ED95 of Ciprofol Combined with Esketamine or Sufentanil in Elderly Patients Undergoing Endoscopic Submucosal Dissection: A Dose-Finding and Randomized Controlled Trial

Abstract

Background

This study aimed to estimate the 95% effective dose (ED95) of ciprofol when combined with esketamine or sufentanil in elderly patients undergoing endoscopic submucosal dissection (ESD), and to explore the associated clinical and safety profiles of these sedation strategies.

Methods

This study was conducted in two phases. In Phase 1, 44 patients aged 65–80 years undergoing ESD were randomized to receive ciprofol combined with esketamine (group E) or sufentanil (group S). Dixon’s up-and-down method was used to characterize the dose-response relationship of ciprofol, and ED95 values were derived as model-based estimates. In Phase 2, 68 patients were randomized to group E or group S. Phase 2 was designed as an exploratory randomized comparison, and intraoperative parameters, hemodynamic variables, and postoperative outcomes were recorded.

Results

Based on model-based analysis, the estimated ED95 of ciprofol combined with esketamine was 0.276 mg/kg (95% CI: 0.264–0.349), while that combined with sufentanil was 0.244 mg/kg (95% CI: 0.236–0.282). No significant differences were observed between the two groups in the proportion of patients requiring rescue sedation or analgesia (P > 0.05). Induction time was shorter in group E than in group S (P = 0.039). During the procedure, group E showed lower incidences of hypoxia and hypotension and less fluctuation in mean arterial pressure (MAP) and heart rate (HR) compared with group S (P < 0.05). In contrast, the time to full alertness was longer in group E than in group S (P = 0.012).

Conclusion

Ciprofol combined with esketamine or sufentanil showed different clinical and hemodynamic profiles in elderly patients undergoing ESD. These findings were derived from an exploratory analysis and should be interpreted as strategy-specific rather than evidence of superiority. The longer time to full alertness with esketamine indicates a potential trade-off.

Trial Registration

Chictr.org.cn; identifier: ChiCTR2500102341.

Introduction

Endoscopic submucosal dissection (ESD) is a minimally invasive technique widely used for the treatment of early-stage gastrointestinal cancers and most mucosal lesions, which provides benefits including a high cure rate, minimal trauma, reduced bleeding, and shorter recovery time.1,2 However, ESD is a technically demanding procedure that often requires prolonged operating time and stable deep sedation to ensure patient comfort and procedural success. In elderly patients, sedation and anesthesia management pose particular challenges as a result of age-related physiological decline and an increased burden of comorbidities.3,4 According to the sedation guidelines of the British Society of Gastroenterology (BSG), although there is no consensus on the optimal sedation strategy for ESD, deep sedation is recommended.5 Traditional anesthetic agents, including opioids and benzodiazepines, are commonly used to alleviate discomfort; however, concerns remain regarding their variable efficacy and potential safety risks.6–8

Sufentanil, a potent opioid analgesic, is known for its strong analgesic efficacy, rapid onset, and relatively short duration of action, while exhibiting a reduced but still significant risk of respiratory depression and hemodynamic instability. These properties make it particularly suitable for procedures requiring precise analgesia, such as minimally invasive and ambulatory surgeries.9,10 Meanwhile, ciprofol, a novel intravenous sedative, has been recognized for its potent sedative effects and improved safety profile compared to propofol, with a more stable hemodynamic profile and reduced incidence of respiratory depression.11 However, both ciprofol and sufentanil exert dose-dependent central nervous system depression, which may lead to hemodynamic instability, including hypotension and respiratory depression.12,13 Their combined use may further exacerbate these risks, necessitating careful dose adjustments and close intraoperative monitoring. Notably, in elderly patients undergoing ESD, the optimal dosing regimen for the ciprofol–sufentanil combination remains inadequately investigated, highlighting the need for further research to optimize its clinical application.

Esketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, not only provides potent analgesic effects but also potentiates sedation through NMDA receptor modulation when combined with other agents.14 Compared with opioid analgesics, esketamine does not cause significant respiratory depression, making it a valuable component in multimodal analgesia.15,16 Its clinical use has expanded, particularly in multimodal analgesic regimens, where it has demonstrated promising efficacy and a favorable safety profile. Esketamine activates the sympathetic nervous system, promoting norepinephrine release, which induces vasoconstriction and subsequently increases blood pressure and heart rate.17 This unique pharmacological property can counteract the hypotensive and bradycardic effects of ciprofol, thereby contributing to hemodynamic stability in elderly patients undergoing ESD. However, esketamine is also associated with dose-dependent neuropsychiatric effects, including hallucinations and delayed recovery, which may be of particular concern in elderly patients.

This study was designed to compare the clinical and safety characteristics of ciprofol combined with esketamine versus sufentanil in elderly patients undergoing ESD. In addition, a dose-finding approach was used to estimate the ED95 of ciprofol for each combination to inform sedation strategies in this population. From a clinical perspective, 95% effective dose (ED95) rather than ED50 may be more relevant for procedural sedation, as it reflects a dosing strategy aimed at minimizing sedation failure and the need for rescue interventions during technically demanding procedures such as ESD.

Methods

Study Design

This study was approved by the Ethics Committee of Shanghai Xuhui Central Hospital (Approval No.: 2024–019) and registered in the Chinese Clinical Trial Registry (www.chictr.org.cn, Registration No.: ChiCTR2500102341). Trial registration was completed on May 13, 2025, prior to the enrollment of the first participant. Participant enrollment was conducted between May and July 2025. The study was conducted in accordance with the Declaration of Helsinki, and written informed consent was obtained from all participants before enrollment. This study was designed and reported in accordance with the CONSORT guidelines and was conducted at a tertiary teaching hospital with a dedicated endoscopy center and anesthesiology department. All sedation procedures were performed by board-certified anesthesiologists who had received standardized training in procedural sedation.

The study was conducted in two phases. Phase 1 was a dose-finding study designed to estimate the effective dose of ciprofol when combined with either esketamine or sufentanil in elderly patients undergoing ESD, using a Dixon up-and-down approach. Phase 2 was an exploratory randomized clinical study designed to evaluate perioperative clinical outcomes, including hemodynamic responses, recovery-related parameters, and safety outcomes, with induction dosing guided by the ED95 estimates derived from Phase 1.

Although the trial was prospectively registered, minor deviations from the registered protocol occurred during study implementation. These deviations were limited to refinements in outcome assessment and data collection procedures to accommodate real-world clinical workflow and ensure patient safety. Importantly, these changes did not affect the primary objectives, eligibility criteria, or overall study design.

Patients Eligibility

Elderly patients scheduled to undergo ESD at our hospital between May and July 2025 were prospectively enrolled in this study.

Inclusion criteria: (1) Age 65 to 80 years; (2) ASA classification II to III; (3) Modified Mallampati score ≤III; (4) Body mass index (BMI) between 18 and 28 kg/m².

Exclusion criteria: (1) Known allergy to anesthetic agents; (2) History of pharyngeal surgery or difficult intubation; (3) Significant impairment of cardiac, pulmonary, hepatic, or renal function; (4) Uncontrolled hypertension (systolic ≥160 mmHg or diastolic ≥100 mmHg); (5) Emergency endoscopic procedures; (6) Psychiatric disorders or Alzheimer’s disease preventing effective communication; (7) Use of study-related drugs within the past three months; (8) Increased aspiration risk due to gastrointestinal obstruction; (9) Respiratory tract infection within the past two weeks; (10) Concurrent participation in other clinical trials.

No interim analyses were planned, and no stopping guidelines were established for this trial.

Phase 1: Dose-Finding

Patients were assessed one day before the procedure. All patients fasted for 8 hours prior to the procedure and were allowed to consume 150–200 mL of glucose-electrolyte solution 2 hours preoperatively, followed by fluid restriction. Patients were randomly assigned to either the esketamine group (E group) or the sufentanil group (S group) using a randomized table method. The random allocation sequence was concealed using sequentially numbered, opaque, sealed envelopes prepared by a member of the study team who was not involved in patient recruitment or intervention. The envelopes were opened sequentially only after the patient had been enrolled and baseline data were recorded, thereby ensuring concealment of group allocation until the time of assignment. Participants and outcome assessors were blinded to group allocation. The anesthesiologists who administered the interventions were not blinded because of the nature of the drugs. This lack of blinding may have influenced certain operator-dependent intraoperative decisions, such as the timing of rescue medication or hemodynamic interventions. Data analysis was performed by an investigator who was unaware of group assignments. Upon entering the operating room, an intravenous (IV) line was established, and 0.9% sodium chloride solution was administered at 5 mL/kg. Routine monitoring, including electrocardiography (ECG), heart rate (HR), blood pressure (BP), and oxygen saturation (SpO₂), was initiated. Patients received facemask ventilation with the anesthesia machine set to 10 L/min oxygen flow at 100% oxygen concentration. After five deep breaths for denitrogenation, a nasal cannula was applied with an oxygen flow rate of 3 L/min.

