Efficacy of wearable transcutaneous electrical acupoint stimulation bracelet on moderate-to-severe postoperative nausea and vomiting in patients after general anesthesia: a study protocol for a multicenter randomized controlled trial

Abstract

Background

Postoperative nausea and vomiting (PONV) is the most common complication following general anesthesia. Currently, pharmaceutical therapy is the primary method of treatment, but it has reached a plateau, and it is accompanied by inherent adverse reactions and high costs. Stimulation of the wrist acupuncture point PC6 is recommended as an effective means of preventing PONV. Our previous study suggests that the wearable transcutaneous electrical acupoint stimulation (TEAS) bracelet can prevent PONV, but its effectiveness in treating moderate-to-severe PONV that has already occurred remains unknown. This trial aims to include female patients who have suffered from PONV after general anesthesia in real-world settings to investigate the therapeutic effect of the TEAS bracelet.

Methods

This trial will be conducted in Shanghai and Tianjin, China, with a total of 232 participants recruited from four academic hospitals. Participants will be randomly allocated into the TEAS group or the control group in a 1:1 ratio. Participants in the TEAS group will wear an EmeTerm bracelet and be injected with normal saline, while participants in the control group will wear a model bracelet and be injected with 10 mg of metoclopramide. Follow-up will be conducted 2 h later, and participants who do not experience relief will be randomly allocated into two groups and given cross-intervention. The primary outcome of the trial is the response rate of moderate-to-severe PONV after 2 h of intervention. Secondary outcomes include the recurrence rate of moderate-to-severe PONV within 24 h after intervention and the response rate of moderate-to-severe PONV at 2 h after cross-intervention in a population insensitive to the initial intervention.

Discussion

This multi-center randomized controlled trial aims to reveal the therapeutic effect of the wearable TEAS bracelet on PONV. It is expected that this bracelet will become an effective supplement for the clinical treatment of PONV, reducing medical expenditure and improving anesthesia quality and patient satisfaction.

Trial registration

Chinese Clinical Trial Registry ChiCTR2400084329. Registered on May 14, 2024.

Administrative information

Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).

Title {1}	Efficacy of wearable transcutaneous electrical acupoint stimulation bracelet on moderate-to-severe postoperative nausea and vomiting in patients after general anesthesia: a study protocol for a multicenter randomized controlled trial
Trial registration {2a and 2b}.	Chinese Clinical Trial Registry: ChiCTR2400084329. May 14th, 2024.
Protocol version {3}	2023.12.25 version 2.0
Funding {4}	The second round of the Shanghai Shenkang Hospital Development Center’s “Three Year Action Plan to Promote Clinical Skills and Clinical Innovation in Municipal Hospitals” research-oriented physician innovation and transformation ability training project (SHDC2023CRD024), the Medical Innovation Reasearch Project of Shanghai Science and Technology Commission (22Y11904000), and Clinical research projects initiated by researchers in demonstration research wards (2023YJBF-PY11)
Author details {5a}	1. Peng Ding, Dong-yu Zheng, Hong-wei Zhu, Ming Gong, Hui-jing Shi, and Yong-hua Li, Department of Anesthesiology, Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), Shanghai, China 2. Peng Ding and Guang-li Ren, Department of Anesthesiology, PLA No.983 Hospital, Tianjin, China 3. Yong-qiang Wang, Department of Anesthesiology, Shuguang Hospital, Traditional Chinese Medicine University, Shanghai, China; 4. Ling-yan Jin, Department of Anesthesiology, Shanghai Fifth People’s Hospital affiliated to Fudan University, Shanghai, China
Name and contact information for the trial sponsor {5b}	No sponsor was involved in the initiation and management of this trial.
Role of sponsor {5c}	The funding source had no role in the design of this study and will not have any role during its execution, analysis, interpretation of the data, or decision to submit results.

