Transauricular vagus nerve stimulation in preventing post-traumatic stress disorder in emergency trauma surgery patients in China: a study protocol for a multicenter, double-blind, randomised, controlled trial

Abstract

Introduction

The incidence of post-traumatic stress disorder (PTSD) in emergency trauma surgery patients is 24%, emphasising the urgent need for effective early interventions and treatments. Transauricular vagus nerve stimulation (ta-VNS) modulates the autonomic nervous system by stimulating the nucleus tractus solitarius while affecting PTSD-related neural networks, including the prefrontal cortex, hippocampus and amygdala, potentially offering new options for PTSD prevention and treatment. This study aims to evaluate the efficacy and safety of ta-VNS in preventing PTSD in emergency trauma surgery patients.

Methods and analysis

This multicentre, double-blind, randomised controlled study aims to evaluate the incidence of PTSD in emergency trauma surgery patients receiving either ta-VNS or sham stimulation. A total of 350 participants will be randomly assigned to receive either active or sham stimulation. The active group will undergo electrical stimulation of the left cymba conchae at 30 Hz with a pulse width of 250 µs, using a 30 s on/30 s off cycle. The intensity will start at 0.4 V, increasing in 0.4 V increments until a tingling sensation is detected, and will be adjusted to the highest tolerable level without causing pain. The initial intervention will begin once informed consent is obtained and randomisation is completed in the preoperative preparation room, continuing until the surgery is finished. For the four postoperative days, the intervention will be administered two times per day in 2-h sessions each morning and evening. The sham stimulation group will follow a similar procedure without actual stimulation. The primary outcome is the incidence of PTSD evaluated on postoperative day 30, with secondary outcomes including recovery quality, sleep quality, and adverse events.

Ethics and dissemination

The protocol received approval from Sir Run Run Shaw Hospital, affiliated with Zhejiang University School of Medicine, on 15 October 2024 (approval number: 20240562). The study will adhere to the Declaration of Helsinki guidelines, and written informed consent will be obtained from all participants. Results will be submitted to a peer-reviewed journal for publication.

Trial registration number

China Clinical Trial Registration Center (ChiCTR2400080342). Trial details: https://www.chictr.org.cn/showproj.html?proj=217809

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• The study will recruit emergency trauma surgery patients from multiple hospitals and regions, enhancing sample representativeness and generalisability of the results.

• This study will employ rigorous randomisation, blinding and evaluation methods.

• The effectiveness of transauricular vagus nerve stimulation (ta-VNS) may be affected by patient adherence, which can be lower in emergency trauma patients.

• The complex and unpredictable environment of emergency trauma surgery patients may introduce variables that impact the evaluation of the intervention’s effectiveness.

Introduction

Globally, more than 70% of adults have experienced a traumatic event at some point in their lives, with 31% having encountered four or more such events.¹ Notably, road injuries accounted for 14.0% of these traumatic events and were the leading cause of disability-adjusted life years (DALYs) in the 10–49 age group.^{1 2} Post-traumatic stress disorder (PTSD) is a common mental health condition triggered by traumatic events, characterised by persistent and intense avoidance responses related to the trauma, changes in cognition and emotions, a pervasive sense of threat, sleep disturbances and hypervigilance.³ These symptoms can last for years or even decades, severely disrupting daily life and social activities.^{4 5} Recently, the global incidence of PTSD has increased to 10%–22% due to frequent road injuries, natural disasters, wars and terrorist attacks.⁶,⁸ In the USA, PTSD prevalence is 6%–8% in the general population, but 13%–35% among veterans, refugees and assault victims.^{9 10} Moreover, the incidence of PTSD following hospitalisation for trauma can be as high as 24%.^{11 12} PTSD is challenging to manage and is associated with an increased risk of suicide, placing a significant burden on families and society.¹³ Despite various treatments, including trauma-focused cognitive behavioural therapy (CBT), medication, transcranial magnetic stimulation and early CBT, individual responses vary widely, and non-response rates remain high.⁷ Consequently, exploring new intervention methods has become a key focus in PTSD research.

