
==== Front
BMJ Open
BMJ Open
bmjopen
bmjopen
BMJ Open
2044-6055
BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR

10.1136/bmjopen-2024-088633
bmjopen-2024-088633
Protocol
Anaesthesia
1682
1506
Acustimulation combined with pharmacological prophylaxis versus pharmacological prophylaxis alone in postoperative nausea and vomiting (PONV) prophylaxis among patients undergoing laparoscopy abdominal surgery: a research protocol for a randomised controlled trial
http://orcid.org/0009-0009-8375-4396
Chen Junjie 121045034956@qq.com

http://orcid.org/0000-0002-9474-4769
Che Lu 2tracymaobao@126.com

Cui Quexuan 2lilly-love-jenny@163.com

Lang Jiaxin 2langjx09@163.com

http://orcid.org/0000-0001-7990-9003
Zhang Yuelun 3yuelunzhang@outlook.com

Zhu Bo 2zhubo@pumch.cn

Huang Yuguang 2garypumch@163.com

1 Peking Union Medical College, Beijing, China
2 Department of Anaesthesiology, Peking Union Medical College Hospital, Beijing, China
3 Peking Union Medical College Hospital, Beijing, China
DrLuChe; tracymaobao@126.com
None declared.

2024
23 9 2024
14 9 e08863311 5 2024
27 8 2024
Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

Abstract

Introduction

This study evaluates the efficacy of integrating percutaneous electrical nerve stimulation at the pericardium 6 (PC6) acupuncture point through a wearable acustimulation device with standard pharmacological prophylaxis to prevent postoperative nausea and vomiting (PONV) compared with pharmacological prophylaxis alone in patients undergoing laparoscopic abdominal surgery.

Method and analysis

This prospective study will enrol 302 patients scheduled for elective laparoscopic surgery. Participants will be randomly allocated to one of two groups: acustimulation combined with pharmacological prophylaxis or sham stimulation combined with pharmacological prophylaxis. Randomisation will involve a computer-generated sequence, with allocation concealment implemented through sealed envelopes. The acustimulation group will receive electrical stimulation at the PC6 point starting 30 min before surgery and continuing until discharge from the postanaesthesia care unit. Sham group will wear a wristband that does not provide stimulation. The primary outcome is the incidence of PONV. Secondary outcomes include the severity of PONV, incidence rates of nausea and vomiting at different postoperative intervals and indices of gastrointestinal functional recovery. Exploratory outcomes will assess haemodynamic parameters, baroreflex sensitivity, hospital stay duration, costs and both short-term and long-term postoperative recovery.

Ethics and dissemination

All participants will provide written informed consent. The study has been approved by the Ethics Committee of Peking Union Medical Hospital (approval number: I-23PJ1712). Results will be published open access.

Trial registration number

NCT06241547.

SURGERY
Randomized Controlled Trial
Adult anaesthesia
Acupuncture
National High Level Hospital PUMCH-B-006
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pmcSTRENGTHS AND LIMITATIONS OF THIS STUDY

The randomised controlled trial design allows for balancing confounding factors contributing to postoperative nausea and vomiting (PONV).

We use a sham group with an inactivated acustimulation device prepared by covering the electrodes with silicone, ensuring the same patient experience and maintaining blinding.

Besides evaluating the incidence of PONV, we also incorporate PONV frequency and its impact on recovery to provide a comprehensive picture to guide clinical management.

We have designed a prespecified exploratory analysis to investigate the potential effects of acustimulation on PONV.

Our study population includes only adult women undergoing laparoscopy abdominal surgery, thus limiting the generalisation of our findings to other populations.

Introduction

Postoperative nausea and vomiting (PONV) is one of the most common complications after general anaesthesia surgery, with an incidence ranging from 20% to 60%, and even up to 80% in high-risk populations.1 In addition to causing discomfort, PONV can also lead to a series of complications, such as wound dehiscence and bleeding, resulting in prolonged hospitalisation and increased medical costs.2 Currently, a series of medications have been studied for the prevention of PONV, including serotonin-3 (5-HT3) receptor antagonists, neurokinin-1 (NK1) receptor antagonists, glucocorticoids, antihistamines, anticholinergics and dopamine-2 (D2) receptor antagonists.3 However, there is still an urgent and realistic need for non-pharmacological treatment still, due to potential adverse reactions of chemical drugs, such as headache and constipation (5-HT3 receptor antagonists); extrapyramidal symptoms, sedation, arrhythmia and QT prolongation (D2 receptor antagonists); hyperglycaemia, immunosuppression and poor wound healing (corticosteroids).4 5 Furthermore, although prophylactic antiemetic drugs are commonly administered during the perioperative period, it is estimated that approximately 30% of surgical patients still experience PONV.6

