic of interest.

My New Response: Many thanks for your comments and suggestions. This time, discussion has been re-organized to introduce our outcome measures from the previous literature (Lines 373 to 427). For our outcome measures, we mention some previous literature (if similar literature exists). And we agree with you that the simple descriptive literature review is unnecessary here. So, we decided to delete the section. We hope you are satisfied with our revision, and thank you again for helping us improve the quality of this paper.

Weakness:

• English language used is very lucid, has several grammatical mistakes and lacked scientific tone.

• Some design flaws are quite obvious.

• No clarity on control or sham treatment group.

• No clear comparison with already recommended pharmacological treatment group.

• No obvious risk assessment or use of scoring system.

• Several repetitions of statistical methods in the methodology and result section. Especially the result section is confusing.

• The literature review is incomplete without targeted comparative analysis.

Reviewers’ question: Why no comment here?

My Last Response: We apologize for not replying to your comments. Thank you for the reviewer’s careful reading of our manuscript. In light of all the above issues, we have carefully revised the document item by item.

Reviewers’ repeat response: Your all loopholes and gaps need to be highlighted in the limitation section clearly.

My New Response: Thank you for pointing out those weakness of our manuscript. We sincerely apologize for all these shortcomings. In light of all the above issues, we have carefully revised the document item by item. For the issues (Some design flaws are quite obvious; No clear comparison with already recommended pharmacological treatment group; No obvious risk assessment or use of scoring system.) that could not be revised, we have listed them in the limitations (Lines 480 to 487).

We highly agree your comments. We moved the description of groups with active or inactive with or without needles to the literature search section. Thank you again for your advice (Lines 106 to 115).

Initial impression: Good intent of analyzing the efficacy of non-pharmacological measure in very relevant PONV which is still an intriguing issue despite abundance of antiemetics. But the manuscript still needs several modifications, refinement before I can accept it.

Reviewers’ question: Why no comment here?

My Last Response: Thank you for taking the time to read our revision and giving us your constructive comments. We have made the corresponding changes in the revised manuscript, and we think that the revised manuscript has become more rigorous and convincing. In the answer to the fifteenth question, we explained why we did not analyze the frequency of PONV. In addition, we rewrote the literature review and analytic discussion section. Thank you again for giving us the opportunity to have our manuscript reconsidered. We earnestly appreciate the reviewers’ hard work and hope that the corrections will meet with approval. Should you have any questions, please contact us without hesitation.

Reviewers’ Renewed Impression: Although the manuscript has matured much, but still there are areas which need to be improved further including the English language as well as targeted comparative literature review. I shall like to give authors another chance to improve the manuscript as it is improving in right direction. If they come up with clear explanations on the points I have raised and modify the manuscript accordingly I will give another look.

My New Response: We thank you for the positive comments and suggestions. We have tried our best to revise the manuscript according to your suggestions including grammatical mistake, mistakes in sentence organization as well as use of punctuation. As you say, we hope for help from the editor in grammar editing. Furthermore, the question about targeted comparative literature review, we rewrote the literature review and analytic discussion section. We have added the targeted and comparative literature to the discussion accordingly (Lines 373 to 427). For our outcome measures, we mention some previous literature. We hope this revision is appropriate. Thank you again for giving us the opportunity to revise our manuscript.

Reviewer #4:

1. Please describe the treatment methods, including the treatment site, treatment schedule, electrical stimulation intensity, evaluation schedule, and the results of RCTs included in this study in more detail.

My response: Thank you for your question and suggestion. We are happy to describe the treatment methods as your suggestions. We have added a Table 2 that include the treatment site, electrical stimulation intensity, and evaluation schedule. Treatment schedule and the results of RCTs included in this study had been describe in table 1, so we have not added these two to S2 Table. Thanks again to the reviewer for professional suggestions.

2. Please provide the literature search strategy of each electronic database as a additional file in a supporting information.

My response: Thank you for your advice. We have added the literature search strategy of each electronic database as an additional file in a supporting information (S1 Table). We hope that our modification is satisfactory to you.

3. Although the quality of evidence was moderate to low, the conclusion in the abstract section is too positive. Please revise it.

My response: Thank you for pointing this out. We agree with you that the conclusion in the abstract section is too positive. We have modified the sentences in abstract section (Lines 44 to 45). Again, thanks for this point.

My response: We are so sorry for the mistake. “EAS is becoming increasingly popular in clinical practice due to its repeatability and standardization of frequency, intensity and duration” in the introduction section is not objective. Therefor we delete this sentence including the reference (Line 83).