Subsequently, patients in the E group received esketamine 0.5 mg/kg, while those in the S group received sufentanil 0.1 μg/kg, both administered over 60 seconds. This was followed by an intravenous injection of ciprofol over 30 seconds. Thirty seconds after the ciprofol injection, the depth of sedation was assessed using the Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) scale,18 which is defined as follows: 5 points: Responds readily to name spoken in normal tone; 4 points: Lethargic response to name spoken in normal tone; 3 points: Responds only after name is called loudly and/or repeatedly; 2 points: Responds only after mild prodding or shaking; 1 point: Responds only after painful trapezius squeeze; 0 points: Does not respond to painful trapezius squeeze. The absence of objective monitoring tools, such as bispectral index (BIS), may have limited the precision of sedation assessment, particularly in this elderly population.

Endoscope insertion began once the eyelash reflex was completely abolished and the MOAA/S score reached 0–1. If sedation failure occurred (defined as nausea, coughing, movement, or other responses interfering with the procedure within 5 minutes of endoscope insertion),19 an additional ciprofol dose of 0.15 mg/kg was administered over 10 seconds. Each additional dose was spaced at least 2 minutes apart, with a maximum of five supplemental doses within a 15-minute period.

The dose of ciprofol was adjusted using the Dixon up-and-down sequential method.20 According to the Ciprofol Injection Prescribing Information, the recommended dose for adult patients is 0.4 mg/kg, while for elderly patients, the initial dose was set at 0.3 mg/kg, with an increment/decrement step of 0.02 mg/kg to allow fine dose adjustment. The dose for the next patient was adjusted according to the sedation outcome of the previous patient. The stopping rule of the Dixon method requires at least six crossover points. In this study, dose adjustment continued until seven crossover points were obtained, at which point the study was terminated.21 Although Dixon’s up-and-down method is primarily designed for ED50 estimation, ED95 values in this study were derived using a model-based extrapolation approach and should therefore be interpreted with appropriate caution.

Phase 2: Safety and Efficacy Assessment

After induction with a ciprofol dose guided by the ED95 estimates from Phase 1, anesthesia was maintained using continuous intravenous infusion at a clinically established maintenance rate (mg/kg/h), with dose adjustments made according to sedation depth and procedural requirements. Before mucosal dissection, patients in the E group received an intravenous bolus of esketamine 0.5 mg/kg, while those in the S group received sufentanil 0.1 μg/kg. If intraoperative sedation was inadequate (MOAA/S >1), an additional bolus of ciprofol 0.15 mg/kg was administered. If analgesia was insufficient, an additional bolus of esketamine 0.25 mg/kg or sufentanil 0.05 μg/kg was administered based on group allocation.

If SpO₂ dropped below 92%, oxygen flow was increased, and the jaw thrust maneuver was performed to open the airway. If SpO₂ fell below 85%, positive pressure ventilation via a face mask was applied, and a laryngeal mask airway (LMA) was used if necessary. In the event of hypotension, patients received ephedrine 6 mg or phenylephrine 40 μg intravenously. For hypertension, urapidil 10–25 mg was administered intravenously. For bradycardia, atropine 0.5 mg was given intravenously. For tachycardia, intravenous esmolol (0.5–1 mg/kg) was administered as needed.

At the end of the procedure, ciprofol infusion was discontinued, and MOAA/S scores were assessed every minute until the patient achieved a score of ≥4, at which point they were transferred to the post-anesthesia care unit (PACU). In the PACU, postoperative pain was assessed using the Numeric Rating Scale (NRS).22 If NRS ≥4, flurbiprofen axetil 50 mg was administered intravenously for pain management. Recovery was assessed using the Modified Aldrete Score,23 which evaluates five components: activity, respiration, circulation, consciousness, and SpO₂. Each component was scored from 0 to 2, with a total possible score of 10. Patients were eligible for discharge from PACU once they achieved a Modified Aldrete Score of ≥9 on three consecutive assessments, after which they were allowed to leave under the supervision of a family member.

