Trial setting and eligibility criteria

This trial is a single-centre, randomised, controlled, patient and outcome assessor-blinded trial conducted at Beijing Tiantan Hospital, Capital Medical University. A study coordinator screens elective neurosurgery patients daily to determine eligibility. The inclusion criteria are as follows: scheduled to undergo craniotomy for supratentorial tumours with general anaesthesia; 18 years ≤ age ≤ 65 years; American Society of Anesthesiologists physical status of I to III; and signed informed consent (online supplemental 1). The exclusion criteria are as follows: body mass index ≥35 kg/m²; severe hepatic or renal insufficiency; cognitive dysfunction, aphasia or other states that did not cooperate with the assessment; preoperative MRI of the head showing midline displacement >5 mm;8 electrophysiological monitoring during surgery; and pregnancy or lactation. The schedules of the activities for the registration, intervention and assessment of the participants are shown in table 1 and figure 1.

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Figure 1

Study implementation flow chart. NRS, Numerical Rating Scale.

Discontinuation or withdrawal of study subjects

Each participant has the right to withdraw from the research at any time for any reason voluntarily, and the researcher may also stop a subject’s involvement for any number of reasons, most commonly protocol infractions or safety concerns.

Assignment of interventions

Patients identified as eligible by the study investigator will be randomly assigned to the opioid-free anaesthesia group or the opioid-based control group in a 1:1 ratio. Randomisation is performed on the day of surgery. The table of random numbers is generated by independent researchers via computer software (SPSS V.26.0). In this study, block randomisation is adopted, and the block length is 4. The subjects’ random results are placed in light-tight envelopes numbered in strict accordance with their enrolment order. The researchers open the envelopes in the order in which they are assigned, ensuring that the assignment information is unpredictable. Before anaesthesia begins, the envelopes are opened by researchers who are unaware of the randomisation procedure, and the subjects are assigned to either the opioid-free anaesthesia group or the opioid-based control group. Because of the specificity of the intervention method, the anaesthesiologist knew the grouping of patients, but the surgeon and other members of the medical team did not. The participants and primary outcome evaluators are blinded. The randomisation results are known only when patients experienced a serious adverse event (such as death or life-threatening emergency rescue) that required additional visits.

Interventions

Patients in the opioid-free anaesthesia group will not be given opioids during the procedure. Anaesthesia is induced with 1–1.5 mg/kg lidocaine, 1.5–2.5 mg/kg propofol or 0.15–0.3 mg/kg etomidate, and 0.6–0.8 mg/kg rocuronium after loss of consciousness. A visual laryngoscope is placed to expose the epiglottis and glottis, and oral pharyngeal surface anaesthesia is administered with 2% lidocaine. The needles are sprayed evenly in the airway, vocal cords and epiglottic laryngeal surface. Mask ventilation is continued after surface anaesthesia, and endotracheal intubation is performed after lidocaine surface anaesthesia takes effect. According to our local practices, anaesthesia is maintained with a 0.3–0.6 minimum alveolar concentration (MAC) of sevoflurane or desflurane combined with 0.12 mg/kg/hour esketamine, 0.4–0.6 µg/kg/hour dexmedetomidine, and 2–4 mg/kg/hour propofol. The anaesthesiologist may adjust the drug type and dosage (without opioids) according to the specific situation of each subject, and all medications must be recorded in detail. If there are any adverse events associated with esketamine and dexmetomidine during the procedure, such as severe bradycardia, the medication should be discontinued, and opioids may be appropriately administered to ensure a smooth operation. If patients in the opioid-free anaesthesia group have strong pain stimulation during surgery, resulting in persistent tachycardia or elevated blood pressure, opioid analgesia can be appropriately administered to ensure stable haemodynamics.

For patients in the opioid-based control group, 0.3–0.5 µg/kg sufentanil, 1.5–2.5 mg/kg propofol or 0.15–0.3 mg/kg etomidate, and 0.6–0.8 mg/kg rocuronium are used for anaesthesia induction. According to our local practices, anaesthesia is maintained with a 0.3–0.6 MAC of sevoflurane or desflurane combined with 0.05–0.2 µg/kg/min of remifentanil and 2–4 mg/kg/hour propofol. Sufentanil is administered intermittently at 0.1 μg/kg as required by surgery. The anaesthesiologist can adjust the drug type and dosage according to the specific situation of each subject, and all medications should be recorded in detail.

