Optimal dose of ciprofol combined with remifentanil for laryngeal mask placement without muscle relaxant: a biased-coin up-and-down sequential allocation trial

Abstract

Objective

To determine the effective dose of ciprofol in combination with remifentanil for successful laryngeal mask airway (LMA) placement without the use of muscle relaxants.

Design

A two-phase, biased-coin, up-and-down sequential allocation trial.

Setting

Single tertiary hospital; general anesthesia induction.

Patients

106 American Society of Anesthesiologists (ASA) physical status I–II adult patients (aged 18–75 years) scheduled for elective surgery under LMA anesthesia.

Interventions

• Phase 1: Ciprofol was fixed at 0.4 mg/kg, while remifentanil doses were adjusted using a biased-coin design to estimate the median effective dose (ED₅₀) and 95% effective dose (ED₉₅).

• Phase 2: Remifentanil was fixed at the ED₅₀ determined in Phase 1, and ciprofol doses were similarly titrated to determine its effective dose.

Measurements

Successful LMA placement was defined as the absence of coughing or gagging, along with an effective seal (air leak pressure > 20 cmH₂O). Secondary outcomes included hemodynamic fluctuations (ΔMAP > 20%), apnea, and injection pain.

Results

The ED₅₀ of remifentanil was 0.7 μg/kg when combined with ciprofol 0.34 mg/kg. Adverse events included hypotension (12.7%) and bradycardia (9.5%).

Conclusions

The combination of ciprofol 0.34 mg/kg and remifentanil 0.7 μg/kg provides effective conditions for LMA placement without muscle relaxants. This regimen reduces opioid requirements and may promote faster recovery.

Trial registration

Chinese Clinical Trial Registry ChiCTR2200062686; registered on August 15, 2022 (retrospectively registered).

Introduction

Ciprofol [1, 2], a propofol analog associated with reduced injection pain and rapid recovery, offers a promising basis for neuromuscular blocking agents free (NMBA-free) anesthesia when combined with the ultrashort-acting opioid remifentanil [3]. This combination can potentially provide smooth insertion conditions for the LMA while avoiding the risks of residual neuromuscular blockade [4–6]. However, the optimal dosing synergy for LMA placement has not been established. This study aimed to determine the median and 95% effective doses (ED₅₀/ED₉₅) of ciprofol and remifentanil for successful NMBA-free LMA insertion [7, 8].

Methods

Trial registration

This study was prospectively registered in the Chinese Clinical Trial Registry (ChiCTR) under the identifier ChiCTR2200062686 on August 15, 2022.

Study population

Following approval by the Institutional Ethics Committee (Ruijin Hospital, No. 202207) and trial registration (ChiCTR2200062686), 106 adult patients (American Society of Anesthesiologists physical status I–II, aged 18–75 years, body mass index ≤ 30 kg/m²) scheduled for elective surgery under general anesthesia with LMA were enrolled. Eligible surgeries were primarily urological and gynecological procedures with an anticipated surgical duration of 30–90 min. Patients requiring prone or lithotomy positions were excluded due to their potential influence on airway management and hemodynamic stability. Exclusion criteria also included predicted difficult airway (defined as Mallampati classification III or IV, or mouth opening < 3 cm), gastroesophageal reflux disease, known allergy to opioids, pregnancy, and recent participation in another clinical trial. All enrolled patients provided written informed consent. Patients were followed for up to one year postoperatively to assess long-term safety outcomes.

Three patients were excluded on the day of surgery due to the onset of fever. These cases were classified as “others”.

Anesthesia protocol

Pre-induction

Standard monitoring was established, including electrocardiography, pulse oximetry, non-invasive blood pressure, and bispectral index (BIS).

Drug administration

Phase 1

Ciprofol was administered intravenously at a fixed dose of 0.4 mg/kg, injected over 30 s. Remifentanil was then started at 1 µg/kg, also injected over 30 s, and subsequently adjusted according to the biased-coin sequential allocation design.

Phase 2

Based on the results of phase 1, remifentanil was fixed at its ED₅₀ (0.7 µg/kg), injected over 30 s, followed by ciprofol administered over 30 s at doses titrated using the same sequential design.

No sedative premedication (e.g., midazolam or penehyclidine) was administered. All drugs were given through a fast-running intravenous line to ensure rapid delivery.

LMA insertion

Laryngeal mask airway insertion was performed 90 s after ciprofol administration by anesthesiologists who were blinded to the drug doses. Adequate depth of hypnosis was confirmed by a BIS value below 60 immediately before LMA insertion.

Blinding

An independent anesthesiologist not involved in patient care or outcome assessment prepared the study drugs according to the sequential allocation schedule and labeled the syringes only with the patient’s study ID. The attending anesthesiologist, who performed LMA insertion and assessed outcomes, was blinded to the drug doses. The randomization sequence was concealed until database lock.

Outcome assessment

Primary outcome

Successful LMA insertion was defined as adequate jaw relaxation, absence of gagging or coughing during or after placement, and an oropharyngeal leak pressure > 20 cmH₂O, measured by closing the adjustable pressure-limiting valve and observing the airway pressure at which an audible leak occurred during manual ventilation.

