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Effective dose of ciprofol combined with low-dose sufentanil for sedation of gastroscopy: a dose-finding study using a biased coin design

BMC Anesthesiology volume 25, Article number: 124 (2025) Cite this article

Abstract

Objective

This study aimed to determine the 90% effective dose of ciprofol combined with 5 µg of sufentanil for sedation during gastroscopy.

Methods

This was a double-blind, single-center dose-finding study. The ciprofol dose was assigned using a biased coin design according to the response of the previous patient, except for the first one, for which the dose was 0.3 mg/kg. All patients received 5 µg of sufentanil. The criterion for successful sedation was gastroscope insertion without choking, coughing, or body movement. If the sedation of the previous patient was unsuccessful, the dose for the next patient was increased by 0.05 mg/kg; if the sedation of the previous patient was successful, the next dose was reduced by 0.05 mg/kg or remained the same according to the biased coin result. The 90% effective dose was obtained using isotonic regression (the 95% confidence interval was obtained using the bootstrapping method) as the primary method, and the results were obtained using probit regression as a sensitivity analysis.

Results

Fifty-three patients were included in this study. Patients were assigned to one of four dose groups using a biased coin toss: group A (0.30 mg/kg), group B (0.35 mg/kg), group C (0.40 mg/kg) or group D (0.45 mg/kg). The 90% effective dose was 0.367 (95% CI: 0.344–0.416) mg/kg according to isotonic regression and 0.368 (95% CI: 0.347–0.419) mg/kg according to probit regression. The differences in the incidence of hypotension, mean arterial pressure and heart rate among the dose groups were not statistically significant. However, there was a statistically significant decrease in the mean arterial pressure and heart rate (P < 0.05) after the administration of ciprofol.

Conclusion

The 90% effective dose of ciprofol combined with 5 µg of sufentanil for sedation during gastroscopy was determined to be 0.367 (95% CI: 0.344–0.416) mg/kg. Within the dose range of 0.3–0.45 mg/kg, ciprofol reduced the mean arterial pressure and heart rate in patients, but these effects were not dose-dependent.

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Introduction

Drugs such as propofol, midazolam, and etomidate are the choices for sedation/anesthesia for gastroscopy, with the utilization of propofol representing one of the widely embraced sedation protocols. An advantage of propofol is that the effect compartment concentration can quickly reach equilibrium, and its elimination half-life does not increase after prolonged infusion, allowing rapid adjustment of the depth of sedation. However, propofol has a narrow therapeutic window that may lead to apnea, airway obstruction, hypoxemia, and hypotension at higher doses.

Ciprofol is a novel benzocyclobutene derivative that was first reported in 2017 [1, 2]. Like propofol, ciprofol is a positive allosteric modulator and direct agonist of the γ-aminobutyric acid subtype A (GABAA) receptor [3]. The pharmacokinetic parameters of ciprofol are similar to those of propofol [2, 4, 5]. Hence, ciprofol may be employed for sedation or anesthesia in a manner akin to propofol [6,7,8,9]. Moreover, ciprofol is superior to propofol across various dimensions. Ciprofol exhibits a broader safety margin [5], less injection-site pain [10,11,12,13], and a lower incidence of hypotension, respiratory depression, nausea, and vomiting [12, 14,15,16,17]. In addition, ciproflol has a lesser effect on swallowing than does propofol [18].The available evidence indicates that ciprofol is a viable alternative to propofol.