Introduction

Background and rationale {6a}

Postoperative nausea and vomiting (PONV) is the most common complication following general anesthesia, accounting for 43% of all inpatients, with an incidence rate of 70–80% among high-risk patients [1, 2]. Severe cases can lead to wound dehiscence, incisional hernia, aspiration pneumonia, asphyxia, and even death [3]. Pharmaceutical therapy is currently the primary method, with commonly used drugs including 5-HT3 receptor antagonists, glucocorticoids, dopamine receptor antagonists, substance P antagonists, anticholinergics, and antihistamines [1]. The multitude of drug types indicates the lack of a specific drug against PONV. Pharmaceutical therapy has reached a bottleneck, and the inherent adverse reactions of these antiemetic drugs, such as headache, dizziness, and arrhythmia, coupled with relatively high drug costs, limit their widespread use. Therefore, it is urgent to explore clinically effective non-pharmaceutical therapies [4, 5], including acupuncture, acupressure, and transcutaneous electrical acupoint stimulation (TEAS). However, these traditional methods have high personnel skills and equipment requirements. Our previous randomized controlled trial using a wearable bracelet device based on the principle of TEAS found that it reduced the incidence of PONV in patients undergoing hysteroscopic surgeries [6]. Although previous studies have suggested that the TEAS bracelet can prevent PONV, its effectiveness on PONV that has already occurred remains unknown. Thus, we aim to study the therapeutic effect of the TEAS bracelet on patients who have suffered moderate-to-severe PONV after general anesthesia in real-world settings.

Objectives {7}

The objective of this study is to evaluate the therapeutic effect of the TEAS bracelet on moderate-to-severe PONV in patients after general anesthesia. Our hypothesis is that the wearable non-pharmaceutical device is superior to metoclopramide treatment.

Trial design {8}

The trial is designed as a randomized, controlled, patient-blinded, multicenter, superiority trial with two parallel groups. The primary endpoint of the trial is symptom relief during 2 h after moderate-to-severe PONV. Randomization will be performed using block randomization with a 1:1 allocation ratio.

Methods: participants, interventions and outcomes

Study setting {9}

The trial will be conducted in Shanghai and Tianjin, China. A total of 232 participants will be recruited from four academic hospitals: 82 participants from the Second Affiliated Hospital of Naval Medical University in Shanghai, 50 participants from Shanghai Shuguang Hospital, 50 participants from Shanghai Fifth People’s Hospital, and 50 participants from PLA No.983 Hospital in Tianjin.

Eligibility criteria {10}

Female patients undergoing thyroidectomy or anterior cervical surgery under general anesthesia will be screened for participation.

Inclusion criteria

• Moderate to severe PONV (visual analog score ≥ 4) within 24 h after surgery

• Age 25–55 years

• American Society of Anesthesiologists (ASA) physical status I–II

Exclusion criteria

• Patients with PONV within 24 h before surgery

• Patients who received antiemetic drugs within 24 h before surgery

• Patients with severe hepatic/renal dysfunction

• Patients known to be allergic to metoclopramide

• Patients with unstable vital signs before enrollment

• Patients who have participated in other studies within the last 3 months

• Pregnant or lactating women

Who will take informed consent? {26a}

In this study, an anesthesiologist will approach patients who are eligible for participation. After explaining the general anesthesia procedure and obtaining consent, patients will be informed about the TEAS approach or medication to treat PONV. Patients will only be enrolled in the study if they provide consent for both the general anesthesia and the research. If a patient is unable to provide written consent, it will be obtained from their designated representative. Patients who refuse to participate in the study will still receive the same quality of care as participants. Participants have the right to withdraw from the study at any time, in accordance with the Declaration of Helsinki (2013 version).

Additional consent provisions for collection and use of participant data and biological specimens {26b}

Not applicable. We will not collect any biological specimens from participants, and we are not currently considering the use of these data for ancillary studies.

Interventions

Explanation for the choice of comparators {6b}

The Fourth Consensus Guidelines for the Management of PONV recommend the use of multimodal prophylaxis in patients with one or more risk factors [1]. In this study, both groups will be routinely treated with a combination of dexamethasone and dolasetron, which are the two most commonly used classes of drugs: glucocorticoids and serotonin agonists. For participants who have already developed PONV, repeated use or higher doses of these drugs often have little benefit. Therefore, we have chosen a new type of antiemetic, metoclopramide, as the comparative intervention in the control group. Metoclopramide is a dopamine 2 (D2) receptor antagonist and 5-hydroxytryptamine 4 (5-HT4) receptor agonist and has a mild inhibitory effect on the 5-HT3 receptor. It acts on the dopamine receptor in the chemoreceptor trigger zone of the medulla to increase the threshold of the chemoreceptor trigger zone and has a central antiemetic effect. It is a drug recommended in the guidelines (Evidence A1) and its price is relatively low, so we chose metoclopramide 10 mg as the comparative intervention in the control group.