Outcome Measures

In Phase 1, the primary outcome was the dose–response relationship of ciprofol in combination with esketamine or sufentanil in elderly patients undergoing ESD. ED95 values were subsequently derived using model-based analysis.

In Phase 2, the primary outcome was the incidence of intraoperative hypotension. Secondary outcomes included hemodynamic parameters, induction time, recovery-related outcomes, use of rescue medications, and the incidence of other perioperative adverse events. Phase 2 was designed as an exploratory analysis and was not specifically powered to detect differences across all secondary outcomes. In addition, some adverse events, such as hallucinations and agitation, were based on subjective assessment and may have been underreported; cognitive outcomes, including delirium and postoperative neurocognitive function, were not systematically assessed. Mean arterial pressure (MAP) and heart rate (HR) were recorded at the following time points: before anesthesia induction (T0), after ciprofol injection (T1), after endoscope insertion (T2), at the start of mucosal dissection (T3), at endoscope removal (T4), and upon PACU admission (T5). Additionally, the induction time, defined as the interval from the end of drug administration to the disappearance of the eyelash reflex and an MOAA/S score of 0–1, the time to full alertness, defined as the duration from endoscope removal until an MOAA/S score of ≥4 was reached, and the recovery time, measured from PACU admission until a Modified Aldrete Score of ≥9 was achieved, were recorded. The study also documented intraoperative rescue medication use for sedation and analgesia, as well as the occurrence of adverse events, including hypoxia, hypotension, hypertension, bradycardia, and tachycardia, along with postoperative symptoms in the PACU, such as nausea, vomiting, dizziness, headache, hallucinations, agitation, and postoperative analgesia requirements. Hypoxia was defined as SpO₂ < 92%, while hypotension and hypertension were defined as a MAP decrease or increase of more than 20% from baseline, respectively. Bradycardia and tachycardia were defined as a HR decrease or increase of more than 20% from baseline lasting for more than 30 seconds.

Statistical Analysis

GraphPad Prism 10.0.3 was used to generate the Dixon up-and-down sequential plot, while SPSS 26.0 was employed to fit a Probit regression model to characterize the dose–response relationship of ciprofol. Based on this model, ED95 values and corresponding 95% confidence interval (95% CI) were derived. Sample size was determined using PASS 11.0 software. Based on a pilot study (10 patients per group), the incidence of hypotension was 10% in the E group and 40% in the S group. With a significance level of α = 0.05, a power of 1-β = 0.8, and an equal allocation ratio (1:1), the minimum sample size per group was calculated to be 31 patients. Accounting for a 10% dropout rate, the final sample size was set at 35 patients per group.

Statistical analysis was conducted using SPSS 26.0. The Kolmogorov–Smirnov test was used to assess the normality of continuous variables. If data followed a normal distribution, they were presented as mean ± standard deviation () and analyzed using the t-test. If data did not conform to a normal distribution, they were expressed as the median and interquartile range (IQR) and analyzed using the Mann–Whitney U-test. Categorical variables were analyzed using the χ²-test. If more than 20% of expected counts in a 2×2 contingency table were <5, or if any expected count was <1, Fisher’s exact test was applied. A P-value <0.05 was considered statistically significant. Given the exploratory nature of Phase 2, no formal adjustment for multiple comparisons was applied, and the results for secondary outcomes should be interpreted descriptively. Analyses of hemodynamic variables at predefined time points were specified a priori, whereas other secondary analyses were considered exploratory.

Results

Dose-Finding

A total of 44 patients were enrolled in Phase 1, with 24 in the E group and 20 in the S group. No statistically significant differences were observed between the two groups regarding age, sex, BMI, ASA classification, or the prevalence of diabetes and hypertension (Table 1). Based on model-based analysis, the estimated ED95 of ciprofol was 0.276 mg/kg (95% CI: 0.264–0.349) when combined with esketamine and 0.244 mg/kg (95% CI: 0.236–0.282) when combined with sufentanil. The dose adjustments for ciprofol using the up-and-down sequential method are shown in Figure 1 (group E) and Figure 2 (group S).