Percutaneous electrical nerve stimulation involves the placement of electrodes on a nerve to deliver electrical impulses, triggering a cascade of physiological responses.7 The specific mechanisms underpinning the effects of acustimulation on PONV prevention remain unclear. However, several hypotheses have been proposed: (1) regulation of the release of endogenous opioid8; (2) increase of cortisol level in the brain9; (3) reduction of plasma serotonin concentration10 and (4) sympathetic depression and parasympathetic activation.11 Notably, the balance of sympathetic and parasympathetic excitability is crucial in the control of nausea and vomiting.12

Some studies showed that nerve stimulation at the Pericardium 6 (PC6) point (figure 1) effectively reduced the incidence of PONV as a prophylaxis strategy compared with placebo or sham control.13 14 Furthermore, stimulation of PC6 or/and other acupuncture points can theoretically promote the recovery of postoperative gastrointestinal function such as shortening duration to the first flatus and bowel movement postsurgery.15 16 However, these studies often did not incorporate baseline PONV risk minimisation strategies, such as the use of total intravenous anaesthesia and routine combined pharmacological prophylaxis, which limits the generalisability of their results to current medical practice.

Figure 1 Diagram showing PC6 position.

With the development of wearable devices nowadays, it is theoretically more feasible and convenient to apply percutaneous electrical stimulation in the perioperative period to prevent PONV. A small-scale study confirmed the effectiveness of a novel wearable device in preventing PONV in ambulatory patients after hysteroscopic surgery via PC6 electric stimulation, but their patients did not receive routine PONV pharmacological prophylaxis treatment.17

With current guidelines recommending routine use of a combined pharmacological prophylaxis regimen (Fourth Consensus Guidelines for the Management of PONV),18 there is a need to assess the additional benefits of PC6 electrical stimulation in this context. To fill the knowledge gap, we designed this current prospective randomised trial to evaluate whether PC6 percutaneous electrical stimulation, administered through a wearable device alongside ondansetron and dexamethasone, is superior to the pharmacological agents alone in preventing PONV.

We hypothesise that acustimulation enhances the prophylactic effect against PONV by modulating the autonomic nervous system. Baroreflex sensitivity (BRS), quantified from baroreflex function by observing the RR interval (time between two consecutive R-waves on ECG) response to an arterial blood pressure (BP) change, is a reliable marker reflecting resilience of the autonomic nervous system.19 20 As part of this investigation, we will measure BRS before and after surgery to explore potential mechanisms on how acustimulation could affect PONV.

Furthermore, given that PONV and delayed bowel function recovery can prolong hospital stays and increase healthcare-related costs,21 22 we will also evaluate the cost-effectiveness of incorporating a wearable acustimulation device into a multimodal strategy for PONV prophylaxis. These findings aim to provide comprehensive insights into both the clinical efficacy and economic viability of this novel approach.

Methods and analysis

Patient and public involvement

No patient is involved.

Study design

This study is a single-centre, prospective, randomised controlled trial to be conducted in Peking Union Medical College Hospital.

Eligibility criteria

Inclusion criteria

Patients could choose to participate in the study when they meet all the following conditions:

Patients aged 18–65 years.

Gender: female.

Patients undergoing gynaecological, hepatobiliary, gastrointestinal and urological surgeries performed using laparoscopic techniques.

American Society of Anesthesiologists (ASA) grades I–III.

Anaesthesia: general anaesthesia, tracheal intubation.

Body mass index (BMI): ≥18, <28.

Apfel score ≥323 (Apfel simplified risk score is based on four predictors: female sex, history of PONV and/or motion sickness, non-smoking status and use of postoperative opioids.0, 1, 2, 3 and four risk factors correspond PONV risks of approximately 10%, 20%, 40%, 60% and 80%, respectively).

Patients or their family members are able to comprehend the study protocol and are willing to participate in this research by providing written informed consent.

Exclusion criteria

There are incisions or scars in the wearing position of the device.

There is a local infection in the wearing position of the device.

Upper extremity nerve injury.

History of spinal cord surgery.

Participated in other clinical trials within 4 weeks.

Suffering from severe central nervous system disease or mental disorder.

Suffering from nausea and vomiting caused by other reasons.

Patients need to return to the intensive care unit after surgery in prediction before surgery.

Discharge criteria

Patients will be withdrawn from the clinical study when they have any of the following conditions:

The patient requests to withdraw for various reasons after enrolling.

