Effect of transcutaneous auricular vagus nerve stimulation on postoperative sleep quality in older patients undergoing laparoscopic cholecystectomy: protocol for a prospective, randomised, double-blind, controlled trial

Abstract

Introduction

Postoperative sleep disturbances (PSDs) are highly prevalent in older surgical patients, leading to impaired recovery and increased complications. Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neuromodulation technique. This study aims to evaluate the efficacy of perioperative taVNS in reducing the incidence of PSD in older adults undergoing laparoscopic cholecystectomy (LC).

Methods and analysis

This is a single-centre, prospective, randomised, double-blind, sham-controlled trial. A total of 210 patients aged 66–79 years scheduled for elective LC will be enrolled. Participants will be randomly allocated (1:1) to receive either active taVNS (25 Hz, 200 μs pulse width, cyclic 30 s on/off) at the left cymba conchae or identical sham stimulation without electrical current. The intervention will be applied throughout the intraoperative period and repeated 30 min on postoperative day 1. The primary outcome is the incidence of PSD on postoperative day 2. Secondary outcomes include PSD incidence on postoperative days 1 and 3, anxiety and depression scores, postoperative pain and analgesic consumption, quality of recovery and adverse events.

Ethics and dissemination

The study protocol has been approved by the Ethics Committee of Ningbo No.2 Hospital (Approval No. PJ-NBEY-KY-2025-195-02). It is registered with the Chinese Clinical Trial Registry (Registration number: ChiCTR2500110972). Written informed consent will be obtained from all participants. The findings will be submitted for publication in a peer-reviewed journal.

Trial registration number

ChiCTR2500110972.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• This study is designed as a prospective, randomised, double-blind, sham-controlled trial to minimise selection and assessment bias.

• The intervention in this study specifically targets the intraoperative period during the acute inflammatory response phase and the first postoperative day, when sleep disturbances are most prevalent.

• The assessment of sleep disturbance relies on subjective scales and may be influenced by patient reporting bias.

• The short intervention period may not fully reflect the potential benefits of longer-term transcutaneous auricular vagus nerve stimulation.

Introduction

Postoperative sleep disturbances (PSDs), characterised by difficulties in falling asleep, frequent awakenings and poor sleep quality, are among the most common yet frequently overlooked complications following surgery.^1–3 Their incidence is exceptionally high in older surgical patients during the early postoperative period,^{4 5} due to their reduced physiological reserve and heightened vulnerability to surgical stress.^{6 7} The pathogenesis of PSD arises from a complex interplay among the hospital environmental disturbances, psychological factors, anaesthesia and surgical trauma-induced inflammation.⁸ PSD is not a benign inconvenience; it is an independent risk factor for a cascade of adverse outcomes, including exacerbated postoperative pain,^9–11 heightened risks of delirium^{12 13} and elevated cardiovascular risks,¹⁴ which delay recovery^{15 16} and further underscore its significance as a critical target for perioperative intervention.

Transcutaneous auricular vagus nerve stimulation (taVNS) represents a novel, non-invasive neuromodulation technique that delivers electrical stimulation to the auricular branch of the vagus nerve through the external ear,^{17 18} and it has already been applied in the treatment of refractory epilepsy and depression.^{19 20} Compared with implanted vagus nerve stimulation, taVNS is easier to administer, less expensive and more acceptable in routine clinical settings. Prior work indicates that vagal stimulation can influence autonomic regulation and central pathways involved in sleep modulation,^{21 22} thereby altering arousal state and promoting greater sleep stability and depth.²³ Its mechanisms include the inhibition of inflammatory cytokines^24–26 and the modulation of neurotransmitters.^27–29 These observations provide a biologically plausible basis for investigating taVNS as a perioperative intervention to improve sleep. However, most existing evidence has focused on chronic insomnia^{30 31} or other non-surgical conditions, and its role in PSD remains poorly characterised.

Older patients undergoing laparoscopic cholecystectomy (LC) represent a clinically relevant population in whom PSD may still occur despite the minimally invasive nature of the procedure. Patients with poor preoperative sleep quality may be at particularly high risk of PSD and therefore more likely to benefit from a sleep-targeted intervention. Identifying a safe, non-pharmacological strategy for improving postoperative sleep in this setting is particularly valuable, given concerns regarding sedative-related adverse effects in older adults.