Table 1.

Basic Characteristics for Two Groups in Phase 1

Variable	Group E (n=24)	Group S (n=20)	t/χ2	P value
Age (years)	71.1±4.1	71.8±3.7	0.572	0.570
Sex (male/female)	14/10	12/8	0.013	0.911
BMI (kg/m2)	22.9±2.1	22.2±2.0	1.082	0.285
ASA classification (II/III)	11/13	8/12	0.151	0.697
Diabetes*	3 (12.5)	3 (15.0)	–	1.000
Hypertension*	2 (8.3)	1 (5.0)	–	1.000

Notes: Data are presented as mean ± SD or n (%); *Fisher’s exact test.

Abbreviations: ASA, American Anesthesiologists Association; BMI, body mass index.

Figure 1.

Individual responses (sedation success) to ciprofol combined with esketamine evaluated using Dixon’s up-and-down method.

Figure 2.

Individual responses (sedation success) to ciprofol combined with sufentanil evaluated using Dixon’s up-and-down method.

Safety and Efficacy Assessment

Patient Characteristics

In the E group, one patient was excluded due to a BMI below 18 kg/m², while in the S group, one patient was withdrawn at their family’s request. Thus, 34 patients were included in each group. The CONSORT diagram is shown in Figure 3. No statistically significant differences were observed between the two groups regarding age, sex, BMI, ASA classification, prevalence of diabetes and hypertension, or procedure duration (Table 2).

Figure 3.

CONSORT flow diagram of patient enrollment.

Table 2.

Basic Characteristics for Two Groups in Phase 2

Variable	Group E (n=34)	Group S (n=34)	t/χ2	P value
Age (years)	72.2±4.1	71.8±3.9	0.364	0.717
Sex (male/female)	22/12	20/14	0.249	0.618
BMI (kg/m2)	22.8±2.4	23.3±2.3	0.859	0.393
ASA classification (II/III)	15/19	17/17	0.236	0.627
Diabetes*	4 (11.8)	3 (8.8)	–	1.000
Hypertension*	5 (14.7)	3 (8.8)	–	0.709
Procedure duration (min)#	56.5 [32.8, 76.3]	53.0 [31.0, 65.0]	0.693	0.488

Notes: Data are presented as mean ± SD or n (%); *Fisher’s exact test; ^#Median [IQR].

Abbreviations: ASA, American Anesthesiologists Association; BMI, body mass index.

Intraoperative Outcomes

The number of patients requiring rescue sedation or analgesia did not differ significantly between the two groups (P > 0.05). The induction time was significantly shorter in the E group than in the S group (P = 0.039). The incidence of hypoxia and hypotension was significantly lower in the E group than in the S group (P < 0.05). The incidence of hypertension, bradycardia, and tachycardia did not differ significantly between the two groups (P > 0.05) (Table 3).

Table 3.

Intraoperative Outcomes for Two Groups in Phase 2

Variable	Group E (n=34)	Group S (n=34)	t/χ2	P value
Rescue sedation*	3 (8.8)	2 (5.9)	–	1.000
Rescue analgesia*	5 (14.7)	1 (2.9)	–	0.197
Induction time (s)	57.7±14.6	65.2±14.8	2.105	0.039
Hypoxia	2 (5.9)	9 (26.5)	5.314	0.021
Hypotension*	1 (2.9)	11 (32.4)	10.119	0.001
Hypertension*	2 (5.9)	1 (2.9)	–	1.000
Bradycardia*	1 (2.9)	3 (8.8)	–	0.614
Tachycardia*	1 (2.9)	0 (0)	–	1.000

Notes: Data are presented as mean ± SD or n (%); *Fisher’s exact test.

Hemodynamic Changes

At T1, T2, and T3, the MAP in the E group was significantly higher than in the S group (P < 0.05) (Figure 4). Similarly, at T1 and T3, the HR in the E group was significantly higher than in the S group (P < 0.05) (Figure 5). No significant differences in MAP or HR were observed between the two groups at other time points (P > 0.05).

Figure 4.