Reference

Attachment

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PLoS One. doi: 10.1371/journal.pone.0285943.r007

Decision Letter 3

Ahmed Mohamed Maged

5 May 2023

Efficacy and safety of electrical acupoint stimulation for postoperative nausea and vomiting: A systematic review and meta-analysis

PONE-D-21-05426R3

Dear Dr. Song,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

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Kind regards,

Ahmed Mohamed Maged, MD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #4: All comments have been addressed

Reviewer #5: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #4: Yes

Reviewer #5: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #4: I Don't Know

Reviewer #5: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #4: Yes

Reviewer #5: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #4: Yes

Reviewer #5: Yes

**********

6. Review Comments to the Author

Reviewer #4: Thank you for your revision. The authors have adequately addressed my comments raised in a previous round of review. this manuscript is now acceptable for publication

Reviewer #5: Hi, thank you for submitting the revision. i am going to accept this article in pleasant way. this revision will definitely make a good impression on your article.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #4: No

Reviewer #5: No

**********

PLoS One. doi: 10.1371/journal.pone.0285943.r008

Acceptance letter

Ahmed Mohamed Maged

22 May 2023

PONE-D-21-05426R3

Efficacy and safety of electrical acupoint stimulation for postoperative nausea and vomiting: A systematic review and meta-analysis

Dear Dr. Song:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Professor Ahmed Mohamed Maged

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Checklist. PRISMA 2009 checklist.

(DOC)

Click here for additional data file.^{(65.5KB, doc)}

S1 Fig. Risk of bias summary: Review authors’ judgments of each included trial.

(TIF)

Click here for additional data file.^{(959.7KB, tif)}

S2 Fig. Subgroup analyses about postoperative nausea and vomiting.

A: Forest plots of types of surgical procedures. B: Forest plot of EAS vs. placebo.

(TIF)

Click here for additional data file.^{(3.1MB, tif)}

S3 Fig. Forest plots of the numbers of patients needing antiemetic rescue in EAS vs control.

(TIF)

Click here for additional data file.^{(498KB, tif)}

S4 Fig. Forest plots of the adverse events in EAS vs control.

(TIF)

Click here for additional data file.^{(492.5KB, tif)}

S5 Fig. Funnel plot for the assessment of publication bias for postoperative nausea and vomiting.

A: Funnel plot for postoperative nausea and vomiting. B: Funnel plot for postoperative nausea. C: Funnel plot for postoperative vomiting.

(TIF)

Click here for additional data file.^{(1.1MB, tif)}

S1 Table. Search strategy.

(DOCX)

Click here for additional data file.^{(28.9KB, docx)}

S2 Table. Details of the included trials for treatments methods.

(DOCX)

Click here for additional data file.^{(47KB, docx)}

S3 Table. Sensitivity analyses by excluding one study at a time.

(DOCX)

Click here for additional data file.^{(96KB, docx)}

S4 Table. Sensitivity analysis by changing the effects model for outcome analysis.

(DOCX)

Click here for additional data file.^{(22.1KB, docx)}

S5 Table. AMSTAR 2: A critical appraisal tool for systematic reviews.

(DOCX)

Click here for additional data file.^{(35.5KB, docx)}

S1 Raw data

(RAR)

Click here for additional data file.^{(75.2KB, rar)}

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Data Availability Statement

All relevant data are within the manuscript and its Supporting Information files.

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PERMALINK

Efficacy and safety of electrical acupoint stimulation for postoperative nausea and vomiting: A systematic review and meta-analysis

Liyue Lu

Chenlong Xie

Xing Li

Yalan Zhou

Zhiyu Yin

Pan Wei

Hao Gao

Jian Wang

Yue Yong

Jiangang Song

Roles

Abstract

Background

Methods

Results

Conclusions

Introduction

Methods

Literature search

Inclusion and exclusion criteria

Study selection and data collection

Outcomes

Risk of bias assessment

The Grades of Recommendation Assessment Development and Evaluation

Statistical analysis

Results

Study selection

Fig 1. Flow diagram of the literature search.

Description of the included studies

Table 1. Characteristics of the included trials.

Risk of bias within studies

Incidence of PONV

Fig 2. Forest plots of the incidence of postoperative nausea and vomiting in EAS vs control.

Fig 3. Forest plots of the incidence of postoperative nausea and vomiting within 24 h.

Incidence of PON

Fig 4. Forest plots of the incidence of postoperative nausea in EAS vs control.

Incidence of POV

Fig 5. Forest plots of the incidence of postoperative vomiting in EAS vs control.

Number of patients needing antiemetic rescue

Adverse events

Publication bias

Sensitivity analysis

GRADE evaluation

Table 2. GRADE evaluation of evidence quality.

Discussion

Conclusion

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

Elisa Panada

Roles

Author response to Decision Letter 0

Decision Letter 1

Pradipta Bhakta

Roles

Author response to Decision Letter 1

Decision Letter 2

Huijuan Cao

Roles

Author response to Decision Letter 2

Decision Letter 3

Ahmed Mohamed Maged

Roles

Acceptance letter

Ahmed Mohamed Maged

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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