The present study is therefore designed as a prospective, randomised, double-blind, controlled trial evaluating the effect of taVNS on postoperative sleep quality in older patients with poor preoperative sleep quality undergoing LC. Sleep during the early postoperative phase may be substantially influenced by residual anaesthetic effects, immediate analgesic use and acute environmental disruption. These transient perioperative influences are expected to be less dominant by postoperative day 2, while sleep disturbance remains common and clinically relevant. The primary outcome is therefore the incidence of PSD on postoperative day 2, with secondary outcomes including other recovery-related measures and safety outcomes.

Methods and analysis

Study design

This is a single-centre, prospective, randomised, double-blind, sham-controlled, parallel-group trial. The protocol has been developed in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines. The trial flow is summarised in figure 1. The scheduled process of enrolment, intervention and measurement is presented in table 1.

Figure 1. Participant flow diagram. taVNS, transcutaneous auricular vagus nerve stimulation.

Table 1. Summary of enrolment, intervention and assessment timelines.

Study period	Enrolment	Allocation	Intervention and assessment	Follow-up
Timepoint	Preoperative day (anaesthesia clinic)	Day of surgery (T0)	Postoperative day 1 (T1)	Postoperative day 2 (T2)	Postoperative day 3 (T3)
Enrolment
Eligibility screen	✕
Informed consent	✕
Assessments
Demographic data	✕
Medical history	✕
PSQI	✕
HADS	✕
Interventions
Randomisation		✕
Active taVNS / Sham Stimulation		✕(Session 1)	✕ (Session 2)
Outcomes
AIS, NRS			✕	✕	✕
HADS			✕	✕	✕
QoR-15			✕	✕	✕
Pain VAS and analgesic use			✕(24 hours)	✕(48 hours)
Adverse events		✕	✕	✕	✕

AIS, Athens Insomnia Scale; HADS, Hospital Anxiety and Depression Scale; NRS, Numeric Rating Scale; PSD, postoperative sleep disturbance; PSQI, Pittsburgh Sleep Quality Index; QoR-15, Quality of Recovery-15 scale; taVNS, transcutaneous auricular vagus nerve stimulation; VAS, Visual Analogue Scale.

Participants and recruitment

Elderly patients scheduled for elective LC under general anaesthesia at Ningbo No. 2 Hospital will be screened for eligibility. Potential participants will be identified and approached in the anaesthesia preoperative assessment clinic 1 day prior to surgery. The study procedures, potential risks and benefits will be explained in detail by a trained investigator. Written informed consent will be obtained from all participants before any study-related procedures are performed. An example consent form is provided as online supplemental material 1.

Eligibility criteria

Inclusion criteria

1. Aged 66–79 years.

2. American Society of Anesthesiologists (ASA) physical status I–III.

3. Preoperative Pittsburgh Sleep Quality Index (PSQI) global score >5, indicating pre-existing poor sleep quality.

4. Scheduled for LC with an anticipated operation duration of ≥30 min (from skin incision to closure).

5. Ability to provide informed consent and cooperate with the study assessments.

Exclusion criteria

1. The patient refused to participate in this study.

2. History of severe cardiovascular or cerebrovascular events (eg, myocardial infarction, stroke, transient ischaemic attack) within the preceding 3 months; implantable electronic devices in the body; New York Heart Association (NYHA) functional class > III; acute respiratory distress syndrome; or end-stage renal disease without regular dialysis.

3. Body mass index (BMI) ≥28 kg/m² or a known diagnosis of sleep apnoea syndrome.

4. History of drug abuse (long-term use of 30 mg of morphine per day or equivalent drugs).

5. History of chronic substance or alcohol abuse (defined as >14 standard units/week for men or >7 for women).

6. Regular use of sedative-hypnotic medications within 1 month before surgery.

7. Presence of conditions impairing communication or cognition (eg, significant hearing or visual loss, dementia, psychiatric disorders, use of psychotropic drugs).

Withdrawal and discontinuation criteria

1. The patient requests to withdraw from the study or discontinue follow-up.

2. Serious adverse events: clinical deterioration requiring admission to the intensive care unit or severe vagal reflex symptoms precluding further stimulation.

Randomisation and blinding

Eligible participants will be randomly allocated in a 1:1 ratio to the active taVNS group or the sham control group. The randomisation sequence will be computer-generated by an independent statistician using SAS V.9.4, employing block randomisation with varying block sizes to enhance concealment. Allocation will be concealed using sequentially numbered, opaque, sealed envelopes.