Changes in mean arterial pressure (MAP) at predefined time points. Data are presented as mean ± standard deviation. *P < 0.05 indicates a significant difference between groups.

Figure 5.

Changes in heart rate (HR) at predefined time points. Data are presented as mean ± standard deviation. *P < 0.05 indicates a significant difference between groups.

Postoperative Outcomes

The time to full alertness was significantly longer in the E group than in the S group (P = 0.012). No significant differences were observed between the two groups in recovery time, the number of patients requiring postoperative analgesia, or the incidence of nausea, vomiting, dizziness, headache, hallucinations, or agitation (P > 0.05) (Table 4).

Table 4.

Postoperative Outcomes for Two Groups in Phase 2

Variable	Group E (n=34)	Group S (n=34)	t/χ2	P value
Time to full alertness (min)	5.0±1.8	4.0±1.5	2.577	0.012
Recovery time (min)	41.3±7.1	42.0±6.5	0.460	0.657
Postoperative analgesia*	7 (20.6)	2 (5.9)	–	0.150
Nausea*	3 (8.8)	2 (5.9)	–	1.000
Vomiting*	1 (2.9)	0	–	1.000
Dizziness	5 (14.7)	9 (26.5)	1.619	0.203
Headache*	3 (8.8)	0	–	0.239
Hallucinations*	3 (8.8)	0	–	0.239
Agitation*	0	0	–	–

Notes: Data are presented as mean ± SD or n (%); *Fisher’s exact test.

Discussion

This study aimed to compare the efficacy and safety of ciprofol combined with esketamine versus ciprofol combined with sufentanil in elderly patients undergoing ESD. Based on dose-finding analysis, the ED95 of ciprofol combined with esketamine was 0.276 mg/kg (95% CI: 0.264–0.349), while that of ciprofol combined with sufentanil was 0.244 mg/kg (95% CI: 0.236–0.282). These findings provide preliminary reference values for dose selection and may inform sedation management in elderly patients undergoing ESD.

Ciprofol is a novel short-acting intravenous sedative, acting as a γ-aminobutyric acid type A (GABAA) receptor agonist. It enhances GABA receptor activity, thereby inhibiting central nervous system excitability.24 Compared with propofol, ciprofol exhibits greater selectivity and a more favorable safety profile, particularly showing a milder impact on respiratory depression and hemodynamics.25 Ciprofol induces rapid sedation and has a short half-life, making it suitable for procedures requiring precise sedation control and analgesia.26 Phase III clinical studies have shown that ciprofol provides sedation comparable to propofol, with a significantly lower incidence of adverse events.27 Esketamine, an NMDA receptor antagonist, exerts both analgesic and sedative effects by blocking NMDA receptor-mediated neuronal excitation.28 Unlike traditional opioids, esketamine offers potent analgesia while minimizing the risk of respiratory depression and hypotension.29 In elderly patients, esketamine enhances the analgesic profile of ciprofol while activating the sympathetic nervous system to mitigate potential hypotension.17 Although no studies have specifically investigated the ciprofol-esketamine combination, Song et al30 reported that combining esketamine with propofol reduced the incidence of hypoxia and hypotension by 61% compared to propofol alone. Similarly, Yang et al31 demonstrated that the likelihood of hypotension progressively decreased as the esketamine-propofol dose ratio increased.

This study demonstrated that ciprofol combined with esketamine resulted in a shorter anesthesia induction time and a lower incidence of hypotension compared to ciprofol combined with sufentanil. Given the exploratory design of Phase 2, these comparative findings should be interpreted cautiously and viewed as strategy-specific observations rather than confirmatory evidence of inherent superiority. These differences may be related to the distinct pharmacological profiles of the two drug combinations. Weng et al32 evaluated the efficacy and safety of propofol combined with either esketamine or alfentanil in patients undergoing hysteroscopy. Their results indicated that the propofol-esketamine combination significantly reduced anesthesia induction time and lowered the incidence of hypoxia. Additionally, some studies suggest that esketamine can stimulate the respiratory center, which may partially mitigate the respiratory depression caused by other sedative and analgesic agents.33 The NMDA receptor antagonism of esketamine may mitigate ciprofol-induced hypotension and bradycardia, thereby contributing to intraoperative hemodynamic stability. This effect is particularly important in elderly patients, as age-related physiological decline makes them more susceptible to hemodynamic fluctuations.34 Taken together, these findings suggest that the ciprofol-esketamine combination may represent an alternative sedation-analgesia strategy for elderly patients undergoing ESD.