Intervention description {11a}

All enrolled patients in this study will be routinely administered intravenously with dexamethasone 5 mg at the induction of general anesthesia, and dolasetron 12.5 mg at the end of surgery. Patients with moderate to severe PONV (VAS score ≥ 4) will be allocated into either the TEAS group or the control group.

In the TEAS group, patients with PONV (VAS score ≥ 4) will wear an EmeTerm bracelet and be injected with normal saline. They will be followed up 2 h later to observe the response rate of PONV. If PONV is significantly relieved (VAS ≤ 3), the intervention will be continued for 24 h, and the recurrence rate of moderate and severe PONV within 24 h will be observed and the highest score will be recorded.

In the control group, patients will wear a model bracelet (the light will flash normally, but there will be no electrical stimulation) and will be injected with metoclopramide 10 mg. Two hours later, the response rate of moderate to severe PONV will be observed. If PONV was significantly relieved (VAS ≤ 3), the recurrence rate of moderate and severe PONV within 24 h will be observed and the highest score will be recorded.

In the TEAS group, patients who have no significant relief after the intervention of the electrostimulation bracelet (VAS score ≥ 4) will stop using the bracelet and then be randomly divided into two groups. One group will be injected with metoclopramide 10 mg and the other with an equal-volume of normal saline. They will be followed up 2 h later to observe the response rate of moderate and severe PONV.

In the control group, patients who have no significant relief after metoclopramide medication (VAS score ≥ 4) will be randomly divided into two groups. One group will wear the electrical stimulation bracelet and the other will wear the model bracelet. They will be followed up 2 h later to observe the response rate of moderate and severe PONV.

Criteria for discontinuing or modifying allocated interventions {11b}

If the vital signs of a participant are unstable after enrollment or if the participant does not cooperate with follow-up, the intervention will be suspended. Furthermore, any participant may withdraw from the trial at any time without providing a reason.

Strategies to improve adherence to interventions {11c}

The control group’s intervention, which is a single intravenous injection of metoclopramide, has good compliance. The intervention in the TEAS group, which involves wearing a bracelet, typically does not affect the participant’s activity and has a short duration of 2 h. Therefore, adherence to the intervention is expected to be good. The investigators will ask the ward nurses to monitor whether the patients are wearing the bracelet properly during routine rounds.

Relevant concomitant care permitted or prohibited during the trial {11d}

Participants in both groups received conventional postoperative care. No additional antiemetics (5-HT3 receptor antagonists, glucocorticoids, dopamine receptor antagonists, substance P antagonists, anticholinergics, and antihistamines) will be given. Ondansetron 4 mg will be administered intravenously as rescue medication.

Provisions for post-trial care {30}

The intervention in this trial involved the normal use of a long-marketed product, while the control intervention was clinical routine medication. Participants are not expected to suffer harm from trial participation, and no special provisions for post-trial care are required.

Outcomes {12}

The primary outcome is the response rate of moderate-to-severe PONV after 2 h of intervention (including complete response, defined as the disappearance of all uncomfortable symptoms, and partial response, defined as the transition from vomiting to nausea, or a significant reduction in the degree of nausea). The secondary outcome includes the following: the recurrence rate of moderate-to-severe PONV within 24 h after intervention, the response rate of moderate-to-severe PONV at 2 h after cross-intervention in a population insensitive to the initial intervention.

The primary outcome of the trial is the response rate of moderate-to-severe postoperative PONV after 2 h of intervention. This includes complete response, which is defined as the disappearance of all uncomfortable symptoms, and partial response, which is defined as the transition from vomiting to nausea or a significant reduction in the degree of nausea (VAS ≤ 3). The secondary outcomes include the recurrence rate of moderate-to-severe PONV within 24 h after intervention, as well as the response rate of moderate-to-severe PONV at 2 h after cross-intervention in a population insensitive to the initial intervention.

Participant timeline {13}

The overall schedule of enrolment, allocation, intervention, and follow-up is presented as a schematic diagram in Fig. 1.

Fig. 1.

