Ciprofol-Esketamine Versus Ciprofol-Remifentanil in Hysteroscopic Endometrial Polypectomy: A Randomized Controlled Trial

Introduction

Hysteroscopy is considered the gold standard for the diagnosis and treatment of intrauterine pathologies. Despite this status, certain procedural components, including cervical dilation and endometrial curettage, can induce substantial patient discomfort [1]. According to the 2024 Outpatient Hysteroscopy guidelines, conscious sedation is not recommended for routine use in outpatient hysteroscopic procedures [2]; however, there is evidence that continuous intravenous sedation reduces intraoperative pain compared with local anesthesia in patients undergoing office hysteroscopy [3]. The advent of painless hysteroscopy techniques has addressed this issue by enhancing patient comfort and procedural success rates, leading to widespread clinical adoption. Although routinely used in painless hysteroscopy, intravenous propofol is associated with several clinical challenges, including a high incidence of injection pain, hemodynamic instability manifested as hypotension, and pronounced dose-dependent respiratory depression [1,4,5]. This profile has prompted ongoing interdisciplinary debate regarding the optimization of sedation regimens to achieve high procedural efficacy and better patient safety in hysteroscopic surgery [6].

A novel intravenous anesthetic under investigation, ciprofol (HSK3486), is a 2,6-disubstituted phenolic derivative derived from the propofol structure [7]. A key structural modification – the introduction of a cyclopropyl group – is responsible for its increased binding affinity at the GABA-A receptor compared with propofol [8]. Although ciprofol displays pharmacokinetic properties similar to those of propofol [9], it provides superior sedative efficacy with a lower incidence of adverse effects, particularly respiratory depression and hemodynamic instability. Moreover, ciprofol exhibits a more favorable safety and tolerability profile, characterized by reduced injection pain and higher patient satisfaction [10]. In a study of general anesthesia for gynecological surgery, overall incidences of adverse reactions were 20% in the ciprofol group and 48.33% in the propofol group, indicating a superior safety profile for ciprofol [11]. These advantages establish ciprofol as a promising alternative to propofol for sedation in hysteroscopy. However, ciprofol lacks intrinsic analgesic properties, similar to propofol; thus, administration with opioids is required to blunt hemodynamic responses to noxious stimuli, improve anesthetic control, and reduce ciprofol consumption [12]. The use of opioids such as remifentanil presents a major challenge in hysteroscopy because of their dose-dependent respiratory depression. Consequently, there is an urgent need to develop alternative pharmacological strategies to reduce associated complications. Evidence indicates that, compared with the propofol-alfentanil combination, the propofol-esketamine combination causes less respiratory and hemodynamic depression while demonstrating a more favorable adverse effect profile, which positions it as a superior anesthetic option for hysteroscopy [13]. Esketamine exhibits approximately twice the therapeutic potency of ketamine and has a favorable clinical profile characterized by rapid cognitive recovery, short recovery duration, and a low incidence of psychiatric adverse effects [14].

It remains unknown whether the ciprofol-esketamine combination (CK) offers superior sedative efficacy for hysteroscopy, given the lack of robust evidence. Based on its established use in brief surgical procedures, remifentanil was selected as the active comparator. Therefore, this study evaluated the therapeutic potential of CK, compared with the ciprofol-remifentanil combination (CR), in reducing complications and enhancing recovery after hysteroscopic endometrial polypectomy (HEP).

Material and Methods

STUDY DESIGN:

This single-center, randomized controlled trial was performed at Wuxi Huishan District People’s Hospital, China. Approval was obtained from the Institutional Clinical Research Ethics Committee (No. HYLL20241025001; October 10, 2024), and the trial was prospectively registered with the Chinese Clinical Trial Registry (ChiCTR2400093461; www.chictr.org.cn). All research procedures were conducted in accordance with relevant guidelines and regulations. Written informed consent was obtained from all patients and their families before the procedure. A triple-blinded design was utilized, in which patients, surgeons, and outcome assessors were masked to group allocation.

STUDY POPULATION:

Patients aged 18 to 65 years with endometrial polyps scheduled to undergo HEP were included. Participants were required to display American Society of Anesthesiologists physical status I–II with stable vital signs: respiratory rate 12 to 18 breaths/min, heart rate (HR) 50 to 100 beats/min, systolic blood pressure (SBP) 90 to 180 mmHg, diastolic blood pressure (DBP) 60 to 100 mmHg, and room-air peripheral oxygen saturation (SpO₂) above 95%. Exclusion criteria were allergy to ciprofol, esketamine, or remifentanil; anticipated difficult airway; severe psychiatric disorders; clinically significant cardiopulmonary, hepatic, or renal disease; and any other condition posing excessive risk, as determined by the investigator.