The trial will be double-blinded. Participants, the intraoperative and postoperative care teams and the outcome assessors will all be blinded to group assignment. Only the operator responsible for setting the device parameters will be unblinded; this operator will have no role in outcome assessment or clinical management. To maintain blinding, the stimulator device will be sealed in an opaque envelope after parameter setup. Participants in both groups will undergo the same initial sensation titration to enhance the blinding illusion. Should any participant report discomfort, the investigator will immediately conduct an examination to confirm the condition. Procedures for emergency unblinding and medical intervention in case of serious adverse events are established and will be thoroughly documented.

Intervention

Active taVNS group

Patients allocated to the active taVNS group will receive transcutaneous electrical stimulation at the left cymba conchae, a region densely innervated by the auricular branch of the vagus nerve. A commercial taVNS device (tVNS501, RISHENA) will be used. The stimulation parameters are set as follows: a frequency of 25 Hz, a pulse width of 200 μs, delivered in cyclic mode (30 s on, 30 s off). The stimulation intensity will be individually titrated: starting from 0.4 V, it will be increased in 0.4 V steps until the patient reports a distinct but comfortable tingling sensation; it is then set at the highest level tolerable without pain. The first stimulation session will be administered throughout the intraoperative period, commencing with the skin incision and concluding on wound closure. A second identical 30-minute session will be administered the following morning on postoperative day 1 in the ward.

Sham control group

Patients in the sham control group will undergo an identical procedure, including the placement of electrodes at the left cymba conchae and the same individualised intensity titration process. However, the stimulator will be programmed to deliver no electrical current after the titration phase. The device will be placed and run for the same duration (throughout the intraoperative period from skin incision to closure and 30 min on postoperative day 1) to ensure the blinding is maintained. Both groups will receive standardised anaesthetic and postoperative care as described below.

Standardised anaesthetic and perioperative management

A standardised anaesthetic protocol will be implemented for all participants. Monitoring will include ECG, pulse oximetry, non-invasive blood pressure, core temperature and bispectral index (BIS). Anaesthesia will be induced intravenously with sufentanil (0.3–0.5 µg/kg), propofol (1–2 mg/kg) and rocuronium (0.6–0.8 mg/kg) after preoxygenation. Tracheal intubation will be performed, and mechanical ventilation will be maintained in volume-control mode to keep end-tidal carbon dioxide between 35 and 45 mm Hg. Anaesthesia will be maintained with sevoflurane (1–2% end-tidal concentration) and a continuous infusion of remifentanil (0.1–0.2 µg/kg/min), titrated to maintain BIS between 40 and 60. Rocuronium bromide will be administered as needed during surgery. Haemodynamic stability will be maintained within ±20% of baseline values using vasoactive agents as needed. Active warming will be applied to maintain core temperature ≥36°C. At the end of surgery, parecoxib sodium (40 mg IV) and ondansetron (8 mg IV) will be administered for analgesia and antiemesis, respectively. Neuromuscular blockade will be reversed with sugammadex. Postoperative pain will be managed with intravenous tramadol (50 mg) as rescue analgesia if the patient’s pain score (Visual Analogue Scale, VAS) exceeds 4.

Outcome measures

Primary outcome

The primary outcome is the incidence of PSD on postoperative day 2, when all interventions are completed. PSD is defined as an Athens Insomnia Scale (AIS) score ≥6 or a Numeric Rating Scale (NRS) for sleep score ≥6; higher scores indicate worse sleep disturbance.^{32 33}

Secondary outcomes

1. Incidence of PSD on postoperative days 1 and 3.

2. Anxiety and depression scores, assessed using the Hospital Anxiety and Depression Scale (HADS) on postoperative days 1, 2 and 3.

3. Postoperative pain intensity at rest and during movement, measured using the VAS at 24 and 48 hours postoperatively, and total consumption of rescue analgesics.

4. Quality of recovery, assessed using the Quality of Recovery-15 (QoR-15) scale on postoperative days 1, 2 and 3.

5. Incidence of adverse events and complications related to taVNS or the surgical procedure.

Sample size

The sample size was calculated based on the primary outcome. Assuming a PSD incidence of 60%^{4 5 32} in the control group from previous literature, we aimed to detect a 20% absolute reduction (to 40%) in the taVNS group. Using Power Analysis and Sample Size (PASS) 2021 software for a two-sided test with an alpha of 0.05 and 80% power, a minimum of 95 participants per group was required. Accounting for an estimated 10% dropout rate, the final sample size was set at 210 participants (105 per group).

Statistical analysis

Data will be collected prospectively through face-to-face interviews, medical record review and direct observation, recorded on paper-based case report forms, and then entered into the electronic data capture system. The scientific research management department of our institution will oversee the entire trial and receive annual progress reports. An independent investigator will monitor trial data integrity and adverse events, and patient-reported outcomes will be assessed for completeness and consistency, with subjective content validation excluded.

