Effect of bupivacaine combined with morphine intrathecal injection on postoperative recovery quality in patients undergoing pulmonary surgery: a study protocol for a multicentre, randomised, double-blind, controlled trial

Abstract

Introduction

Acute pain following pulmonary surgery can affect the recovery process of patients. The use of intrathecal morphine (ITM) injections offers a long-lasting analgesic effect, but its clinical application remains controversial. This study aims to investigate the impact of combining bupivacaine with ITM injections on the quality of postoperative recovery in patients who have undergone pulmonary surgery.

Methods and design

This multicentre, randomised, double-blind, controlled trial will enrol 254 patients undergoing elective lung surgery, who will be randomly assigned in a 1:1 ratio to either group IT (receiving an intrathecal injection of 3 mg bupivacaine and 0.25 mg morphine before general anaesthesia induction) or the control group (C group). The primary outcome includes postoperative recovery quality on day 1 (quality of recovery, QoR-15), with secondary outcomes encompassing postoperative recovery quality on days 2 and 3 (QoR-15), pain scores within 72 hours postoperatively, analgesic rescue, intraoperative haemodynamic parameters, opioid consumption, postoperative adverse reactions, recovery metrics, complications, chronic pain incidence and sleep quality.

Ethics and dissemination

The results will be disseminated through peer-reviewed publications. This study protocol (V.2.0, 30 October 2024) involves human participants and has been approved by the Ethics Committee of Affiliated Hospital of Yangzhou University (number 2024-08-02-2), Taicang Hospital Affiliated to Soochow University (number 2025 SR-041) and Yichang Central People’s Hospital (number 2024-513-02). Each individual who agrees to participate in the research will provide written informed consent after the objectives and procedures of this study are explained to them.

Trial registration number

ChiCTR2400092935. Registered on 26 November 2024.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• This is a multicentre, randomised controlled clinical study.

• Pain relief is administered via an intrathecal injection of 3 mg of bupivacaine and 0.25 mg of morphine.

• The QoR-15 will be used as the primary outcome measure in this study.

• The study will exclude elderly patients.

• Since multiple doses of morphine will not be set up for comparison, the optimal dose of intrathecal morphine cannot be recommended.

Background

Early postoperative pain in lung surgery patients restricts deep breathing and coughing for sputum clearance, which hinders early recovery and increases the risk of chronic pain.1,3 Patient-controlled intravenous analgesia is associated with opioid-related adverse reactions.⁴ Epidural block has complications such as hypotension and nerve damage.⁵ Ultrasound-guided nerve block technique is associated with the potential issue of rebound pain.⁶ Intrathecal morphine (ITM) exerts analgesic effects by directly acting on central μ receptors through CSF circulation.⁷ Due to the hydrophilic nature of morphine, spinal capillary absorption is minimal, enabling satisfactory analgesia with low-dose intrathecal administration.⁸ Additionally, the prolonged retention of morphine in CSF allows analgesia effects to last 24–48 hours per injection.⁹

First reported in 1979, ITM shows dose-dependent analgesia, with adverse effects including respiratory depression and pruritus.^{10 11} 5 µg/kg ITM during minimally invasive cardiac surgery significantly reduced postoperative pain within 48 hours without adverse reactions.¹² Calculating morphine dosage per unit weight complicates administration and makes precise preparation difficult. Studies have reported ITM doses ranging from 0.1 to 4 mg.¹³ Doses of 0.2–0.4 mg were effective in postoperative analgesia for major abdominal surgeries without respiratory depression.^{14 15} Recent studies in abdominal and cardiac surgeries indicated that both 0.3 and 0.25 mg morphine regimens provided effective analgesia with good safety profiles.^{16 17} Consequently, this study adopted 0.25 mg for ITM.

However, recent findings indicate that non-dose-dependent ITM significantly increases the incidence of postoperative nausea, vomiting, pruritus and urinary retention.¹⁸ Given the significant analgesic effects and uncertainties regarding postoperative complications, we will evaluate the impact of ITM on the quality of postoperative recovery in lung surgery. Nevertheless, the peak effect of ITM administration occurs 6 hours after injection, which is insufficient to meet intraoperative needs.¹⁹ Previous studies have shown that a combination of 5 µg/kg morphine and 3 mg bupivacaine administered intrathecally can effectively relieve perioperative acute pain in thoracoscopic surgery patients.²⁰

To address this issue, we designed a multicentre, large-sample randomised controlled trial (RCT) to evaluate the impact of 0.25 mg morphine combined with 3 mg bupivacaine intrathecal injection (IT group) on the quality of postoperative recovery in lung surgery patients. This study aims to fill a research gap by using quality of recovery (QoR-15) as the primary outcome measure. We hypothesised that the IT group could improve the QoR from lung surgery and designed this RCT to evaluate its therapeutic potential compared with the control group (C group).