ANESTHESIA MANAGEMENT:

Patients were randomized at a 1: 1 ratio to group CK or group CR using a computer-generated sequence. Allocation was concealed using sequentially numbered, sealed, opaque envelopes. After an envelope was opened, the attending anesthesiologist administered the allocated anesthetic utilizing a predefined protocol. Patients, gynecologists, and outcome assessors were blinded to group assignment. All outcomes were documented by an independent, blinded anesthesiologist who was not involved in clinical care or data analysis. Medications were prepared by 2 independent nurses under a double-check protocol. Esketamine at 0.25 mg/kg (Jiangsu Hengrui Pharmaceuticals, Lianyungang, Jiangsu, China) and remifentanil at 1 μg/kg (Yichang Humanwell Pharmaceutical, Yichang, Hubei, China) were diluted to a total volume of 10 mL with normal saline, thereby standardizing the administered volume across groups. The full 10-mL solution was injected slowly, and each patient’s dose was determined by their body weight. Upon arrival in the operating room, each patient was placed in the lithotomy position. Standard monitoring was performed using a multiparameter monitor (Mindray Biomedical Electronics, Shenzhen, China), including noninvasive blood pressure, electrocardiogram, and SpO₂ assessments. Bispectral index (BIS) values were continuously monitored using a BIS device (BIS Complete Monitoring System, Covidien, Dublin, Ireland).

After initiation of monitoring, supplemental oxygen was administered via nasal cannula at 3 L/min in both groups, beginning before anesthesia induction and continuing until full recovery. Induction commenced with a weight-based intravenous bolus administered over at least 30 seconds: esketamine (0.25 mg/kg) in the CK group and remifentanil (1 μg/kg, ) in the CR group. After a 2-minute interval, anesthesia was induced in all patients with a single intravenous dose of ciprofol (0.4 mg/kg; HaiSiKe, Liaoning, China) [1]. The procedure was initiated when the BIS reached 50 to 60, with loss of the eyelash reflex and absence of substantial body movement confirmed. Maintenance sedation was achieved with supplemental bolus doses of ciprofol (0.1 mg/kg). If a swallowing reflex or substantial body movement occurred, an additional intravenous dose of 5 mg esketamine was administered in the CK group to maintain adequate depth of sedation; a dose of 10 μg remifentanil was administered in the CR group for the same purpose. Body movement was defined as any observable gross motor activity, including limb flexion or head movement, that occurred during the hysteroscopic procedure.

Bradycardia, defined as an HR below 50 bpm persisting for more than 10 seconds, was treated with intravenous atropine (0.5 mg). Hypotension, defined as a greater than 30% decrease in mean arterial pressure (MAP) from baseline or SBP below 90 mmHg for more than 10 seconds, was managed with intravenous ephedrine (6 mg). Transient hypoxemia, defined as SpO2 below 90% for at least 10 seconds, was initially managed with a chin lift and increased oxygen flow. If hypoxemia persisted, advanced airway support was instituted, including mask ventilation or laryngeal mask airway insertion with assisted ventilation using an anesthesia machine. Postoperatively, patients were admitted to the post-anesthesia care unit (PACU) for continuous monitoring. The Aldrete score [15] was assessed at 2-minute intervals; transfer to an observation room required 3 consecutive scores of 9 or higher [6]. Final hospital discharge was based on a Modified Post-Anesthesia Discharge Scoring System score of 10, which considers vital signs, ambulation, nausea/vomiting, pain, and surgical bleeding [16].

OUTCOME MEASURES:

The primary outcome was the occurrence of transient hypoxemia, defined as SpO₂ below 90% for at least 10 seconds. Secondary endpoints were perioperative parameters (hemodynamic changes, induction time, recovery time), consumption metrics (number of rescue analgesic doses, total ciprofol dose), and postoperative adverse events (incidence of nausea, vomiting, and psychiatric symptoms).

Vital signs, including SBP, DBP, MAP, SpO₂, and HR, were recorded at the following time points: before intravenous administration of esketamine or remifentanil (T1 [baseline]), 1 minute after intravenous administration of ciprofol (T2), during cervical dilation (T3), at the end of the operation (T4), and upon discharge from the PACU (T5). Induction time was defined as the duration from the start of ciprofol administration to achieving a Modified Observer’s Assessment of Alertness/Sedation score of 1 or less (seconds); recovery time was defined as the interval from the last administration of investigational drugs to awakening (minutes). Total ciprofol dose was calculated as the cumulative amount administered throughout the anesthesia period. Rescue medications (eg, ephedrine, atropine, dopamine, phenylephrine, and epinephrine) were prepared and available as needed. Psychiatric symptoms associated with esketamine, such as hallucinations and nightmares, were also monitored.

SAMPLE SIZE CALCULATION:

The sample size was estimated using PASS 2025 software (NCSS, Kaysville, UT, USA), based on the reported difference in transient hypoxemia incidence (0% for propofol-esketamine vs 16.7% for propofol-remifentanil) [17]. Given α=0.05 and 90% power, 44 patients per group were required. Allowing for a 20% dropout rate, 60 participants were included in each group.