Peripheral biological factors related to PTSD include genetics,¹⁴ epigenetic regulation,¹⁵ neuroendocrine factors,¹⁶ inflammatory markers,^{17 18} autonomic nervous system (ANS) dysfunction¹⁹ and sleep disturbances.²⁰ Some characteristics, such as FKBP5 gene polymorphisms²¹ and ANS dysfunction,¹⁹ are susceptibility factors present before exposure, while others, like immune system changes, neuroinflammation and post-exposure epigenetic regulation, reflect trauma-induced alterations. Researches have indicated a close link between PTSD and changes in the immune and inflammatory system.²²,²⁵ Compared with healthy controls, PTSD patients have been found to exhibit significantly higher levels of pro-inflammatory factors, such as interleukin (IL)-1β, IL-6, tumour necrosis factor (TNF)-α and C-reactive protein.³²⁶,³² Inflammation is linked to PTSD and may play a crucial role in its pathogenesis and pathophysiology.

Vagus nerve stimulation (VNS) is a widely used method for regulating the ANS and may offer new avenues for preventing and treating PTSD.¹⁹ VNS reduces inflammation through the cholinergic anti-inflammatory pathway by promoting the release of acetylcholine (ACh) .³³,³⁵ Peripherally, it stimulates T lymphocytes in the spleen and cholinergic neurons in the intestinal muscularis to release ACh, modulating the intensity of the inflammatory response.³⁶,³⁸ Centrally, ACh acts on α7-acetylcholine nicotinic receptors (α7-nAChR) on microglia and astrocytes to limit neuroinflammation.³⁹,⁴¹ Studies have shown that transauricular vagus nerve stimulation (ta-VNS) can reduce neuroinflammatory responses³⁹,⁴¹ and activate the nucleus tractus solitarius, affecting PTSD-related neural networks such as the prefrontal cortex, hippocampus and amygdala,^{42 43} impacting emotion regulation and fear learning and memory processes.⁴⁴ Prolonged exposure (PE) and cognitive processing therapy (CPT) are primary treatments for PTSD, widely endorsed by the US Department of Veterans Affairs.^{45 46} VNS can enhance the effects of PE, normalise hypersensitivity and improve PTSD symptoms.⁴⁷ Animal studies indicate that VNS combined with extinction training enhances the extinction of conditioned fear.⁴⁷ Choudhary et al found that VNS can improve attention, declarative memory and working memory in PTSD patients, thereby enhancing their quality of life and occupational performance.⁴⁸ Thus, ta-VNS, as an emerging neuromodulation technology, shows promise for treating PTSD.

Building on this foundation, we hypothesise that early ta-VNS in patients undergoing emergency trauma surgery may reduce the incidence of PTSD. To test this hypothesis, we will conduct a multicenter, double-blind, randomised controlled trial to assess the efficacy and safety of perioperative ta-VNS in preventing PTSD.

Research design and methods

Participants

This study will be conducted at Zhejiang University School of Medicine Affiliated Sir Run Run Shaw Hospital and several major hospitals across the country. These centres will collaborate to recruit emergency trauma surgery patients from various regions, ensuring a representative sample. Recruitment will commence on 20 December 2024 and continue until 31 January 2026. The multicentre approach aims to deliver broadly applicable results on the effectiveness of early ta-VNS intervention in reducing PTSD. All centres will adhere to a standardised protocol to ensure data consistency and reliability (figure 1).

Figure 1. Participant recruitment, allocation and flowchart. tPTSD, post-traumatic stress disorder; a-VNS, transauricular vagus nerve stimulation.

Inclusion criteria

1. Aged 18–60 years.

2. Trauma patients (eg, from car accidents, falls or industrial accidents) requiring emergency surgery at multiple centres, including Sir Run Run Shaw Hospital affiliated with Zhejiang University School of Medicine.

3. American Society of Anesthesiologists (ASA) physical status classification of I E–III E.

4. Expected surgical duration of more than 2 hours and anticipated hospital stay of more than 3 days.

5. Capable of understanding the study process and various assessment scales and able to communicate effectively with research staff.

6. Willingness to participate in the study and provide informed consent.

Exclusion criteria

1. Presence of visual or auditory impairments.

2. History of substance abuse, including opioids.

3. Patients unable to cooperate with assessments.

4. Severe conditions such as brain or spinal cord injuries and uncompensated haemorrhagic shock.

5. Patients pre-existing with mental illnesses, sleep disorders or the use of psychotropic medications; cognitive impairments; critically ill patients (patients on the brink of death or with unstable vital signs identified as unsuitable for participation in this study); minors; and pregnant women.