Methods and design

Study design

This multicentre, prospective, subject-blinded and assessor-blinded RCT will be conducted at the following three hospitals: Affiliated Hospital of Yangzhou University, Taicang Hospital Affiliated to Soochow University and Yichang Central People’s Hospital. The study aims to recruit 254 subjects and randomly assign them in a 1:1 ratio to either the IT or C group using a simple randomisation method. The protocol has received ethical approval and has been registered on chictr.org.cn (Registration Number: ChiCTR2400092935). The study is scheduled to start and finish between 1 August 2024 and 31 March 2026. The SPIRIT 2013 Statement has been followed to explain the minimum key items of the trial protocol (online supplemental file 1).²¹ Figure 1 shows the flow chart of the trial, and table 1 (online supplemental file 2) shows the schedule of subject recruitment, intervention and outcome assessment.

Figure 1. Study flow diagram. Group IT, intrathecal injection of 3 mg bupivacaine combined with 0.25 mg morphine; group C, control group (press the body surface at the L2-3 interspace in the lateral decubitus position without performing subarachnoid puncture). IT: intrathecal.

Subject recruitment

Patients scheduled for pulmonary surgery will be informed of the trial protocol before the procedure, and those who are not interested in participating will be excluded. Postoperative patients who meet the inclusion and exclusion criteria will be asked to voluntarily sign an informed consent form (online supplemental file 3). Those willing to participate in the study before randomisation will be enrolled.

Eligibility criteria

Inclusion criteria

1. Patients scheduled for elective pulmonary surgery.

2. Aged 18–65 years, regardless of gender.

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

4. Body mass index (BMI) 18.5–30 kg/m².

5. Planned postoperative hospital stay ≥48 hours.

6. Clearly understand and voluntarily participate in this study, with informed consent signed by the patient or their family member.

Exclusion criteria

1. Patients with severe preoperative cardiac, hepatic or renal dysfunction.

2. Long-term users of analgesics, sedatives or alcohol.

3. Contraindications for intraspinal puncture.

4. A history of severe cerebrovascular disease, Alzheimer’s disease, epilepsy, Parkinson’s disease or other neuropsychiatric disorders.

5. A history of previous intracranial surgery or craniocerebral injury.

6. Severe visual, auditory or speech impairments, or those unable to communicate for other reasons.

7. Patients with severe cognitive impairment [as indicated by a score of 17 or lower on the Chinese version of the Mini-Mental State Examination (MMSE)].

8. Allergy or contraindication to morphine, local anaesthetics or non-steroidal anti-inflammatory drugs.

Elimination criteria

1. Patients requiring reoperation during the observation period.

2. Patients who experienced failed spinal canal anaesthesia procedures.

3. Patients or their legal representatives requesting withdrawal from the study at any stage and for any reason during the observation period.

Termination criteria for the study

1. Discovery of unexpected, significant or unacceptable risks to patients.

2. Identification of major flaws in the study protocol during execution.

3. The research technology or continuation of the study is deemed meaningless.

4. Completion of the trial appears extremely difficult due to reasons such as severe lag in subject enrolment or frequent protocol deviations.

Random allocation

After informing the patient, signing the consent form and validating the inclusion and exclusion criteria, eligible patients may be randomised (1:1) into the study between the IT group and the C group.

The Research Manager (ResMan, http://www.medresman.org.cn/) is an internet-based public platform designed to achieve standardised data management for clinical trials. It offers comprehensive functionalities, such as centralised randomisation and data management, available at no cost. Our internal use will incorporate the integrated randomisation system within this platform, allowing researchers at each clinical study branch centre to efficiently generate randomised allocations at a 1:1 ratio. The patient will be randomly assigned to a group by the anaesthesiologist who is responsible for performing the intervention on the day of surgery.