Secondary outcomes

These included hypotension (mean arterial pressure < 65 mmHg), bradycardia (heart rate < 50 beats/min), apnea (duration > 30 s), and injection pain assessed using a visual analogue scale (VAS).

Statistical analysis

Effective doses were determined via a biased‑coin up‑and‑down design and probit regression to estimate the median effective dose (ED₅₀) and 95% effective dose (ED₉₅) with their 95% confidence intervals (CIs). The sample size was not determined by conventional power analysis but was based on simulation studies for sequential allocation designs. According to Pace and Stylianou [9], approximately 30–40 patients per phase are sufficient to obtain stable ED₅₀ estimates in biased-coin up-and-down trials. This range is consistent with previous dose-finding studies using similar methodology, and our sample sizes (Phase 1: n = 31; Phase 2: n = 32) fall within this recommended range. All analyses and graphics were conducted in R (v4.2.2) using the MASS and ggplot2 packages.

Results

Patient enrollment and characteristics

Between 2022.08 and 2025.08, a total of 106 patients were assessed for eligibility. After exclusions, 75 patients were enrolled and completed the trial (Phase 1: n = 35; Phase 2: n = 40), with comparable baseline demographics between phases (Table 1). A Consolidated Standards of Reporting Trials (CONSORT) flow diagram is provided in Fig. 1.

Table 1.

Demographic characteristics (n = 63)

Characteristic	Unit	Value
Age	years	52.05 ± 9.20
Weight	kg	69.51 ± 11.80
Height	cm	164.8 ± 12.2
Body mass index	kg/m2	25.33 ± 2.95
ASA grade(Ⅰ/Ⅱ)	%	47(75%)/16 (25%)

Fig. 1.

Study follow diagram

Effective dose estimation

The dose-response relationships for remifentanil and ciprofol were determined by probit analysis of sequential allocation data.

Phase 1 (Ciprofol fixed at 0.4 mg/kg)

In 31 patients, the ED₅₀ of remifentanil for successful LMA placement was 0.7 µg/kg (95% CI: 0.5–0.8 µg/kg) (Fig. 2). The ED₉₅, extrapolated beyond the tested dose range, was estimated at 2.17 µg/kg (95% CI: 1.36–2.97 µg/kg). The sequential allocation and dose-response relationship are shown in Fig. 2A and B, respectively.

Fig. 2.

Determination of the effective dose of remifentanil for successful laryngeal mask airway (LMA) placement with a fixed ciprofol dose (0.4 mg/kg). A Sequential allocation plot. Each point represents an individual patient, with blue circles indicating successful LMA placement and red circles indicating failure. The dotted line connects patients in the order of enrollment. B Probit regression model for the dose-response relationship. The solid blue line represents the predicted probability of successful LMA placement, and the shaded area indicates the 95% confidence interval of the fitted model. Black circles represent the observed success rate at each tested dose (jittered for clarity). The estimated ED₅₀ was 0.7 µg/kg (95% CI: 0.5–0.8 µg/kg)

Phase 2 (Remifentanil fixed at 0.7 µg/kg)

In 32 patients, the ED₅₀ of ciprofol was 0.34 mg/kg (95% CI: 0.32–0.35 mg/kg) (Fig. 3). The ED₉₅ was estimated at 0.47 mg/kg (95% CI: 0.42–0.52 mg/kg), with the upper bound of the confidence interval remaining within a clinically adjacent range to the tested doses. The sequential allocation and dose-response relationship are presented in Fig. 3A and B, respectively.

Fig. 3.

Determination of the effective dose of ciprofol for successful LMA placement with a fixed remifentanil dose (0.7 µg/kg). A Sequential allocation plot (blue, success; red, failure). B Probit regression model with 95% confidence interval (shaded area). Black circles represent the observed success rate at each tested dose. The estimated ED₅₀ was 0.34 mg/kg (95% CI: 0.32–0.35 mg/kg)

Secondary outcomes and adverse events

The incidence of key adverse events across both phases (n = 63) was as follows:

• Hypotension, defined as mean arterial pressure (MAP) < 65 mmHg: 12.7% (8/63)

• Bradycardia (HR < 50 bpm): 9.5% (6/63)

• Apnea (> 30 s): 0

• Injection pain (VAS score > 3): 1.59% (1/63)

• Subgroup analysis suggested that hypotensive events were more frequent in patients with ASA grade II (4/16, 25%) compared to ASA grade I (4/47, 8.5%), although the small number of events precluded formal statistical testing. No clear associations were observed between hemodynamic fluctuations and age or BMI

• No long-term complications directly related to the investigational drug combination or procedural protocol were observed at the one-year follow-up assessment

All adverse events were transient and resolved with standard clinical management.

Discussion

This study translates dose-finding methodology into a directly applicable clinical protocol. We recommend ciprofol 0.34 mg/kg combined with remifentanil 0.7 µg/kg as an evidence-based starting dose for LMA insertion without muscle relaxants, providing a predictable 50% success probability that is safe and effective for initial clinical adoption [10].