Cancellation of surgery or unexpected conversion to open surgery occurs.

Serious adverse events occur.

In the situation that any serious adverse events occur, or patient withdraw from the trial, patients will receive adequate treatments but the primary outcome will still be measured unless the patient refuses the data collection.

Randomisation and blinding

This study will employ a computer-generated random sequence using fixed blocks, each with a length of four. These blocks will be equally divided between group A (multimodal regimen: acustimulation+pharmacological prophylaxis) and group B (pharmacological regimen: sham stimulation+pharmacological prophylaxis), with the sequence arranged randomly. Participants will be assigned numbers sequentially based on the order of admission and will be allocated to these blocks accordingly.

To ensure allocation concealment, sealed opaque envelopes will be used. These envelopes will contain the group assignments and will only be opened by the recruitment personnel once the patient has provided signed informed consent, thus maintaining the integrity of the allocation process.

Blinding will be rigorously maintained for critical personnel to mitigate bias. Specifically, the surgeons, anaesthesiologists, outcome assessment staff and data analysts will be blinded to the assignments.

Protocol

Pretreatment assessment and the participant recruitment process

Patients scheduled to undergo elective laparoscopic abdominal surgery in our centre will be evaluated 1 day before or on the day of surgery, and patients who meet the inclusion criteria will be enrolled after signing an informed consent form. Those patients who participate in our study will be allocated into one of two groups: (A) multimodal regimen: PC6 electric stimulation plus combined ondansetron and dexamethasone and (B) pharmacological regimen: ondansetron and dexamethasone with sham acustimulation in a 1:1 ratio. The schedule of enrolment, interventions and assessment is shown in table 1, and figure 2 illustrates the trial flow chart.

Table 1 Assessment of patient characteristics and outcomes

	Preoperative	Intraoperative	PACU	6 hours	24 hours	48 hours	72 hours	30 days	
Enrolment									
Assessment of eligibility	O								
Informed consent	O								
Baseline assessment	O								
Randomisation	O								
BRS	O		O						
Intervention									
PC6 wristband stimulation	O	O	O						
Assessment									
Postoperative nausea and vomiting			O	O	O	O	O		
Haemodynamic assessment	O	O			O	O	O		
Pain intensity NRS			O	O	O	O	O		
Postoperative recovery assessment					O	O	O	O	
Postoperative complications					O	O	O	O	
Cost and length of hospital day								O	
Use of rescue medication (opoids and antiemetics)			O	O	O	O	O		
BRSbaroreflex sensitivityNRSNumeric Rating ScalePACUpostanaesthesia care unitPC6Pericardium 6

Figure 2 Trial flow chart. BP, blood pressure; BRS, baroreflex sensitivity; HR, heart rate; PONV, postoperative nausea and vomiting.

Baseline assessment

Basic patient information includes gender, age, height, weight, BMI, medical history, smoking and alcohol history.

ASA Physical Status Classification System.

Apfel Score.23

Whether patient has a history of chemotherapy-induced nausea and vomiting.

Preoperative assessment

Preoperative laboratory test: (A) Blood tests: white cell count, lymphocyte count, neutrophil count, platelet count, haemoglobin level, haematocrit and (B) Tests for liver and kidney function: serum potassium level, creatinine, urea, total bilirubin level, direct bilirubin level.

Preoperative baseline BP and heart rate (HR) will be measured after resting for at least 5 min.

Continual non-invasive BP will be measured for BRS assessment.

Anaesthetic management

To provide baseline PONV risk minimisation for our included patients as suggested by guidelines,18 patients will undergo anaesthesia induction using propofol, fentanyl, and rocuronium and avoid volatile anaesthetics and nitrous oxide. Target-controlled infusion of propofol will be used during the surgery with a target plasma concentration of 2.5–5 µg/mL while bispectral index will be maintained between 40 and 60. Total intravenous anaesthesia will be used for maintenance of anaesthesia. Fentanyl and rocuronium will be used at the discretion of anaesthesiologists with intraoperative opioid dosage being recorded. Multimodal anaesthesia incorporating non-opioid pain medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) and dexmedetomidine is recommended and is given at the discretion of attending anaesthesiologists. Adequate hydration will be recommended (15–30 mL/kg during perioperative period) based on evidence supporting enough perioperative volume can reduce PONV risk.24 Patient airway management will include oral tracheal intubation and a lung-protective ventilation strategy. Mechanical ventilation parameters include volume control mode or volume assurance-pressure control mode, tidal volume at 6–8 mL/kg predicted body weight, inspired oxygen concentration at 50% and suction platform pressure (Pplat)<30 cmH2O. Intraoperative assessment includes detailed records of surgery type, intraoperative position, antibiotic usage, nasogastric tube placement, respiratory parameters, dose and types of anaesthetic drugs usage, postoperative analgesia, intraoperative access and postanaesthesia care unit (PACU) status. In PACU, patient records will include an assessment of rescue analgesic and antiemetic use and whether any episodes of nausea and vomiting occur. Postoperative opioids in any form or dosage (patient-controlled analgesia, oral, intravenous, intramuscular) are recorded.