Blinding

This study will blind the anaesthesiologists who administer general anaesthesia in the operating room, as well as the follow-up researchers and subjects. A skilled anaesthesiologist, proficient in intravertebral anaesthesia, will conduct the interventional procedures in accordance with the grouping (this physician will not be blinded and will be solely responsible for the intervention, not participating in other aspects of the research). Another anaesthesiologist (who will be blinded) will enter the operating room to administer general anaesthesia after the intervention has been completed. Patients in the IT group will undergo a subarachnoid puncture intervention, whereas patients in the C group, despite not receiving neuraxial puncture, will still be positioned laterally and undergo a simulated puncture by applying pressure to the L2-3 interspace on the body surface.

Due to the pharmacological effects of bupivacaine, the anaesthesiologist administering general anaesthesia may unintentionally infer the group allocation based on the dosage of analgesic drugs used during surgery. This could compromise the maintenance of blinding during the intraoperative period. However, as this individual is exclusively responsible for the administration of anaesthesia and does not participate in postoperative evaluations or any subsequent data collection and analysis, the risk of unblinding is unlikely to influence the overall validity and reliability of the study outcomes.

When a serious emergency occurs during the research process, unblinding may be conducted in accordance with clinical requirements.

Intervention

IT group: A subarachnoid puncture will be conducted at the L2-3 interspace prior to the induction of general anaesthesia. On verifying that cerebrospinal fluid (CSF) reflux is unobstructed, 3 mg of bupivacaine and 0.25 mg of morphine will be diluted with CSF to a total volume of 3 mL and injected into the subarachnoid space over 15 s. Cases exhibiting CSF reflux obstruction or unsuccessful puncture will be excluded from the study.

C group: After the patient is positioned in the designated posture, the anaesthesiologist will simulate the intrathecal injection procedure by applying digital pressure to the skin.

Nausea and vomiting prevention

Prophylactic antiemetics, including 5-hydroxytryptamine-3 (5-HT3) receptor antagonists, dexamethasone at 8 mg and droperidol at 0.625 mg, will be administered based on the patient’s risk of nausea and vomiting. The Apfel scoring tool is utilised to assess the risk of nausea and vomiting, with the simplified Apfel risk score incorporating four predictive factors: female gender, history of postoperative nausea and vomiting (PONV) and/or motion sickness, non-smoking status and postoperative opioid use. Patients with one to two risk factors receive two antiemetics for PONV prophylaxis, while those with more than two risk factors receive three antiemetics for PONV prevention.²²

Anaesthesia methods

Anaesthesia induction will be performed by an anaesthesiologist (blinded) who will enter the operating room after the intervention is completed. The procedure includes an intravenous injection of midazolam at 0.05 mg/kg, propofol at 1.0–2.0 mg/kg and sufentanil at 0.4 µg/kg. Once the patient’s eyelash reflex disappears, muscle relaxation monitoring will commence, which is assessed through train-of-four (TOF) stimulation. On achieving stable TOF values, intravenous cisatracurium (0.2 mg/kg) will be administered. When muscle relaxation is satisfactory, a double-lumen endotracheal tube will be inserted. Its correct positioning will be verified via fibreoptic bronchoscopy before the final connection to the anaesthesia machine. Ventilation parameters will be set as follows: volume-controlled ventilation mode will be selected, with a tidal volume of 7–9 mL/kg during two-lung ventilation and 4–6 mL/kg during one-lung ventilation (OLV), an inspired oxygen concentration of 60%, an inspiratory-to-expiratory ratio of 1:2 and the ventilation frequency will be adjusted to maintain P_ETCO₂ at 35–45 mm Hg, with airway pressure between 13 and 30 cmH₂O. During OLV, SpO₂ should be maintained above 92%; if this is unattainable, FiO₂ may be increased.

Anaesthesia maintenance will involve the inhalation of 1.5–2.5% sevoflurane, with bispectral index (BIS) values maintained between 40 and 60. All patients will receive an intravenous injection of flurbiprofen axetil at 50 mg and remifentanil at 0.1–0.2 µg/kg/min to maintain blood pressure within 80–120% of baseline. Intermittent boluses of cisatracurium will be administered to maintain muscle relaxation.

During anaesthesia induction, if bradycardia (HR <50 beats per minute) occurs, atropine at 0.5 mg will be administered intravenously; if systolic blood pressure falls below 90 mm Hg, phenylephrine injection at 80 µg will be administered intravenously.