However, as a recently introduced pharmaceutical product, ciprofol still lacks substantial evidence to support its phase IV clinical application, particularly in the context of drug combinations and personalized medicine. Anesthetics combined with low-dose opioids enhance analgesia and sedation. These techniques are commonly employed during gastroenteroscopy procedures conducted under propofol sedation. There is no evidence of their similar use for anesthesia in patients receiving gastroenteroscopy under ciprofol. The combination of sufentanil might decrease the dosage of ciprofol, indicating that the recommended dosage stated on the drug package insert is no longer applicable. Hence, it is essential to explore the pharmacodynamic parameters of ciprofol, such as the minimum effective dose when combined with 5 µg sufentanil, in order to establish the original recommended dose for clinical utilization. In certain early dose-finding studies, the minimum effective dose was frequently defined as the 50% effective dose. However, such as more than 80% effective dose can better meet clinical requirements [19], Most studies are inclined to employ a 90% effective dose (ED90) [20, 21]. Sequential design constitutes an effective approach for such studies and can minimize the requirement for sample size, thereby presenting obvious advantages in terms of ethics and budget conservation [22, 23]. A prevalent strategy involves employing up-and-down method to compute the ED50 and subsequently extrapolate the effective concentration at higher quantiles, such as the ED90, from logistic or probit regression [23]. However, this method is not advocated by statisticians [24, 25]. The biased coin design (BCD) represents a superior approach, it is an adaptive randomization method commonly used in anesthesiology [26, 27]. BCD possesses the capability to concentrate dose levels around any specified target quantile and thus constitutes the preferred approach for estimating the higher or lower quantiles(e.g., ED90) on the response curve [27, 28].

Therefore, this study employed a BCD to determine the ED90 of ciprofol in combination with 5 µg of sufentanil for sedation during gastroscopy, aiming to provide patients with a more precise selection of drug dosage.

Materials and methods

Patient recruitment and enrollment

This study recruited adult patients who underwent gastroscopy as part of their annual routine health check between August 2022 and August 2023. The inclusion criteria for patients were as follows: aged between 18 and 65 years; body mass index (BMI) between 18 and 28 kg/m2; undergoing sedation for elective gastroscopy; and American Society of Anesthesiologists (ASA) physical status I or II. The exclusion criteria for patients were as follows: the presence of a difficult airway; symptomatic cardiovascular or pulmonary disease; gastric retention; pyloric obstruction; intestinal obstruction; severe hepatic and kidney dysfunction; drug addiction; pregnancy or breastfeeding; mental illness/disability; and medication allergy. Withdrawal: sedation time > 30 min; serious adverse reactions/complications; incomplete trial/loss of follow-up/death; insufficient data.

Anesthesia protocol

All patients fasted for at least 4 h before the procedure, were admitted to the procedural room with oxygen at a rate of 3–5 L/min through a nasal straw, and received a 500 ml infusion of lactated Ringer’s solution, the rate of which was determined by the anesthesiologist, who also measured the mean arterial pressure (MAP), heart rate (HR) and blood oxygen saturation (SpO2).

All sedation procedures were performed by the same anesthesiologist and the same endoscopist with more than 10 years of experience. According to the study design protocol, each patient received a sequential administration of 5 µg of sufentanil [1 ml: 50 µg; Yichang Renfu Pharmaceutical Co., Ltd. (Hubei, China); lot number: 21A03151] and a predetermined dose of ciprofol [20 ml: 50 mg; Haisco Pharmaceutical Group Co., Ltd. (Chengdu, China); lot number: 20220311]. Gastroscopy was started when the patient’s Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) score was ≤ 1 after sedation. A single additional dose of 5 mg of ciprofol was given in the event of MOAA/S > 1 or in the presence of coughing, choking, body movement, etc., during gastroscopy.

After gastroscopy, patients were transferred to the postanesthesia care unit (PACU), where nurse anesthesiologists monitored the patients’ HR, BP and SpO2 and attempts to walk. The gastroscope insertion time, gastroscopy time, and recovery time were recorded. The patients spent a minimum of 30 min in the PACU. The criteria for discharge from the PACU were stable vital signs, adequate alertness, ability to walk unaided, and absence of serious medication side effects and surgical complications. The time required for the gastroscope to pass from the mouth into the stomach was defined as the gastroscope insertion time. The time elapsed between starting the procedure and its completion was defined as the gastroscopy time. The recovery time was defined as the duration from cessation of the ciprofol to when the patients responded by opening their eyes upon command.

The treatment for adverse events was as follows: hypotension (a decrease in the MAP of 30% from baseline) was treated with 2–4 mg of dopamine; bradycardia (HR < 50 bpm) was treated with 0.5 mg of atropine; and respiratory depression (SpO2 < 92%) was treated with artificial ventilation.