Immediate clinical advantages

This regimen offers several immediate clinical advantages. First, it provides a validated alternative to higher-dose propofol-remifentanil combinations, directly addressing the need for opioid-sparing techniques in fast-track anesthesia. The lower remifentanil requirement may reduce opioid-related side effects like respiratory depression and nausea, facilitating faster Post-Anesthesia Care Unit (PACU) discharge [11–13]. Second, the dosing is straightforward and the hemodynamic profile manageable, making it suitable for routine surgical lists, while the near-elimination of injection pain with ciprofol improves patient comfort during induction [14, 15]. Third, by definitively avoiding neuromuscular blockers, this protocol eliminates the risks of residual paralysis and simplifies postoperative monitoring, making it ideal for ambulatory and short-stay surgeries within enhanced recovery after surgery (ERAS) programs [16–18].

Comparison with propofol-based regimens

Compared to the well-established propofol-remifentanil combination for LMA insertion, our ciprofol-based regimen offers several potential advantages. The ED₅₀ of remifentanil identified in this study (0.7 µg/kg) is notably lower than the 1.2–1.5 µg/kg typically required when combined with propofol 2.0–2.5 mg/kg. This opioid-sparing effect may reduce the risk of opioid-related adverse events such as postoperative nausea and vomiting and respiratory depression. Furthermore, the incidence of injection pain in our study (1.6%) was substantially lower than the 30–70% reported with propofol [14], enhancing patient comfort during induction. The hemodynamic profile was generally stable, with hypotension (12.7%) and bradycardia (9.5%) rates comparable to or lower than those observed with propofol-based regimens [19, 20]. These findings suggest that ciprofol is a promising alternative to propofol for NMBA-free LMA anesthesia, particularly in fast-track and ambulatory.

From ED₅₀ to bedside titration

The ED₅₀ is the most robust estimate from our sequential design and serves as the optimal clinical anchor. In practice, anesthesiologists can start with this dose and titrate upward in small increments (e.g., increasing ciprofol by 0.05 mg/kg) for patients with higher anticipation of airway reactivity, thereby individualizing therapy while minimizing oversedation or hemodynamic instability [21]. Our ED₉₅ estimate, while indicative of a ceiling effect, should not be the primary clinical target due to the increased side-effect burden at doses far beyond the ED₅₀.

Implementation considerations and future development

Successful implementation requires patient selection akin to our study criteria (ASA I-II, no predicted difficult airway). For widespread adoption, this regimen should be incorporated into institutional anesthesia guidelines and compared against standard practices in real-world effectiveness studies [22, 23]. Future research should evaluate its impact on turnover times, patient satisfaction, and recovery quality scores—key metrics of value-based care.

Limitations

This study has several limitations. First, the study population was predominantly middle-aged (mean age 52.1 ± 9.2 years), with limited representation of elderly patients (> 75 years). As age-related pharmacokinetic and pharmacodynamic changes may alter drug sensitivity and hemodynamic responses, the generalizability of our findings to older populations requires further validation. Future studies should include a broader age range to establish age-specific dosing recommendations. Second, this was a single-center study with a relatively modest sample size, which may limit the generalizability of the results. Third, while we assessed hemodynamic changes, the study was not powered to detect predictors of hypotension or bradycardia. The observed numerical difference in hypotensive events between ASA I and II patients is descriptive and hypothesis-generating only; further research with larger sample sizes is needed to identify patient characteristics associated with hemodynamic instability under this regimen.

Conclusion

We have defined a clinically translatable, ED₅₀-based dosing regimen of ciprofol-remifentanil for NMBA-free LMA insertion. This protocol offers a safe, effective, and opioid-efficient option that is ready for integration into modern anesthesia practice to support enhanced recovery.

Abbreviations

ASA

American Society of Anesthesiologists

BIS

Bispectral index

CI

Confidence interval

CONSORT

Consolidated Standards of Reporting Trials

ED₅₀

Median effective dose

ED₉₅

95% effective dose

ERAS

Enhanced Recovery After Surgery

LMA

Laryngeal mask airway

MAP

Mean arterial pressure

NMBA

Neuromuscular blocking agent

PACU

Post-Anesthesia Care Unit

VAS

Visual analogue scale

Authors’ contributions

L.X. and L.Y. contributed equally to this work. L.X. and L.Y. conceived and designed the study, obtained ethical approval, supervised the entire research process, and are responsible for the overall direction and planning. L.X., L.Y.and W.H. were involved in patient recruitment and the execution of the anesthesia protocol. B.C. contributed to data collection and curation. W.Y. performed the statistical analysis and prepared the figures. L.X. drafted the initial manuscript. L.Y., W.H., B.C., and W.Y. provided critical revision of the manuscript for important intellectual content. All authors reviewed and approved the final version of the manuscript.

Funding

This work was supported by the Bethune Charitable Foundation (Grant No. SX2022-010).

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (No. 202207). All methods were performed in accordance with the relevant guidelines and regulations (e.g., Declaration of Helsinki). Written informed consent was obtained from all individual participants included in the study.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.