After surgery, patients will be transferred to the postanaesthesia care unit (PACU) for extubation. All patients will receive PCIA with an electronic pump (sufentanil at 3 µg/kg plus antiemetics diluted with normal saline to 100 mL, with a self-controlled dose of 2 mL, no background dose and a lockout time of 15 min). The postoperative analgesic pump will be connected in the PACU for observation, and patients will return to the ward on meeting discharge criteria.

For all patients with a numerical rating scale (NRS, 0–10, with 0 indicating no pain and 10 the most severe pain) >3 in the PACU or postoperatively, rescue analgesia will be administered according to postoperative pain management guidelines: intravenous injection of flurbiprofen axetil at 50 mg (which has a different mechanism of action from opioids, enabling synergistic effects for multimodal analgesia and crossing the blood–brain barrier to prevent central sensitisation).²³ If PONV occur, 5-HT3 receptor antagonists will be administered intravenously.

Outcome measures

Primary outcome

The primary outcome is the QoR on postoperative day 1 (assessed using the QoR-15 scale, 0–150). The validated Chinese version of the QoR-15 scale (online supplemental file 4) will be used in this study.²⁴

Secondary outcomes

1. QoR on postoperative days 2 and 3 (assessed using the QoR-15 scale).

2. NRS scores: The intensity of pain at rest and during movement after the operation will be evaluated using the NRS immediately after extubation and at 3 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 1 month, and 3 months post-operation. The follow-up at 1 and 3 months postoperation will be conducted by phone.

3. Analgesic rescue: Time to first analgesic rescue and the total number of rescue analgesia episodes within 72 hours after surgery.

4. Haemodynamics: Invasive arterial pressure monitoring will be performed via radial artery catheterisation on the non-operative side. Haemodynamic variables will be systematically recorded at predefined critical perioperative time points, including mean arterial pressure (MAP) and HR on patient entry into the operating room, following intrathecal blockade, immediately after double-lumen tube insertion and at the conclusion of surgery. In addition, intraoperative extremes—specifically the minimum and maximum systolic blood pressure and peak HR—will be documented to characterise haemodynamic fluctuations during the procedure.

5. Consumption of analgesic drugs: The following analgesic data will be recorded—intraoperative remifentanil dosage, postoperative sufentanil dosage in patient-controlled intravenous analgesia (PCIA), types and dosages of rescue analgesics within 72 hours and types and dosages of analgesics used at 1 and 3 months postoperatively.

6. Adverse effects: ① spinal anaesthesia with bupivacaine hydrochloride typically lasts no more than 150 min. Sensory abnormalities or muscle weakness appearing in the blocked area more than 3 hours post-surgery indicate sensory and motor dysfunction; ② hypotension is defined as less than 75% of the preoperative baseline blood pressure; ③ shivering; ④ respiratory depression is diagnosed when respiratory rate is below 12 breaths per minute with shallow breathing; ⑤ somnolence, stupor, coma, unresponsiveness or delayed response is defined as excessive sedation; ⑥ nausea and vomiting; ⑦ urinary retention: all patients will have a urinary catheter inserted before the operation, and the catheter will be removed the next day. If lower abdominal distension and pain occur after catheter removal, accompanied by a strong urge to urinate but an inability to do so, it should be treated as urinary retention; ⑧ pruritus will be assessed using the peak pruritus numeric rating scale (PP NRS), which measures the worst itch intensity in the past 24 hours on a scale from 0 (no itch) to 10 (worst itch imaginable) (online supplemental file 4).

7. Postoperative recovery indicators (including extubation time, time to first ambulation, time to first flatus, time to first meal, urinary catheter removal time and length of hospital stay).

8. Postoperative complications (such as postoperative pneumonia, atelectasis, pneumothorax, surgical site infection, acute kidney injury, arrhythmia, blood transfusion and unplanned ICU admission).

9. Telephone follow-up at 1 and 3 months postoperatively. Pain intensity was measured using the NRS, assessing the intensity and location of pain, as well as total analgesic consumption.

10. Sleep quality [assessed preoperatively and on postoperative days 1 and 3 using the Richards Campbell Sleep Questionnaire (RCSQ) (online supplemental file 4)].

Other outcome variables

Baseline values which will be collected including ASA physical status classification, age, sex, BMI, presence of comorbidities, and type of surgery.