Statistical analyses will be performed using GraphPad Prism V.9.0 and SPSS software (V.26.0). The primary analysis will follow the intention-to-treat (ITT) principle, participants who are withdrawn or discontinued from the study but have post-baseline data available will remain in the ITT analysis. A supporting per-protocol analysis will also be conducted as a sensitivity analysis. The primary analysis of the primary outcome will be unadjusted. A supportive regression analysis will also adjust for prespecified clinically relevant baseline covariates selected a priori (eg, age, sex, ASA, baseline PSQI score), irrespective of any observed post-randomisation imbalances. For the primary outcome (incidence of PSD), between-group comparisons will be performed using logistic regression to estimate ORs and 95% CIs. Relative risks with 95% CIs will also be estimated and reported as supplementary effect measures to support clinical interpretation. Continuous normally distributed data will be presented as the mean±SD and compared using the independent-samples t-test. Non-normally distributed data will be presented as median (IQR) and compared using the Mann-Whitney U test. Categorical data will be expressed as numbers (percentages) and compared using the χ² test or Fisher’s exact test, as appropriate. For repeated-measures data (eg, HADS, QoR-15 scores over time), a linear mixed-effects model will be employed. Missing data for the primary outcome will be handled using multiple imputation for the ITT analysis. Exploratory subgroup analyses are planned for the primary outcome based on sex, age (<75 vs ≥75 years), ASA (≤II vs III) and baseline PSQI score (median split). The interaction between treatment and subgroup will be tested within the regression model. A two-sided p value<0.05 will be considered statistically significant.

Ethics and dissemination

This study protocol was approved by the Ethics Committee of Ningbo No. 2 Hospital (Approval No. PJ-NBEY-KY-2025-195-02) and is registered with the Chinese Clinical Trial Registry (Registration number: ChiCTR2500110972). The trial will be conducted in accordance with the Declaration of Helsinki. Written informed consent will be obtained from all participants or their legal representatives. The research findings will be submitted for publication in a peer-reviewed journal.

Patient and public involvement statement

Patients or the public were not involved in the design, conduct or reporting of this research. However, preliminary discussions with patients informed our focus on postoperative sleep quality as a key outcome of concern to them.

Data sharing statement

Individual participant data will not be disclosed, as ethics and consent restrictions allow their use only for the primary analysis and do not permit secondary use or external sharing. The study protocol and statistical analysis plan are available from the corresponding author upon reasonable request. Aggregate results will be reported in the primary publication.

Generative AI statement

No artificial intelligence (AI) tools were used in the conception, design or drafting of this study protocol. The authors assume full responsibility for all aspects of the work.

Discussion

This prospective, randomised, double-blind, sham-controlled trial is designed to evaluate the efficacy of perioperative taVNS in preventing PSD in elderly patients undergoing LC, thus yielding secondary benefits such as improvements in emotional state and pain level, ultimately accelerating recovery. Given the high prevalence and clinical relevance of PSD, a safe, non-invasive intervention would be clinically valuable should its effectiveness be confirmed.

Numerous studies have shown that taVNS improves neurological function and alleviates chronic insomnia.^34–36 Although chronic insomnia often requires weeks of taVNS treatment, our intervention was limited to the intraoperative period and the first postoperative day, targeting the critical perioperative window of heightened vulnerability. In this case, taVNS suppresses inflammatory cytokine production^{37 38} during surgery and regulates sleep-wake centres on the first postoperative day, when inflammation peaks and circadian rhythms are most severely disrupted.^{33 39} Other researchers have reported the beneficial effects of perioperative taVNS on postoperative pain^40–42 and cognition,^{43 44} we therefore anticipate that taVNS will exert a beneficial effect on postoperative sleep of the same magnitude.

Nevertheless, several limitations must be acknowledged. First, as a single-centre study focusing exclusively on older patients with poor baseline sleep quality who have not received pharmacological treatment, the generalisability of our findings may be limited. Second, the short duration of the taVNS intervention may not fully capture the potential benefits of a prolonged stimulation regimen. Furthermore, the sole reliance on subjective sleep scales, without objective validation from actigraphy or polysomnography limits the physiological interpretation of our results.

In conclusion, this trial will provide high-quality evidence regarding the efficacy and safety of taVNS as a novel, non-invasive strategy for preventing PSD in elderly surgical patients.