Study design

This drug dose-finding study was conducted with a biased coin design. Success of sedation (positive response) was defined as MOAA/S ≤ 1 and no coughing, choking, body moment, etc. In contrast, failure of sedation (negative response) was defined as MOAA/S > 1 or the presence of coughing, choking, body moment, etc., during gastroscope insertion. The sequential trial tended to start with a low dose, and if the previous patient had a negative response, the dose for the next patient was increased by one step size. If the previous patient had a positive response, the dose used in the next patient was determined by a biased coin-toss (target probability Γ = 0.9), with a probability of b=(1-Γ)/Γ = 0.11 decreasing by one step size and with a probability of 1-b = 0.89 remaining the same dose. The random numbers were generated by R software. There was a negative response in the previous pretest with 0.3 mg/kg of ciprofol, so we set the initial dose at 0.3 mg/kg in this study. Previous evidence suggested that 0.4 mg/kg ciprofol was sufficient to achieve satisfactory sedation during gastroscopy [12] and that 4–8 doses were required to estimate the ED90; the step size was set at 0.05 mg/kg. Although it is generally accepted that a sequential design requires a sample size of only 20–40 individuals, a theoretical study of BCD using computer simulation concluded that 45 positive responders were required to achieve better statistical power [29], so we adopted the latter stopping rule.

Outcome assessments

The primary outcome of this study was the ED90 of ciprofol combined with 5 µg of sufentanil, which was determined for sedation during gastroscopy. The dose and response to sedation with ciprofol used in each patient were recorded, and the ED90 was calculated via regression models constructed from different positivity rates.

The secondary outcome measures included HR and MAP, which were measured at the following time points: before the start of sedation (T0), one minute after sedation (T1), three minutes after sedation (T2), the time of entering the PACU (T3), and the time of leaving the PACU (T4). Respiratory depression (SpO2 < 92%), hypotension, bradycardia, injection pain, and postoperative nausea and vomiting (PONV) were recorded.

Statistical analysis

All of the statistical analyses were performed using SPSS for Windows (ver. 25), with the exception of isotonic regression, which was performed using R for Windows (ver. 4.3.2), and the graphs were generated with GraphPad Prism 8. Normally distributed data are presented as the mean and standard deviation (mean ± SD), skewed data are reported as the median (M) and interquartile range (IQR), and count data are presented as the number and percentage (%). As a normality test for continuous data, the Shapiro‒Wilk test was used. Two regression models, probit regression and isotonic regression, were used to calculate point and interval estimates of ED90. Isotonic regression was the primary method of analysis, and probit regression was used as a sensitivity analysis. For the isotonic regression, the pooled adjacent violators algorithm (PAVA) was used to quadratically optimize the data, while the ED90 was estimated by the \(\:{\widehat{\mu\:}}_{3}\) estimator, and the 95% confidence interval (95% CI) was calculated by bootstrapping [30]. Repeated-measures data were statistically analyzed using generalized estimating equations (GEEs), and comparisons of rates were analyzed using chi-square tests or Fisher’s exact tests. Spearman rank correlation analysis was used to examine the relationship between the time to recovery time /pre- and post-anesthesia MAP drop with dose. A P value < 0.05 (two-sided) indicated a statistically significant difference.

Results

A total of 56 patients were recruited for the study. Patients underwent sedation for gastroscopy as part of their routine annual primary health care. One patient was rescheduled because of gastric retention identified following gastroscopic access to the stomach, whereas two patients were excluded from the study because they presented with gastric polyps requiring gastroscopic intervention, necessitating sedation for more than 30 min. The study was stopped after 45 patients with a positive response were diagnosed, and ultimately, a total of 53 patients were enrolled in the trial (Fig. 1). The median gastroscope insertion time was 3.0 (IQR: 1.0) s, and the mean gastroscopy time was 4.5 (SD: 1.2) min (Table 1).

Fig. 1
figure 1

Flow diagram of the study

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Table 1 Patient characteristics
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Using BCD, 53 patients were anesthetized at four dose levels, with the samples clustered at two dose levels, 0.35 mg/kg and 0.40 mg/kg (Fig. 2). The maximum likelihood estimates (MLEs) of the true positive rates were calculated to be 20%, 87.5%, 95.0% and 100% for Groups A to D, respectively; the estimated value of ED90 obtained by isotonic regression was 0.367 mg/kg, with a 95% CI of 0.344–0.416 mg/kg (Fig. 2); and the ED90 obtained by probit regression was 0.368 (95% CI: 0.347–0.419) mg/kg (Fig. 3).