Quality control and data management

Before the trial officially begins, a clinical research manual will be developed, and all investigators will receive training to ensure compliance with the study protocol and consistency in outcome assessments. Furthermore, unified and standardised operating procedures will be established and provided to the research staff. The electronic case report form (eCRF) will be generated and edited within the ResMan system, which will streamline data collection and management. Each hospital will be assigned an outcome assessor responsible for data entry using the ResMan system. Prior to the trial’s official commencement, the ResMan system will undergo testing, and outcome assessors will receive training on using the eCRF within the system. Subject information will be securely stored in the ResMan system, accessible only to authorised researchers to ensure confidentiality. A Data Monitoring Committee (DMC), consisting of ethicists, clinicians and statisticians, will oversee the integrity and accuracy of the trial data. The DMC will be responsible for reviewing raw data to ensure the trial is conducted according to the protocol. On completion of the trial, the database will be rendered inaccessible to prevent any data alterations. All documents related to the study will be retained for at least 5 years following the publication of the research.

Independent statisticians will conduct a final analysis on datasets with personal identifiers removed. All participants have the right to withdraw from the study at any time during the research process. The reasons for withdrawal must be recorded in the original documents and simultaneously notified to the ethics committee. The definitions of adverse events and serious adverse events will strictly adhere to the ICH E2A guidelines and China’s ‘Good Clinical Practice’. We will evaluate each adverse event, and all adverse events, whether related to the trial or not, must be meticulously documented in the original medical records and CRFs. On learning any serious adverse event, investigators must submit a written “Serious Adverse Event Report Form” to the sponsor and the ethics committee of the participating centre within 24 hours. After receiving the serious adverse event report, the sponsor must report to the ethics committees of all participating research centres within a specified timeframe. Investigators must follow-up on serious adverse events and submit follow-up reports within 24 hours of obtaining new information or changes in event outcomes. Investigators will use a five-level classification system (definitely related, possibly related, possibly unrelated, unrelated, or undetermined) to assess the association between adverse events and the trial, based on factors such as temporal relevance, pharmacological characteristics, desensitisation/re-sensitisation responses and individual subject conditions. The DMC will meet quarterly to review all serious adverse events and cumulative safety data, providing recommendations to the sponsor on whether the trial should continue. The data management department will conduct monthly consistency checks between the clinical database and the safety database to ensure that all serious adverse event information is accurate in both databases.

This study will perform an interim safety analysis during the course of the clinical trial, and the findings will be used to determine whether early termination is warranted.

Sample size

The sample size was calculated using the QoR-15 score on postoperative day 1 as the primary outcome variable. A clinically significant difference of 6.0 points in the QoR-15 score between groups has been established.²⁵ Based on our preliminary study, the QoR-15 score on postoperative day 1 in the C group was 95.3±12.0. We hypothesised that the IT group would show a 6-point improvement in the QoR-15 score compared with the C group. With an intraclass correlation coefficient set at 0.1 and calculated using a mixed model assuming no centre interaction, 114 patients per group were required to achieve 80% power with a type I error of 0.05. Accounting for a 10% dropout rate, 127 patients per group were needed, totalling 254 patients to be recruited for this study.

Statistical analysis

Continuous variables will undergo normality testing. Variables conforming to a normal distribution will be summarised using the mean±SD, while non-normally distributed variables will be described using the median and IQR. Categorical variables will be presented as absolute counts and percentages. To assess significant differences in baseline clinical characteristics between the IT group and the C group, t-tests or Mann-Whitney U tests will be employed for continuous variables, and chi-square tests or Fisher’s exact tests will be applied to categorical variables, as appropriate. The primary outcome is defined as the QoR-15 score measured on the first postoperative day, with possible scores ranging from 0 (very poor QoR) to 150 (excellent QoR). A mixed-effects model will be utilised to compare QoR-15 scores between the two groups on postoperative day 1. For secondary continuous outcomes, repeated measures mixed-effects models will be applied. Secondary categorical outcomes will be analysed using logistic regression or chi-square tests, depending on the data structure and assumptions. To account for multiple comparisons in the analysis of secondary outcomes, the Benjamini-Hochberg procedure will be applied. All statistical analyses will be conducted using IBM SPSS (version 25.0; IBM Corp., Armonk, NY, USA) and other appropriate statistical software. All hypothesis tests will be two-sided, with statistical significance defined as p≤0.05, and 95% CIs will be used for parameter estimates.