Routine combined pharmacological prophylaxis

Based on consensus guidelines on PONV prophylaxis,18considering the cost and adverse effects associated with pharmacological interventions, using two prophylaxis pharmacological interventions in adults at high risk (Apfel score 3) for PONV is recommended. Usable medication includes (1) 5HT3 receptor antagonists: ondansetron and dolasetron; (2) NK-1 receptor antagonist: aprepitant, casopitant and rolapitant; (3) corticosteroid: dexamethasone; (4) antidopaminergics: amisulpride and (5) antihistamine: meclizine. In our institution, ondansetron (4 mg intravenously) and dexamethasone, the best prophylaxis regimen for patients undergoing laparoscopic cholecystectomy,25 are routinely used as a combined therapy for PONV prophylaxis among high risk patients. A dose of 4–8 mg dexamethasone will be administered intravenously after routine anaesthesia induction while 4 mg ondansetron will be administered intravenously at the end of the operation.

Study interventions

The intervention group will receive percutaneous electrical acustimulation at PC6 acupoint, provided by a wearable device, the EmeTerm bracelet (WAT Medical Enterprise, Vancouver, BC, Canada) (figure 3). The device will be applied at the dominant upper extremity routinely. The device has five levels and we will gradually increase the intensity until the patient reports a tingling sensation, then the level right before the tingling sensation will be chosen. The optimal stimulation time point and duration are not clear right now, with various choices in different trials including preoperative,26 27 intraoperative,28 29 postoperative or combination.13 30 In our experiment, considering patient compliance and clinical feasibility, stimulation will start 30 min before surgery and stop right before patients are discharged from PACU. Sham acustimulation involves an inactivated acustimulation device prepared by inactivating the electrodes with a silicone cover in advance, whose appearance is completely same as the activated one. Therefore, the sham group wears the equipment but without any electric stimulation.

Figure 3 EmeTerm bracelet.

Outcomes

Primary outcomes

Incidence of nausea or/and vomiting within 24 hours after surgery, based on the follow-up record assessed by a researcher who is blinded to the allocation.

Secondary outcomes

Nausea and vomiting

The secondary outcomes to evaluate nausea and vomiting include:

The incidence of nausea 24 hours after surgery.

The incidence of vomiting 24 hours after surgery.

PONV Impact Scale.31

Nausea and vomiting within four different time windows: discharge from the recovery room within 6 hours, from 6 to 24 hours, from 24 to 48 hours and from 48 hours to 72 hours.

Physiological outcomes

Time to first flatus and time to first defecation are recorded for evaluation of gastrointestinal function, based on the follow-up record assessed by a researcher who does not know the allocation.

Explorative outcomes

Haemodynamic outcomes

To investigate the potential effects of acustimulation on the autonomic nervous system, we will document changes in BP, HR and BRS. BP and HR will be measured at baseline, as well as 24, 48 and 72 hours postsurgery. The changes in these parameters will be calculated by comparing postoperative values to baseline measures.

BRS will be assessed in two steps per protocol that has been previous published.32 Initially, continuous HR and beat-to-beat BP will be monitored using the LiDCO Rapid V3 (Masimo, USA) for 15 min with an ambient temperature of approximately 25℃ and constant lighting status in the ward during baseline assessments, and in the PACU after the surgery. All included patients will have been fasted for at least 8 hours before the test. Subsequently, Matlab program will be used to evaluate BRS from continuous pulse data. BRS corresponds to RR interval variation per mm Hg in reaction to variations in systolic BP (SBP), measured in milliseconds. The sequence method will be used to assess baroreflex function, identifying instances where both SBP and RR intervals escalate consistently over three or more successive beats.33 34 Thresholds for SBP and RR interval alterations will be set at 1 mm Hg and 6 ms, respectively. BRS will be calculated as the slope of regression line relating changes in SBP to changes in RR interval. The Baroreflex Efficiency Index (BEI) is defined as the proportion of SBP fluctuations effectively managed by HR, presenting as progressively increasing/decreasing with RR interval shifts.35 We define an increase in RR interval with escalating SBP as BRS+/BEI+ and a decrease as BRS−/BEI−.