Randomisation and blinding

In this study, trauma time is defined as the period from the emergency call to anaesthesia induction.¹² Trauma severity is assessed using the Acute Physiology and Chronic Health Evaluation II and the Injury Severity Score, which also help screen patients according to the inclusion and exclusion criteria. After receiving an emergency call confirming the need for urgent surgery, researchers will go to the emergency centre to assess patients and provide detailed information about the study to eligible patients and their families. After obtaining the consent of the patient or their authorised representative, an informed consent form will be signed (Supplementary material). Information of eligible patients such as medical records and measurement results will be entered into the electronic data capture (EDC) system and reviewed by staff at the coordinating centre, who will review item-by-item inclusion and exclusion criteria and queries will be sent to study staff at study sites if confirmations are needed regarding participant eligibility. After eligibility is confirmed at the coordinating centre, the EDC will generate a randomisation number, and the participant will be assigned to either treatment groups. The randomisation will be conducted on stratification of study sites. At each study site, block randomisation will be used with randomly selected block sizes of 4. Study investigators at each study sites will be informed of the assignment of specific participants via the EDC system and a baseline visit will be followed.

The study will employ a double-blind design, where only the personnel administering ta-VNS will be aware of the group assignments. Anaesthesiologists, surgeons, outcome assessors, statisticians and patients will remain unaware of which treatment group the patients belong to.

Intervention

The active stimulation group will receive electrical stimulation to the left cymba conchae at a frequency of 30 Hz and a pulse width of 250 µs, with a 30 s on/30 s off cycle. The intensity will start at 0.4 V and will be increased in 0.4 V increments until a tingling sensation is felt, then adjusted to a pain-free level. Eligible patients will receive standardised monitoring (non-invasive blood pressure, ECG, pulse oximeter) on arrival at the operating room, and begin the first stimulation, which will continue until the end of the surgery. Postoperatively, on days 1 through 4, stimulation will be administered for 2 hours each morning and evening. Similarly, the intensity of stimulation received by sham group will gradually increase until a tingling sensation is felt and then adjust to the painless level. Turn off the stimulator, and the left cymba conchae will remain in the carrying state. Participants will be informed that they may or may not feel any sensation.

All patients will follow a standardised anaesthesia protocol. Intraoperative monitoring will include non-invasive blood pressure, ECG, pulse oximetry, entropy, radial artery pressure and temperature. Pre-oxygenation at a flow rate of 6 L/min will be provided for 3 min before induction with propofol, sufentanil and rocuronium. Endotracheal intubation will be performed after 3 min of mask-assisted ventilation using a video laryngoscope. Mechanical ventilation settings will include a tidal volume of 6–8 mL/kg, a respiratory rate of 12–16 breaths per minute, an inspiratory to expiratory ratio of 1:1.5–2, an FiO2 of 50%, a flow rate of 2 L/min and positive end-expiratory pressure (PEEP) of 5 cmH2O. Maintenance anaesthesia will be provided with sevoflurane, propofol, remifentanil and intermittent doses of rocuronium. Blood pressure and heart rate will be maintained within 20% of baseline values, with phenylephrine 6 mg and urapidil 5–15 mg administered as needed. Ventilation settings will aim to keep PetCO2 between 35 and 45 mm Hg, and entropy values will be maintained within the range of 40–60.

After surgery, a standardised patient-controlled intravenous analgesia pump will be used. Sufentanil, 250 µg, will be diluted with normal saline to a total volume of 250 mL. The pump will deliver a background dose of 1 mL/h, a bolus dose of 2 mL, with a lockout interval of 5 min and a maximum limit of 12 mL per hour.

Primary outcome

Incidence of 1 month post-traumatic stress disorder (PTSD)

The incidence of PTSD will be assessed 1 month after surgery using the Clinician-Administered PTSD Scale for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (CAPS-5). The CAPS-5 scores will determine the severity of PTSD. The CAPS‐5 is a structured diagnostic interview and the gold standard for assessing the DSM‐5 symptoms of PTSD. The scale also assesses social and occupational functioning, dissociation symptoms and the validity of symptom reports. The CAPS-5 provides a continuous measure of the severity of overall PTSD and of the four symptom clusters (intrusions, avoidance, negative alterations in cognition or mood, and arousal and reactivity) and the presence or absence of PTSD diagnosis, which can be administered by appropriately trained paraprofessionals.⁴⁹ The diagnosis requirement can be summarised as an exposure to a stressor that is accompanied by at least one intrusion symptom, one avoidance symptom, two negative alterations in cognitions and mood symptoms, and two arousal and reactivity turbulence symptoms, persisting for at least 1 month, with functional impairment.⁵⁰ Two diagnostic evaluations will be conducted in a quiet setting by specially trained physicians who are blinded to the treatment group. Patients diagnosed with PTSD will be referred to the psychiatric department for further evaluation and treatment.