The primary efficacy analysis will be conducted using the intention-to-treat (ITT) principle. To ensure the robustness of the results, additional analyses will be performed, including per-protocol set (PPS) analysis, case-completion analysis and sensitivity analysis based on multiple imputation.

Procedure for protocol deviation

Definition and documentation of protocol deviations: Any non-compliance with the approved study protocol (including violations of inclusion/exclusion criteria, intervention deviations, missed visit windows, or incomplete data collection) shall be classified as protocol deviations. All deviations shall be documented in real time by site investigators on a dedicated ‘Protocol Deviation Log’ and reported to the principal investigator (PI) and data administrator via the ResMan platform.

Classification and Severity Grading of Deviations: We classify deviations into two categories based on their potential impact on the safety, rights and scientific integrity of the study.

• Secondary deviations: Those with minimal effect on subject risk or primary outcomes and can be promptly corrected (eg, minor deviations in non-critical visit times, missing documentation records).

• Major deviations: Deviations that may materially affect the assessment of the safety, benefits or efficacy of the primary/key secondary outcomes of the study (eg, misclassification, serious violations of inclusion/exclusion criteria, missing key data, etc.).

The process for handling deviations is as follows:

1. Identification and reporting: The investigator identifies the deviation and reports it within 24 hours.

2. Evaluation and classification: The PI and DMC conduct regular assessments to determine the classification and severity level.

3. Corrective and preventive actions: Take immediate corrective actions and notify all research centres to prevent recurrence.

4. Reporting and archiving: All deviations and measures taken will be summarised and reported to the ethics committee, and detailed in the final study report.

Treatment in statistical analysis: In the statistical analysis plan (SAP), we will specify that all major deviations will be evaluated in sensitivity analyses (eg, excluding major deviation cases in the ‘protocol-compliant set’ analysis) to test the robustness of the study results.

Adherence to the ITT principle

This study’s primary analysis will adhere to the ITT principle. All 254 randomised participants—regardless of whether they received the full intervention, experienced protocol deviations or were dropped—will be included in the analysis of their original randomised group. This approach ensures maximum replication of the randomised effect and accurately reflects the intervention’s efficacy in real-world clinical practice.

Missing data

Missing data will be minimised. Missing data will be reported and summarised by treatment arm. The distribution of missing data will be explored to assess the assumption that data are missing at random, and multiple imputation will be utilised as appropriate, with sensitivity analyses undertaken to explore the missing assumptions.²⁶

Sensitivity analysis

Sensitivity analysis will enhance the robustness of the results. To validate the reliability of the findings, we will conduct the following predefined sensitivity analyses:

1. PPS analysis: This will include only participants who completed all study interventions, had no major protocol deviations and met the primary endpoint criteria.

2. Comparison of different datasets:

3. ITT vs PPS: This comparison will evaluate the consistency between the analysis results of the two groups.

4. Complete case analysis: Only subjects with no missing data for the primary endpoint will be included.

5. Analysis after missing data processing using multiple imputation: Assuming the missingness is at random, the missing values for the primary endpoint (QoR-15 score on postoperative day 1) will be addressed through multiple imputation and subsequently re-analysed.

6. Analysis of specific biases: The results of the analysis comparing ‘including all cases of loss to follow-up’ and ‘excluding cases of loss to follow-up’ will be presented.

Patient and public involvement

Patients and the public will not be involved in the design, conduct, reporting or dissemination planning of the study.

Ethics and dissemination

The investigator will ensure that this trial is conducted in accordance with the principles of the Declaration of Helsinki. The results will be disseminated through peer-reviewed publications. This study protocol (V.2.0, 30 October 2024) involves human participants and has been approved by the Ethics Committee of Affiliated Hospital of Yangzhou University (number 2024-08-02-2), Taicang Hospital Affiliated to Soochow University (number 2025 SR-041) and Yichang Central People’s Hospital (number 2024-513-02). If modifications to the research plan are necessary, the ethics committee will be informed and approval must be obtained before notifying the Chinese Clinical Trial Registry. Each individual who agrees to participate in the research will provide written informed consent after the objectives and procedures of this study are explained to them.

Trial status

We are currently recruiting participants for this trial. The first patient was enrolled on 11 December 2024, and recruitment is expected to close in December 2025.