Effective doses of ciprofol combined with alfentanil in inhibiting responses to gastroscope insertion, a prospective, single-arm, single-center study

This study has been approved by the Medical Ethics Committee of the Second Affiliated Hospital of Hainan Medical University (approval number: LW202051), and registered at http://​www.​chictr.​org.​cn (registration number: ChiCTR2200061727, 1/7/2021). The research protocol was carried out under the guidance of relevant guidelines. All patients or their families signed informed consent.

This study is a prospective, single-blind, single-center research carried out in the Second Affiliated Hospital of Hainan Medical University. Participants underwent painless gastroscopy in our hospital from July to August 2022. To ensure homogeneity, the inclusion and exclusion criteria of this study are as follows. Patients included were those aged 18–64 years of either sex, with a Body Mass Index (BMI) 18–28 kg/m², and American Society of Anesthesiologists (ASA) grade I or II. Exclusion criteria include presence of difficult airway, allergy to the anesthetic used, history of alcohol, sedative or analgesic abuse, mental illness, pregnant and lactating women. Patients who required manual control of ventilation or whose gastroscopy lasted more than 30 min were excluded.

To ensure accurate dosing, we used 0.9% sodium chloride injection to dilute alfentanil (Yichang Renfu Pharmaceutical, China, 13S11041) to 50 µg/ml; ciprofol (Liaoning Hesco Pharmaceutical Co., Ltd., China, 20211104) was diluted to 1.25 mg/ml with 0.9% sodium chloride injection according to its Instructions for Use.

According to the American Society for Gastrointestinal Endoscopy (ASGE) guideline, all patients routinely fasted for solids for at least 6 h and fasted for water for at least 2 h [13]. Venous access was established when patients entered the endoscopy room. Patients lay on their left sides before being connected to a monitor (Bene View N15 OR monitor, Myriad Biomedical Electronics Co., Shenzhen, China) for continuous monitoring of electrocardiogram (ECG), non-invasive blood pressure (NIBP), saturation of peripheral oxygen (SpO₂), respiratory rate (RR) and heart rate (HR). All indicators were measured three times, and the average of each was determined as the baseline value. 3-5 min before the start of gastroscopy, the patients were given nasal cannula for oxygenation (4–6 L/min) in a spontaneous breathing mode and continued until the end of the examination and were fully awake.

In this study, the dose-finding strategy of ciprofol followed a modified Dixon’s up-and-down method with an arithmetic sequence. The modified Dixon’s up-and-down design is a classic method to explore the median effective dose of an agent where the dosage of a participant is determined based on the response of the previous one. The biggest advantage of this method is that it only needs 1/4 to1/3 of the sample size of the traditional method (usually ≥ 6 pairs of negative-positive responses are recommended) to draw the same reliable conclusions [14]. According to relevant literature and preliminary experiments, the initial dose of ciprofol was 0.30 mg/kg with an increment of 0.02 mg/kg [5]. Alfentanil was injected intravenously at 7 µg/kg (administration duration 30 s), followed by intravenous administration of ciprofol at a uniform speed for 30 s, and a gastroscope was inserted 2 min after the end of dosing, that is, when the plasma concentration of ciprofol reached its peak [9]. When the insertion response of one participant was positive, an escalation of 0.02 mg/kg would be given to the next participant; otherwise, a de-escalation of 0.02 mg/kg would be administered. The study was terminated when negative response and positive response alternated 8 times. The definition of a positive response referred to reactions such as body movement, coughing, and eye opening during gastroscopy insertion [15]. All gastroscopic exams were performed by endoscopists with rich experience and mature technique who had been engaged in endoscopy for more than 3 years. All anesthesia operations were completed by the same anesthesiologist, and another anesthesiologist who was not aware of the research oversaw data documentation.

The depth of sedation was evaluated using the Modified Observer’s Assessment of Alert Score (MOAA/S) (see Additional Supplementary Table 1) after each successful gastroscope insertion and before the completion of the endoscopic exam. Studies have shown that a MOAA/S ≤ 2 means that patients meet all requirements of endoscopy [16]. For patients showing positive responses during endoscope insertion or the MOAA/S score was above 2 points anytime during the exam, ciprofol 0.05–0.2 mg/kg would be injected intravenously to deepen the anesthesia (administration duration of 10 s, each additional dose should be given with an interval ≥ 2 min, and no more than 5 additions per 15 min) [9], until the completion of endoscopy. In case of bradycardia where HR < 50 beats/min during the exam, 0.5 mg of atropine would be administered intravenously. For hypotension (30% drop in blood pressure from preoperative baseline), ephedrine would be injected intravenously to maintain blood pressure. When patients’ SpO₂ dropped below 90%, oxygenation would be provided by either jaw lift or pressurized mask ventilation, and an oropharyngeal airway would be established when necessary. Depending on the degree of hypoxia in the patient, the decision to terminate the test is made.

The modified Dixon’s up and down method requires at least 6 pairs of negative-positive responses to calculate a reliable ED₅₀ [14]. This study was stopped when negative and positive responses alternated 8 times. A total of 25 patients were included, and the sample size was reliable.

Statistical analysis was performed using SPSS 25.0 statistical software (SPSS Inc., Chicago, IL, U.S.A.). The Kolmogorov-Smirnov test was used for normal distribution examination. Normally distributed indicators were described as mean ± standard deviation. Categorical variables were expressed as percentages (%). Data at different time points were analyzed by repeated measures ANOVA. ED₅₀, ED₉₅ and their corresponding 95% confidence intervals (CI) were calculated using the Probit method; based on the probability model, the fitting equation was derived and the dose-effect curve was drawn. The up-and-down dose-finding curve and the dose-effect fitting curve were drawn using Microsoft Excel 2016 software. A P value < 0.05 is statistically significant.

A total of 25 cases were included in this study. The participant flow diagram is shown in Fig. 1. Demographic characteristics of these patients are shown in Table 1, and no cases were excluded.

Of the 25 patients, 13 had positive responses and 12 had negative responses. Results of the up-and-down experiment are shown in Fig. 2. The ED₅₀ of ciprofol combined with 7 μg/kg of alfentanil in inhibiting responses to gastroscope insertion was 0.217 mg/kg (95% CI: 0.203–0.234 mg/kg), and the ED₉₅ was 0.247 mg/kg (95% CI: 0.232–0.339 mg/kg). The dose-effect fitting curve is shown in Fig. 3.

Changes in patients’ vital signs are shown in Table 2. Compared with T0, MAP significantly decreased at T1, T2, T3, and T4 (P < 0.001); HR slowed down at T2 (P < 0.05).

The recovery time was 11.04 ± 1.49 min, and the discharge time was 9.64 ± 2.38 min. Among all patients, 2 (8%) had hypotension, and 1 (4%) had SpO₂ < 90% (the overall incidence of adverse reaction was 12%), and they returned to normal quickly after ephedrine injection to boost blood pressure and jaw lift for oxygenation, respectively. No anesthesia-related adverse events occurred (such as bradycardia, injection pain, muscle stiffness, nausea and vomiting, intraoperative awareness, restlessness during recovery, and delayed recovery).