Fig. 2
figure 2

Response of patients to sedation with different doses of ciprofol. ED90: 90% effective dose; CI: confidence interval

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Fig. 3
figure 3

The curve of the inverse cumulative distribution function (ICDF). MLE: maximum likelihood estimate, CI: confidence interval

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Patients were administered four different doses of ciprofol for sedation. For subgroup analyses based on varying dose levels, patients were categorized into Group A (0.30 mg/kg), Group B (0.35 mg/kg), Group C (0.40 mg/kg), and Group D (0.45 mg/kg) according to the dose they received. GEE was used to analyze within- and between-group differences in the MAP and HR. T0 data were used as a covariate, and Bonferroni correction was used to adjust p values for pairwise comparisons. (a) The main effects were analyzed because the interaction effect of time and group on MAP was not statistically significant (Wald χ2 = 9.816, P = 0.632). After adjusting for the effect of group, the difference in the MAP between time points was statistically significant (Wald χ2 = 362.842, P < 0.001). The differences in the mean MAP between T0 and T1, T2, T3 or T4 were statistically significant (adjusted P < 0.001), and the differences were 13.6 (Wald 95% CI: 11.1–16.0), 17.8 (Wald 95% CI: 16.0-19.7), 14.0 (Wald 95% CI: 11.6–16.5) and 13.1 (Wald 95% CI: 10.6–15.6) bpm, respectively. After adjusting for the effect of time, the difference in the MAP between the groups was not statistically significant (Wald χ2 = 0.160, P = 0.984) (Fig. 4A). (b) The main effects were analyzed because the interaction effect of time and group on the HR was not statistically significant (Wald χ2 = 9.813, P = 0.632). After adjusting for the effect of group, the difference in HR between time points was statistically significant (Wald χ2 = 97.723.15, P < 0.001). The difference in the mean HR between T0 and T1, T2, T3 or T4 was statistically significant (adjusted P < 0.001), and the differences were 6.7 (Wald 95% CI: 4.8–8.7), 10.2 (Wald 95% CI: 7.9–12.4), 10.9 (Wald 95% CI: 8.6–13.1) and 8.7 (Wald 95% CI: 6.3–11.1) bpm, respectively. After adjusting for the effect of time, the difference in HR between groups was not statistically significant (Wald χ2 = 1.494, P = 0.684) (Fig. 4B).

Fig. 4
figure 4

(A) Comparisons of the differences in MAP within and between dose groups. (B) Comparisons of the differences in HR within and between dose groups

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The Shapiro‒Wilk test revealed that neither the dose nor the MAP drop fit a normal distribution (P < 0.001 and P = 0.002). Spearman rank correlation analysis was also conducted to evaluate the correlation between the MAP drop and dose. The results revealed no correlation (rs=0.074, P = 0.599). The median MAP decrease was 13 mmHg, with an IQR of 11 mmHg.

The Shapiro‒Wilk test revealed that neither the dose nor the recovery time fit a normal distribution (both P < 0.001). Spearman rank correlation analysis was also conducted to evaluate the correlation between recovery time and dose. The results revealed no correlation (rs=0.085, P = 0.543). The median recovery time was 5 min, with an IQR of 6 min.

The incidences of hypotension in Groups A to D were 20.0%, 25.0%, 15.0% and 0%, respectively. Fisher’s exact test revealed no significant difference between the groups (P = 0.760, Table 2). Bradycardia occurred in 3 patients, and severe choking cough occurred in 2 out of 53 patients. None of the patients developed severe airway obstruction, hypoxemia, PONV or injection pain.

Table 2 Incidence of hypotension in different dose groups
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Comparisons of the MAP, HR and incidence of hypotension between dose groups were exploratory because the samples were not randomly assigned to each group, resulting in unbalanced sample sizes between groups.

Discussion

The aim of this study was to determine the 90% effective dose of ciprofol combined with 5 µg of sufentanil for sedation during gastroscopy. This pharmacodynamic parameter can serve as a valuable tool for anesthesiologists in achieving more precise dosing, as the utilization of a lower dosage may yield favorable outcomes for patients.

