This was a prospective, double-blinded randomized controlled study conducted in Beijing Friendship Hospital of Capital Medical University. This study protocol was approved by the Institutional Ethics Committee of Beijing Friendship Hospital, Capital Medical University (Approval No: 2023-P2-246-02), registered on the Chinese Clinical Trial Registry (http://www.chictr.org.cn; registration number: ChiCTR2300077170, 1 November 2023).

Elderly male patients scheduled for painless ureteroscopy were enrolled and signed the informed consent if they accorded with the inclusion criteria: (1) body mass index (BMI) 18 ∼ 28 kg/cm2; (2) ≥ 60 years old; (3) gender: male; (4) American Society Anesthesiologists physical status (ASA) I ∼ III. The exclusion criteria included: (1) allergic to the trial medication; (2) psychiatric disorders; (3) severe liver or kidney disorders; (4) uncontrolled hypertension or malignant hypertension; (5) severe diseases of circulatory system; (6) acute respiratory tract infections or other chronic respiratory disorders; (7) high intracranial pressure or high intraocular pressure. Discharge criteria: (1) change of surgery type when entering operation room; (2) accidents such as severe hemodynamic instability or high cough sensitivity after injecting intravenous anesthetics; (3) inability to tolerate ureteroscopy under intravenous anesthesia; (4) other unexpected circumstances. If patient refused to continue the trial or violated the scheme, they were also excluded from the trial.

50 patients were randomly divided into two groups: SK group (0.25 mg/kg esketamine, n = 25) and SF Group (0.1 µg/kg sufentanil, n = 25). The patients, anesthesiologists and urologists were all blinded to the grouping. A random sequence of numbers was generated by a computer and divided into two groups at a ratio of 1:1 into sealed envelopes. After the patients were included, the groups were randomly allocated and the envelope were opened. Then an anesthesiologist nurse would prepare the experimental drugs in colorless syringe, seal and give them to the anesthesiologist according to the numbers placed in the the envelopes.

The patients fasted from food and water for 8 h before ureteroscopic procedures according to our routine practice and non-invasive blood pressure (NBP), pulse oxygen saturation (SpO2), heart rate (HR) and electrocardiography (ECG) were continuously monitored after entering operating room. Patients were placed in the lithotomy position and an intravenous access was established. Before given intravenous anesthetics, patients inhaled 6 L/min oxygen continuously via a facemask and received scopolamine 0.3 mg via a vein.

The experimental drugs, including both esketamine and sufentanil solutions, were diluted into 10 ml and prepared by a specialized nurse. The patients received 0.25 mg/kg esketamine in SK group and 0.1 µg/kg sufentanil in SF group, respectively. 3 min after experimental drugs administration, an initial bolus of propofol (1.5 mg/kg in both groups according to our previous experience) was intravenously injected in 30–60 s for anesthesia induction.

The modified observer’s assessment of alertness/sedation (MOAA/S) score [16] (5: response readily to name spoken; 4: lethargic response; 3: response after name called loudly; 2: response after mild to moderate shaking; and 1: response to trapezius squeeze) was utilized to evaluate the sedation depths of patients. After propofol was administered intravenously and the patients’ MOAA/S score ≤ 1, the ureteroscope insertion was performed by an experienced urologist. The patient’s responses to the ureteroscope insertion were classified as either ‘movement’ or ‘no-movement’. The ‘movement’ response was defined as movement of limbs to the whole body requiring a propofol increment. The conditions of endoscope insertion were only evaluated at the first attempt and a bolus of 20 mg propofol, as a rescue medication, was administered immediately once movement responses or condition of MOAA/S score ≥ 2 occurred during the procedure.

All adverse events during propofol sedation and ureteroscopy were recorded. Hypotension was determined when mean artery pressure (MAP) decreased below 65 mmHg, and 5 mg ephedrine was intravenously administered immediately if necessary. Bradycardia was determined when HR decreased below 45 beats/min, and 0.25–0.5 mg atropine was intravenously injected as needed. Hypoxemia was determined if SpO2 decreased to lower than 90%, and maybe needed assisted ventilation with a facemask even an artificial ventilation support.

The primary endpoint was the ED50 of propofol for successful ureteroscope insertion in elderly male patients. ED50 of propofol was evaluated according to the modified Dixon’s up-and-down method (MDUDM) [17]. The previous studies had determined ED50 of propofol in combination with lidocaine for gastrointestinal endoscopy sedation in adult patients [18] and ED50 of propofol combined with single dose of ketamine during the UGI endoscopy in elderly patients [19]. As mentioned above, 1.5 mg/kg propofol was set for the first patient in our study. According to MDUDM, if the response of the first participant was ‘no-movement’, the induction dose of propofol would be decreased by 0.1 mg/kg in the subsequent patient, otherwise increased. A crossover point was determined when patient’s response was changed from ‘movement’ to ‘no-movement’. After seven crossover points were obtained, patient recruitment was stopped.

The secondary endpoints were the induction time and all adverse events from propofol sedation until the end of ureteroscopy procedure.

Previous studies have reported that anesthesia achievement using the up-and-down methodology routinely needs 20–40 patients each group [15, 20]. Given a dropout rate of 10%, the estimated sample size was set as 25 patients per group and a total of 50 patients will be enrolled.

Statistical analysis of data was performed using SPSS statistical software (version 26.0, SPSS Inc, Chicago, IL, USA) and P values < 0.05 indicated a significant difference. For continuous variables, the normality test was performed by using the Kolmogorov–Smirnov test firstly. Data with a normal distribution was expressed as mean ± SD and intergroup comparisons were analyzed with an independent Student’s t-test. For data with a non-normal distribution, medians (inter quartile range, IQR) was used for expression and intergroup comparisons were performed by Wilcoxon signed-rank test. Categorical variables were expressed as number and/or percentage and the Fisher’s exact test or χ2 test was used to analyze the data according to the frequency.