Standardised anaesthesia management

Standardised anaesthesia management is adopted for all patients. The intravenous route is established according to anaesthesia and surgical requirements after admission. ECGs, heart rate, blood pressure and pulse oxygen saturation are routinely monitored. After induction of anaesthesia, bilateral scalp nerve block is performed with 0.5% ropivacaine. The scalp nerve blocks included the supraorbital nerve, supratrochlear nerve, auriculotemporal nerve, zygomaticotemporal nerve, major occipital nerve and minor occipital nerve. The nerve block site is selected according to the location of the surgical incision and head nail, and 2–3 mL of local anaesthetic is injected into each block site. Scalp nerve blocks are performed by an anaesthesiologist under ultrasound guidance. Dexamethasone is not used as a local anaesthetic for nerve block. Rocuronium bromide is added intermittently according to the course of surgery. The respiratory parameters should be regulated, the patient should be properly hyperventilated, and partial pressure of carbon dioxide in arterial blood (PaCO₂) should be maintained at 30–35 mm Hg. The anaesthesiologist, on the basis of the patient’s response to the drug, adjusts the dose of the sedative drugs (propofol and sevoflurane) to ensure that the bispectral index (BIS) is between 40 and 50. During surgery, anaesthesiologists do not routinely administer steroids. Steroid therapy is only continued perioperatively for patients who require ongoing steroid treatment due to pre-existing medical conditions. After the operation, the sevoflurane is removed, and the fresh gas flow is adjusted to 6 L/min. All the subjects are given 8 mg of ondansetron intravenously during anaesthesia to prevent postoperative nausea and vomiting. For subjects with severe nausea and vomiting (three or more episodes of vomiting or inability to perform daily activities due to nausea and vomiting), additional medications such as ondansetron may be administered for postoperative remedial antiemetic therapy. Patients with postoperative pain scores ≥4 can be given analgesic drugs, such as oxycodone and acetaminophen, for postoperative remedial analgesic treatment, and all drugs should be recorded in detail (online supplemental 2). If intraoperative blood loss exceeds 40% of the blood volume or if there are other adverse events that threaten the life of the patient, the study is terminated, and opioids can be given as needed. The anaesthesiologist should actively handle the situation according to the situation and record the processing process.

Primary outcome

The primary outcome measure is the Quality of Recovery-15 (QoR-15) Score on the second day after surgery. The QoR-15 Scale is used to evaluate the postoperative recovery of patients in five dimensions: pain, physical comfort, physical independence, psychological support and emotional state.9 Each item is scored on a 10-point scale ranging from 0 (worst recovery) to 150 (best recovery).9 According to the results of previous meta-analyses, a change in the QoR-15 Scale Score to 6 points is considered to be clinically significant.10–12

Secondary outcomes

The secondary outcomes in this study included the QoR-15 Score on the fifth day after surgery; the incidence of nausea and vomiting within 48 hours after surgery (including nausea, retching or vomiting episodes); the Numerical Rating Scale Pain Score on the second and fifth days after surgery; the sleep quality on the second and fifth days after surgery; and the incidence of chronic pain at 3 months and 6 months after surgery.13 Chronic pain is defined as pain that lasts longer than 3 months.13 Perioperative sleep quality is assessed via the Athens Insomnia Scale. Safety indicators, including the incidence of intraoperative bradycardia (heart rate <60 bpm), tachycardia (heart rate >100 bpm), hypertension (more than 30% of baseline blood pressure and requiring drug intervention), hypotension (less than 30% of baseline blood pressure and requiring drug intervention) and postoperative intracranial haemorrhage, should also be considered. For patients who develop postoperative intracranial haemorrhage, we will document the following parameters: clinical manifestations, haemorrhage volume (measured in millilitres), management strategies (including the need for surgical intervention and/or blood transfusion), and clinical outcomes.