Compared with propofol, ciprofol has comparable sedative effects but fewer adverse reactions. One study confirmed that the use of ciprofol was not inferior to the use of propofol for the treatment of patients who underwent gastroenteroscopy [12]. Therefore, ciprofol can replace propofol for sedation during gastroscopy. However, akin to propofol, the administration of ciprofol inevitably affects the respiratory and circulatory systems, although both are deemed safe and efficacious. Teng et al. reported that anesthesia-related adverse events occurred in 21.9% of patients who received 0.5 mg/kg ciprofol, whereas 16.1% of those who received 0.4 mg/kg ciprofol experienced anesthesia-related adverse events [15]. The adverse effects of drugs usually exhibit dose-dependent characteristics, indicating that lower doses tend to mitigate adverse effects. However, it is essential to establish a lower threshold for dosage to ensure adequate drug efficacy. The ED90 is frequently employed as the recommended target for the lower dose limit or serves as a reference value for estimating an individualized lower dose. An alternative approach involves the combination of anesthetics and opioids, such as propofol anesthesia combined with sufentanil, which effectively reduces the required dosage. Similar results were obtained when ciprofol was combined with opioids [9]. Thus, the determination of ED90 for patients receiving ciprofol combined with sufentanil during gastroscopy can better achieve the goal of minimizing the ciprofol dose.

Our study revealed that the ED90 of ciprofol combined with 5 µg of sufentanil for sedation during gastroscopy was 0.367 (95% CI: 0.344–0.416) mg/kg according to isotonic regression and 0.368 (95% CI: 0.347–0.419) mg/kg according to probit regression. The advantage of isotonic regression is that if the observed MLEs violate the monotonic increase in the cumulative distribution function (CDF), a secondary optimization can be performed using PAVA. In contrast, the probit model assumes that the probability density function follows a normal distribution. The data obtained for the study did not violate the monotonicity of the CDF, so to make the results more credible, the results of the two regression models were used for comparison.

Notably, previous studies have already established the satisfactory nature of the 0.4 mg/kg dose [11, 12, 15]. The result from our study was not significantly lower than the recommended dose in previous studies. This may be due to the stricter definition of anesthetic success. In certain studies, the dose of ciprofol that allowed successful completion of endoscopy was considered the effective dose for anesthesia, whereas our study defined successful anesthesia as not involving body movement or even swallowing or frowning, in a very strict way. Another possible reason why gastroscopy required a higher dose of ciprofol in our study than colonoscopy did in previous studies is the need to inhibit reflexes due to the rich distribution of nerves in the throat. Complete suppression of the patient’s body movements is essential to prevent accidental perforation or injury of the upper gastrointestinal tract. Therefore, in comparison with other studies, this study overestimated the ED90 because of its adherence to more rigorous criteria for anesthesia success. However, comparisons between the results of different studies cannot balance the individual differences of subjects, so the comparison between this study and previous studies aims to discover the possible reasons. The reliability of this conclusion needs to be further verified by designing randomized controlled trials of ciprofol combined with sufentanil and ciprofol alone for sedation during gastroscopy.

Propofol can cause hypotension by inhibiting myocardial contraction or decreasing vascular tone [31, 32]. This may also explain why ciprofol causes hypotension. However, the drop in blood pressure caused by ciprofol is usually temporary, with levels returning to baseline within 18 min [33]. This study reproduced the transient drop in MAP, which did not exceed 20 mmHg (Fig. 3). However, the MAP did not return to baseline levels in our study, and 18.9% of the MAP drops met the criteria for hypotension (Table 2). This may be attributed to the impact of sufentanil, a long-acting opioid, on the cardiovascular system. Our study revealed no statistically significant differences in the MAP, HR, or incidence of hypotension among the different dose groups. Additionally, Spearman’s correlation analysis revealed no correlation between the dose and the MAP drop after anesthesia. These results suggest that the combination of 5 µg of sufentanil with ciprofol in the dose range of 0.3–0.45 mg/kg does not have a dose-dependent effect on the cardiovascular system. Importantly, the biased coin-toss resulted in unbalanced and nonrandom samples in the dose groups. Therefore, more rigorous designs are needed to confirm the hemodynamic effects of ciprofols.