Quality of life

Quality of life will be measured by 15-item quality of recovery scale at 1, 2, 3, 30 days after surgery to evaluate patients’ recovery.

Use of medication

Medication of patients during hospitalisation will be recorded in detail, including but not limited to, analgesics, antiemetic drugs, gastrointestinal motility drugs, sedative and hypnotic drugs.

Adverse events

Adverse events will be recorded, including mild pain, redness and itching on the skin on electrode surface.

Length of hospital stay and hospitalisation expenses

The length of hospital stay and hospitalisation expenses will be recorded by reviewing electronic medical record.

Sample size calculation

Assuming a significance level of α=0.05 (two sided) and a power of 1–β=0.8, previous studies have reported PONV incidence rates ranging from 20% to 80% in the general surgical population. Considering that this study focuses on a high-risk population for PONV, it is estimated that the pharmacological regimen group will have a PONV incidence rate of 35%36 while the combined group will experience an absolute decrease of 15%, resulting in a PONV incidence rate of 20%. Therefore, it is anticipated that 109 patients per group will be needed for the study with an additional 10% allowance for potential dropouts, bringing the anticipated total to 300 patients (151 patients per group).

Statistical data analysis

The statistical analysis will be based on the principle of intention-to-treat analysis. Descriptive analysis will be used to present the basic characteristics of the patients. The χ2 test will be used to compare the main outcome of the study, which is the difference in the incidence of PONV between the two groups. The analysis strategy for the binary secondary outcomes of nausea/vomiting incidence will be similar to the main outcome, with multiple comparation correction by Bonferroni method. The main and secondary binary outcomes will use the relative risk as the measure of effect size. Continuous variables, including BP, HR changes, BRS changes will be compared between groups using the t-test, and the mean difference will be used as the measure of effect size. Besides, time to first flatus and defecation will be compared between groups using survival analysis. The Mann-Whitney U test will be used to compare the hospitalisation costs and pain scores between groups, and the median difference based on the Hodges-Lehmann algorithm will be used as the measure of effect size. Cox regression model will be used to compare the length of hospital stay between groups after surgery, and the HR will be used as the measure of effect size. A difference with a bilateral p<0.05 will be considered statistically significant.

Ethics and dissemination

The study has been approved by the Ethics Committee of Peking Union Medical Hospital with approval number I-23PJ1712. The study has also been registered at clinical.gov with trial registration number NCT06241547. Participants will need to provide written informed consent. Any changes to the protocol will be reported and approved by the local institutional review board (IRB), and communicated with the trial registry, investigators and data monitoring committee. The trial outcomes will be published in peer-reviewed journals and scientific conferences. Additionally, summaries of the findings will be shared with participants and relevant healthcare professionals through newsletters. We will also engage with social media and institutional platforms to further disseminate the study outcomes to a wider audience.

Discussion

There is currently limited evidence to suggest that combining PC6 acustimulation with recommended combined pharmacological PONV prophylaxis antiemetic therapy can further reduce the incidence of PONV.1728 3741 This randomised controlled study aims to investigate if adding nerve electric stimulation through the EmeTerm bracelet to standard dual antiemetic pharmacological prophylaxis can further prevent PONV.

Strengths and limitations

However, our study has several limitations. One significant concern is the potential risk of compromising blinding. The tingling sensation caused by the activated device, but not by the sham, might inadvertently reveal group assignments to the participants or the staff setting up the equipment. Another limitation is the inclusion of only adult female participants, which restricts the generalisability of our findings to other populations, such as men or children. Additionally, the acustimulation treatment regimen varies widely in the published literature. Our trial does not encompass all variations of acustimulation, such as those involving longer durations or higher energy levels, and focuses solely on prophylaxis rather than treatment effects in cases where PONV has already occurred. Future research is needed to evaluate the efficacy and safety of electrical stimulation in these scenarios and to explore its potential benefits across different demographic groups.

Trial status

The trial is currently in the recruitment phase. The first patient was randomised on 12 January 2024. Currently, (as of 14 April 2024), 146 patients have been completely enrolled in the trial.

Review Process File
23 09 2024

Funding: This work is supported by the National High Level Hospital Clinical Research Funding (grant number 2022-PUMCH-B-006).

prepub: Prepublication history for this paper is available online. To view these files, please visit the journal online (https://doi.org/10.1136/bmjopen-2024-088633).

Patient consent for publication: Consent obtained directly from patient(s).

Provenance and peer review: Not commissioned; externally peer reviewed.

Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
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