Data collection

At patient enrolment, the researchers collected the demographic and baseline characteristics of the patients. All patients are assessed using the Apfel Score. Patients’ vital signs, anaesthetic administration, fluid volume, blood loss, and urine volume are recorded intraoperatively. The quality of recovery, pain score, sleep quality, postoperative nausea and vomiting, postoperative complications and adverse events are recorded during postoperative follow-up. Pain scores are obtained via telephone at 3 months and 6 months after surgery. The researchers also collected information on the percentage of patients in the opioid-free anaesthesia group who used opioids. Considering the influence of the pathological type of a tumour on patient prognosis, researchers should also collect the pathological results of patients after surgery. All participants enrolled in the randomisation are followed up until 6 months after surgery. To promote the participation of the subjects in this study and ensure the integrity of the data, we collect the contact information of their families in addition to the subjects for follow-up after discharge. All patients in our centre use electronic versions of medical records and anaesthesia sheets. In this study, a paper case report form is used to record the information of the participants.

Data management

Raw data for all patients are collected via paper case report forms specially designed by the researchers and placed in dedicated lockers with locks. The paper case report form for this study is destroyed 3 years after the end of the study. The electronic data of this study are stored encrypted after hiding personal information. Only leading researchers have access to the electronic database. All researchers involved in this study strictly abided by the rules of professional confidentiality and kept all personal information of patients confidential.

Sample size

According to unpublished data from a preliminary study of 20 patients in our centre, the QoR-15 Score of neurosurgery patients on the second day after surgery was 109±14. Changes of up to 6 points on the QoR-15 Scale are considered clinically significant.10–12 Finally, with the use of the Power Analysis and Sample Size-15 (PASS-15), a total of 170 patients are needed to detect differences in the primary outcome with 80% power and a two-sided alpha of 0.05, allowing for a 5% loss to follow-up.

Statistical methods

All patients enrolled in the randomisation process, including those who discontinued the study due to intraoperative adverse events such as bleeding, are included in a modified intentionality analysis. The primary outcome will be analysed via modified intentionality analysis and per-protocol analysis. All analyses will be conducted by researchers who are unaware of the intervention. The continuous variables used in this study are tested for normality via the Kolmogorov‒Smirnov test. Data conforming to a normal distribution will be expressed as the mean±SD, and non-normally distributed data will be expressed as the median and IQR. The t test will be used for continuous variables that conform to a normal distribution, and the Mann‒Whitney U test will be used for continuous variables that do not conform to a normal distribution. Categorical variables are expressed as percentages and are analysed via χ² tests, corrected χ² tests or Fisher’s exact tests. Intraoperative haemodynamic parameters, including systolic blood pressure, diastolic blood pressure, mean arterial pressure and heart rate, will be compared between the two groups via repetitive measurement deviation analysis. For the missing data, the last observation and the worst-case imputation scenarios are used as the main interpolation methods. A value of p=0.05 or less (double-tailed letter level) is considered statistically significant. No interim analysis is planned for this study.

Data safety and monitoring

The accuracy and security of all the data are governed by an appointed data monitoring committee. The Data Safety Monitoring Board is independent of the researchers and includes an anaesthesiologist, a neurosurgeon and a biostatistician. The data monitoring committee will review the contents of the database every 6 months to ensure that all the data are collected accurately and in a timely manner. The principal investigator regularly monitored and tracked the anaesthesiologist’s compliance with the protocol.

Serious adverse events

An adverse event is defined as an adverse event or worsening of a pre-existing medical condition that occurred during the study period, whether or not it is related to the intervention in this study. All adverse events associated with this study will be closely monitored until the adverse events are resolved and the condition stabilises. Adverse events are reported to the research department immediately after they occur, and the severity of the adverse events is determined by the principal investigator. In addition, the principal investigator should report this information to the Ethics Committee (Institutional Review Board, IRB) within 24 hours. The Data Monitoring Board will be responsible for monitoring clinical safety and reviewing all adverse events reported to the IRB to determine the risks and benefits of the study. If a patient’s health is compromised as a result of participation in this study, we will be responsible for receiving appropriate treatment. Beijing Tiantan Hospital will pay for the treatment of patients in accordance with relevant national regulations and pay corresponding financial compensation to patients.

Patients and public involvement

Patients and the public were not directly consulted during the formulation of the research questions or outcome measurements and did not participate in the study’s design, recruitment or implementation. The study’s results will be disseminated to all study participants via their preferred method.