Our study revealed that the median recovery time was 5.0 (IQR: 6.0) minutes, which is consistent with the findings of a previous study in which 0.4 mg/kg ciprofol was used [33]. Furthermore, Spearman correlation analysis revealed no correlation between dose and recovery time (Fig. 4B). In the present study, no patients reported experiencing injection pain, possibly due to the analgesic effect of sufentanil. However, because of the lack of a control group, the evidence derived from this study is insufficient to assert that the combination of sufentanil and ciprofol confers an advantage in this regard. Therefore, further studies are needed to confirm these findings.

Our study has certain limitations. As a single-arm study, subgroup analyses with different doses face challenges related to the nonrandom assignment of subjects and unbalanced sample sizes in each group. Therefore, the conclusions drawn for the secondary clinical end points in the subgroup analyses are exploratory in nature, and further studies are needed to validate their reliability.

Conclusion

The ED90 of ciprofol in combination with 5 µg of sufentanil for sedation during gastroscopy was 0.367 mg/kg, with a 95% CI of 0.344–0.416 mg/kg. The MAP drops still decreased after anesthesia but did not decrease by more than 20 mmHg. The MAP did not demonstrate a dose-dependent effect within the range of 0.3–0.45 mg/kg ciprofol in this study.

Data availability

The data sets utilized and/or examined during the present investigation can be obtained upon reasonable request from the first author. The contact email address is whoboy555@hotmail.com.

Abbreviations

GABAA :

(Apolipoprotein E)

BCD:

The 50% effective dose

ED90 :

The 90% effective dose

BMI:

Body mass index

ASA:

American Society Anesthesiologists

MAP:

Mean arterial pressure

HR:

Heart rate

SpO2 :

Blood oxygen saturation

MOAA/S:

Modified Observer’s Assessment of Alertness/Sedation

PACU:

Post-anesthesia care unit

PONV:

Postoperative nausea and vomiting

SD:

Standard deviation

M:

Median

IQR:

Interquartile range

PAVA:

Pooled adjacent violators algorithm

GEE:

Generalized estimating equation

MLE:

Maximum likelihood estimate

95% CI:

95% confidence interval

MED:

Minimum effective dose

ICDF:

Inverse cumulative distribution function

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Funding

This work was supported by the Medical Health Science and Technology Project of Zhejiang Province (2022PY044).

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Authors and Affiliations

  1. Department of Anesthesiology, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China

    Bingwei Hu, Ting Guan, Chenyuan Yu, Danfeng Wang, Qing Wang & Hongwei Wang

  2. The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China

    Ting Guan, Chenyuan Yu & Hongwei Wang

Authors
  1. Bingwei Hu
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  2. Ting Guan
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  3. Chenyuan Yu
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  4. Danfeng Wang
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  5. Qing Wang
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  6. Hongwei Wang
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Contributions

BWH contributed to the study by assisting in data analysis and revising the manuscript during the revision process. TG assisted in conducting the study, collecting data, and writing the manuscript. CYY was involved in drafting tables, creating figures, and gathering data. DFW served as the executor of the clinical trial procedure. QW provided assistance with executing the clinical trial process. HWW played a role in designing the study and approving the manuscript.

Corresponding author

Correspondence to Hongwei Wang.

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Ethics statement

The study was approved by the Medical Ethics Committee of Tongde Hospital of Zhejiang Province (number: ZTD-2022-061) and registered at the Chinese Clinical Trial Registry (registration number: ChiCTR2200062764, principal investigator: Hongwei Wang, date of registration: 18/08/2022); the URL is https://www.chictr.org.cn/showproj.html?proj=177021. The study adheres to CONSORT guidelines and Declaration of Helsinki. Written informed consent was obtained from all patients.

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Not applicable.

Competing interests

The authors declare no competing interests.

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Hu, B., Guan, T., Yu, C. et al. Effective dose of ciprofol combined with low-dose sufentanil for sedation of gastroscopy: a dose-finding study using a biased coin design. BMC Anesthesiol 25, 124 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12871-025-02986-3

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12871-025-02986-3

Keywords

BMC Anesthesiology

ISSN: 1471-2253

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