Schematic diagram. Timepoint: − t₁, before anesthesia; 0, allocation; t₁, primary intervention (after PONV occurs and last for 2 h); t₂, 2 h after intervention; t₃, cross intervention (last for 2 h); t₄, 2 h after cross intervention

Sample size {14}

The sample size for this trial was calculated based on the primary outcome. We previously found that metoclopramide was routinely administered intravenously in patients suffering from moderate-to-severe PONV, and the effective response rate was 37.5% (6/16) after 2 h of follow-up. We estimate that the effective rate will be increased to 60% by using the TEAS bracelet. Based on the primary outcome (37.5% vs. 60%), test power (1-β = 90%), and bilateral significance level (α = 5%), a minimum of 104 samples are required for each group using PASS software. To account for a 10% dropout rate, we plan to recruit 232 participants (116 in each group) for this trial.

Recruitment {15}

Each center participating in the trial has a dedicated anesthesiologist who is responsible for screening all women undergoing thyroid and anterior cervical surgery, particularly those with more than two Apfel’s PONV risk factors. Participants are provided with detailed information about the potential complications of PONV, current mainstream treatments, and the potential benefits and risks of participating in the trial. The number of subjects enrolled in each center is determined based on the type and number of operations performed at the center, ensuring that the target sample size can be achieved across all four centers by the end of the enrollment period.

Assignment of interventions: allocation

Sequence generation {16a}

Participants in the trial will be randomly assigned to either the control group or the TEAS group in a 1:1 ratio using sealed envelopes. Permuted block randomization will be performed using variable block sizes ranging from 4 to 10. The random numbers will be generated using SAS software to ensure the randomization process is unbiased and reliable.

Concealment mechanism {16b}

Allocation concealment will be ensured by using sealed opaque envelopes that will be kept by a research nurse. The allocation of participants to either the control group or the TEAS group remains unknown to both the participants.

Implementation {16c}

The statistical expert from the main research center (The Second Affiliated Hospital of Naval Medical University) will be responsible for generating the allocation sequence, preparing the envelopes, and sending them directly to the research nurses in each center. Participants will be enrolled by the anesthesiologist who administered the anesthesia and will be assigned to the interventions by a specialized anesthesiologist who will be blinded to the group allocation.

Assignment of interventions: blinding

Who will be blinded {17a}

In this trial, both the patients and the follow-up researcher will be kept blind about the group allocation and interventions. A designated anesthesiologist will be responsible for postoperative follow-up, but will not interfere with clinical anesthesia and PONV treatment. After the end of the trial, the data will be summarized and sent to the full-time statistical personnel for analysis.

Procedure for unblinding if needed {17b}

Emergency unblinding is not involved in this trial because the safety of the intervention has been fully validated and does not affect routine postoperative treatment and rehabilitation.

Data collection and management

Plans for assessment and collection of outcomes {18a}

Independent investigators at each center will be responsible for following up with the participants at 2 and 24 h after the intervention. They will fill out case report files and print them out for storage. The case report files from each center will then be sent to the statistical expert of the leader unit for further analysis.

Plans to promote participant retention and complete follow-up {18b}

Follow-up in this trial will generally be completed within 24 to 48 h after surgery, during which time participants are usually still hospitalized, so the investigator can easily conduct face-to-face follow-up. If a participant has any concerns or wishes to discontinue participation, he or she can contact his or her physician-in-charge or the study administrator at any time for assistance.

Data management {19}

Case report files are filled out by an independent investigator and stored in a locked cabinet in each center, and these documents are not seen by study administrators, recruiters, allocation, and intervention implementers. A research nurse enters the data into a computer and sends it directly to a statistical expert.

Confidentiality {27}

The case report files will be stored in a locked cabinet accessible only to the investigators. Personal information that may reveal the privacy of participants will not be recorded in the file.

Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}

No biological specimens will be collected in this trial.

Statistical methods

Statistical methods for primary and secondary outcomes {20a}

The primary outcome will be analyzed according to the intention-to-treat principle, and worst-case imputation will be used when there are missing data. Data normality is measured using the Shapiro–Wilk test. The intergroup differences are analyzed using the Student’s t-test or Mann–Whitney U test according to the data distribution. Binary and categorical variables are analyzed using Fisher’s exact tests. Ordinal data are analyzed using the Wilcoxon signed-rank test. A two-sided P value less than 0.05 is considered statistically significant.

Interim analyses {21b}

No interim analyses are planned in the trial.

Methods for additional analyses (e.g., subgroup analyses) {20b}

Participants who are not sensitive to the initial intervention will receive cross-intervention, and the additional outcome is the remission rate of PONV at 2 h after cross-intervention, which will be analyzed using Fisher’s exact tests.

Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}

The primary outcome will be analyzed according to the intention-to-treat principle, and worst-case imputation will be used when there are missing data. A per-protocol analysis will be performed to enhance the results.

Plans to give access to the full protocol, participant-level data and statistical code {31c}

This protocol is publicly available and the data sets generated/anal analyzed during the current study are available from the corresponding authors on reasonable request.

Oversight and monitoring

Composition of the coordinating center and trial steering committee {5d}

The trial is led by the Department of Anesthesiology of the Second Affiliated Hospital of Naval Medical University and involves four participating centers. A senior professor from the leading unit and the administrators of the other three centers form a coordinating center that will meet online once a week to coordinate the progress of the trial, review the inclusion and exclusion criteria, and oversee the consent, recruitment, and follow-up process, without knowing the allocation, intervention, and outcomes of any specific participant.

Composition of the data monitoring committee, its role and reporting structure {21a}

The trial does not require a data monitoring committee because of the short duration and minimal known risks.

Adverse event reporting and harms {22}

Possible adverse events in this trial include numbness in the palms and fingers, allergies to the electrodes or silicone strap, allergies to metoclopramide or related lethargy, irritability, and fatigue. These adverse events are usually mild and recover quickly after the intervention. Adverse events and harms will be recorded by the investigator and eventually included as categorical data in the secondary outcome analysis.

Frequency and plans for auditing trial conduct {23}

Audit is not planned in this trial.

Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25}

The trial will follow the latest version of the protocol. Any changes to the protocol or informed consent will be considered as amendments and version updates. These changes will be submitted for review to the Ethics Committee of Shanghai Changzheng Hospital and the ethics committees of the other three centers.

Dissemination plans {31a}

The results of this trial will be communicated through conference presentation and publication of peer-reviewed research article.

Discussion

This multi-center randomized controlled trial aims to evaluate the therapeutic effect of a wearable TEAS bracelet on moderate-to-severe PONV. The trial is expected to provide valuable information about the effectiveness of the TEAS bracelet as a supplement for clinical treatment of PONV, and could potentially reduce medical expenditure and improve anesthesia quality and patient satisfaction.

It is important to note that the trial includes only female participants, which may introduce gender bias into the study. However, this decision was made in order to enroll a sufficient number of participants faster, as women are at higher risk for PONV.

It is also important to note that blinding through a model bracelet may not be entirely reliable for some participants, as some of them may find that they have no sensation at all after wearing the bracelet. Additionally, some participants may discover the true role and experience of the bracelet through internet searches. Therefore, this may not be a very rigorous patient-blinded trial and may be biased due to the subjective feelings of some subjects. Despite these potential limitations, the trial is still expected to provide valuable information about the effectiveness of the TEAS bracelet as a treatment for PONV.

Trial status

The protocol version 2.0 was approved by all authors on Dec 25th, 2023. The first participant was enrolled at The Second Affiliated Hospital of Naval Medical University on May 20th, 2024. Subsequent recruitment will be conducted after approval by the Ethics Committee of each center. The recruitment will be completed on December 2024.

Abbreviations

PONV

Postoperative nausea and vomiting

TEAS

Transcutaneous electrical acupoint stimulation

VAS

Visual analog score

ASA

American Society of Anesthesiologists

Authors’ contributions {31b}

PD, DYZ, HWZ, and MG contributed to the study concept, design, data management, and draft of the manuscript; YQW, LYJ, GLR, and HJS are the chief investigators of each research center, and contributed to the study design, data collection, and data management; YHL contributed to the study concept, design, drafting, funding, and supervising project administration. All authors read and approved the final manuscript.

Funding {4}

The second round of the Shanghai Shenkang Hospital Development Center’s “Three Year Action Plan to Promote Clinical Skills and Clinical Innovation in Municipal Hospitals” research-oriented physician innovation and transformation ability training project (SHDC2023CRD024), the Medical Innovation Reasearch Project of Shanghai Science and Technology Commission (22Y11904000), and Clinical research projects initiated by researchers in demonstration research wards(2023YJBF-PY11).

Data availability {29}

The data sets generated and analyzed during the current study are available from the corresponding authors on reasonable request.

Declarations

Ethics approval and consent to participate {24}

The study protocol is approved by the Ethics Committee of the Second Affiliated Hospital of Naval Medical University (No.2023SL074). Written informed consent to participate will be obtained from all participants.

Consent for publication {32}

Not applicable.

Competing interests {28}

The authors declare that they have no competing interests.