Hemodynamic stability is crucial for the success of ESD, particularly in elderly patients, where fluctuations in blood pressure and heart rate can increase the risk of intraoperative complications.35 This study indicates that, from a hemodynamic perspective, the E group maintained greater stability in mean arterial pressure (MAP) and heart rate (HR) at multiple time points compared to the S group. Notably, during anesthesia induction, the MAP and HR were significantly higher in the E group than in the S group, suggesting that the ciprofol-esketamine combination was associated with more favorable hemodynamic profiles at certain time points. Maintaining hemodynamic stability is critical for successful ESD, especially in elderly patients, who are more vulnerable to intraoperative complications due to blood pressure and heart rate fluctuations. However, the time to full alertness was significantly longer in the E group than in the S group. The prolonged time to full alertness observed in this study has potential clinical implications, particularly in elderly patients. However, the observed prolongation was transient and was not associated with serious adverse events, with all patients meeting discharge criteria within the monitored setting. Therefore, these findings should be interpreted in the context of overall procedural safety. These findings suggest that when considering ciprofol-esketamine combination, the benefit of hemodynamic stability must be weighed against the potential delay in postoperative recovery. No statistically significant difference in postoperative pain was observed between the two groups. These results underscore the importance of postoperative pain monitoring and adequate analgesic management when using ciprofol-esketamine as an anesthetic regimen. From a safety perspective, the use of esketamine involves a trade-off between potential hemodynamic benefits and an increased risk of neuropsychiatric adverse effects. In terms of postoperative adverse events, the incidence of hallucinations was 8.8%, highlighting the need for particular attention to the neuropsychiatric side effects of esketamine. Since esketamine modulates NMDA receptors, it may disrupt normal neural transmission and sensory processing in the brain, leading to hallucinogenic effects.36 Interestingly, recent studies suggest that esketamine may lower the incidence of postoperative delirium and cognitive dysfunction, possibly due to its anti-inflammatory effects.37–39

This study has several limitations. First, Phase 2 of this study was designed as an exploratory analysis rather than a confirmatory trial. Accordingly, the comparative findings should be interpreted with caution and viewed as strategy-specific observations rather than evidence of inherent superiority. In addition, although ED95 was used to guide induction dosing, it was estimated using the Dixon up-and-down method, which is primarily designed for ED50 estimation. The ED95 values were therefore obtained by model-based extrapolation, introducing additional uncertainty compared with alternative designs specifically targeting ED95, such as the biased coin design. Second, cognitive outcomes, including postoperative delirium and neurocognitive function, were not systematically assessed in this elderly cohort, which represents a major limitation of the present study. Given the vulnerability of elderly patients to cognitive impairment, future studies should incorporate standardized cognitive and delirium assessments to better characterize the neurocognitive safety profile of these sedation strategies.

Conclusions

In conclusion, ciprofol combined with esketamine or sufentanil demonstrated distinct perioperative clinical characteristics in elderly patients undergoing ESD. In this exploratory study, the ciprofol-esketamine regimen was associated with more favorable hemodynamic profiles at certain time points, while a longer time to full alertness was also observed. These findings should be interpreted cautiously and considered strategy-specific rather than evidence of inherent superiority. Postoperative pain management and monitoring for neuropsychiatric adverse effects remain important, particularly in elderly patients. Further adequately powered, prospectively registered confirmatory studies are required before definitive clinical practice recommendations can be made and to better evaluate long-term safety outcomes.

Funding Statement

This study was supported by the Key Discipline Construction Fund of the Health System in Shanghai Xuhui District (SHXHZDXK202324).

Data Sharing Statement

The datasets generated and analyzed in the present study are not publicly available owing to institutional restrictions but are available from Ilyar Mamtili upon reasonable request.

Ethics Approval and Informed Consent

This study was approved by the Ethics Committee of Shanghai Xuhui Central Hospital (Approval No.: 2024–019) and registered in the Chinese Clinical Trial Registry (www.chictr.org.cn, Registration No.: ChiCTR2500102341). All the participants provided written informed consent.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.