Secondary outcomes

Incidence of 6 months post-traumatic stress disorder (PTSD)

The incidence of PTSD will be assessed 6 months after surgery using the CAPS-5. Also, the severity of PTSD will be recorded.

Sleep quality

This study will assess patients’ nocturnal sleep using the Richards-Campbell Sleep Questionnaire preoperatively and on postoperative days 1, 2 and 3. The questionnaire evaluates sleep depth, difficulty falling asleep, frequency of awakenings, challenges in returning to sleep and overall sleep quality. Scores range from 0 to 25 (very poor), 26–50 (poor), 51–75 (good) to 76–99 (excellent), providing a detailed measure of sleep quality.

Postoperative recovery quality

The Quality of Recovery-15 scale will assess postoperative recovery over three consecutive days using 15 items that evaluate comfort, emotional state, self-care ability, psychological support and pain. Scores are classified as follows: 0–30 (very poor recovery), 31–45 (poor recovery), 46–60 (fair recovery), 61–75 (good recovery) and 76–90 (excellent recovery).

Adverse events

During the ‘ta-VNS’ procedure, any adverse events, such as ear pain, skin irritation, arrhythmia, nausea, stomach discomfort and headache, will be carefully recorded and reported. By systematically documenting and analysing these events, the research team will gain a thorough understanding of potential side effects and will promptly implement any necessary interventions to ensure participant safety and adherence to research protocols.

Sample size estimation

The sample size calculation is based on a postoperative PTSD incidence of 24%¹² and a clinically significant reduction to 12%. Using a significance level (α) of 0.05, a power (1-β) of 0.8 and a two-sided test, G*Power software (V.3.1.9.7) determines that 321 participants are needed. To account for a 10% dropout rate, the study will enrol 350 patients, with 175 patients in each group.

Data management

To ensure data integrity and accuracy while providing a secure and efficient method for data management, this study will use electronic case report forms integrated into an EDC system developed by DAP Software (Beijing) Co. Ltd. This system will centrally manage and store data from all centres, ensuring its security and precision. Researchers and data monitors will have real-time access to the data, allowing them to quickly identify and address any issues, thereby improving research efficiency and data quality.

The paper case report form (CRF) will be used to systematically record participants' basic information, treatment processes and data collection. As a physical backup, the paper CRF will ensure data are preserved in case of electronic system failures and will facilitate future reference or review. The paper CRF will be stored in a locked file cabinet, accessible only to authorised personnel, and equipped with a security monitoring system to ensure data protection.

Statistical analysis

All statistical analyses will be performed using IBM SPSS Statistics V.22. Continuous variables will be tested for normality. If the data are normally distributed, they will be reported as mean (SD) and compared using the t-test. If the data are not normally distributed, they will be reported as median (25th to 75th percentiles) and compared using the Mann-Whitney U test. Categorical variables will be reported as counts (n) and percentages (%) and analysed using the χ² test or Fisher’s exact test. A two-sided p value of less than 0.05 will be considered statistically significant.

We will first perform a per-protocol analysis, focusing on participants who complete the full stimulation protocol as planned. This will help us assess the intervention’s efficacy under ideal conditions. Following that, we will conduct an intention-to-treat analysis, including all randomised patients regardless of protocol completion. This approach provides a more comprehensive evaluation of the intervention’s effectiveness, reflecting real-world scenarios and accounting for adherence issues while preserving the benefits of randomisation.

Ethics and dissemination

The study received approval from Sir Run Run Shaw Hospital Affiliated with Zhejiang University School of Medicine on 9 January 2024 (approval number: 20240015). It will be conducted in accordance with the Declaration of Helsinki guidelines, with written informed consent obtained from all participants. Results will be submitted to a peer-reviewed journal. Additionally, the trial was registered with the China Clinical Trial Registration Centre on 26 January 2024 (registration number: ChiCTR2400080342).