STATISTICAL ANALYSIS:

All statistical analyses were conducted using SPSS 22.0 (IBM, Armonk, NY, USA). Normality was assessed using the Shapiro-Wilk test. Continuous data are presented as mean±standard deviation (t-test) for normally distributed variables or as median (range) for non-normally distributed variables (Mann-Whitney U test). Categorical data are presented as frequencies (percentages) and were analyzed using the chi-square (χ²) test or Fisher’s exact test. The threshold for statistical significance was defined as P<0.05.

Results

BASELINE PATIENT CHARACTERISTICS:

Between November 2024 and October 2025, 120 patients scheduled for hysteroscopy at Huishan District People’s Hospital, Xinglin College of Nantong University, were screened. After exclusions, 120 patients were enrolled and randomized to receive sedation with either CK or CR (Figure 1). The groups were well matched in terms of baseline demographic and clinical characteristics (P>0.05) (Table 1).

ANESTHETIC USE AND SEDATION TIME:

Total amounts of ciprofol used during surgery were 55.4±16.4 mg in the CK group and 55.0±14.7 mg in the CR group (P=0.879). Time to loss of consciousness and time to regain consciousness did not significantly differ between groups (P=0.145 and P=0.193, respectively) (Table 2).

PRIMARY AND SECONDARY OUTCOMES:

One patient in the CK group (1.7%) and 21 patients in the CR group (35.0%) developed hypoxemia (P<0.001) (Table 3). After prompt interventions – including increased oxygen flow, jaw thrust, and face mask oxygen administration – SpO2 returned to normal levels in all cases, and no procedures were interrupted. The incidence of intraoperative hypotension was lower in the CK group than in the CR group (16.7% vs 33.3%; P=0.035) (Table 3). The incidences of postoperative adverse events, including postoperative nausea and vomiting and psychiatric adverse reactions, were comparable between groups (P>0.05) (Table 3).

HEMODYNAMICS:

Figure 2 summarizes SBP, DBP, MAP, and HR across time points. Baseline MAP and HR were similar between groups (P>0.05). After anesthesia induction, SBP was significantly lower in the CR group (122.6±15.8 vs 116.7±16.5; P=0.047); no significant between-group differences were observed in other hemodynamic parameters.

SATISFACTION AND VAS SCORE:

Patient satisfaction scores did not significantly differ between groups (Table 4). The VAS score at 10 minutes postoperatively was lower in the CK group than in the CR group (2.2±0.7 vs 2.9±0.9; P<0.001).

Discussion

In this study, the CK group experienced significantly fewer hypoxemic events during HEP relative to the CR group. Compared with the CR regimen, the CK regimen was associated with a lower incidence of intraoperative hypoxemia and slightly improved hemodynamic stability; however, gynecologist satisfaction did not significantly differ between the 2 anesthesia protocols.

During HEP, the CK regimen resulted in a substantially reduced incidence of intraoperative hypoxemia compared with the CR regimen (1.7% vs 35.0%), consistent with findings by Nie et al [17]. Supporting evidence indicates that subclinical doses of esketamine are associated with fewer episodes of apnea and asphyxia [18]. A report by Weng et al [13] reinforced this advantage in hysteroscopy, identifying esketamine as a preferable alternative to alfentanil due to its reduced respiratory and hemodynamic depression. Compared with propofol, ciprofol demonstrates a superior safety and tolerability profile during HEP, characterized by reduced injection pain, fewer and less severe adverse events, enhanced patient satisfaction, and more stable hemodynamics, suggesting its utility as an alternative sedative [1]. The sympathomimetic effects of esketamine help maintain airway patency and support respiratory drive, promoting hemodynamic stability and enabling effective sedation-analgesia with a reduced risk of respiratory depression [19]. A modest elevation in post-induction SBP was observed in the CK group relative to the CR group, but no significant differences in DBP or MAP were evident. These findings suggest that esketamine can provide slightly greater hemodynamic stability compared with remifentanil. This stability is consistent with reports that ketamine-propofol combinations provide superior hemodynamic control relative to alfentanil-propofol combinations [13,19]. Goswami et al [20] demonstrated that intravenous ketamine (0.75 mg/kg) is an effective sedation method for office hysteroscopy, offering high patient comfort and surgeon satisfaction. Notably, although neither esketamine nor remifentanil completely suppressed the hemodynamic response to cervical dilation in the present study, this pressor response was generally transient and self-limiting, indicating good patient tolerability without a requirement for clinical intervention.

Respiratory depression is a critical concern in the postoperative setting, given that it carries a risk of serious sequelae and is closely associated with opioid administration [21]. In the present study, the use of esketamine was associated with a pronounced reduction in the incidence of respiratory depression compared with remifentanil among patients undergoing hysteroscopy. This effect maintained adequate oxygenation and may reduce the need for invasive airway interventions (eg, laryngeal mask insertion, tracheal intubation), thereby shortening recovery time and minimizing adverse events. Esketamine exerts respiratory-stabilizing effects via N-methyl-D-aspartate receptor (NMDAR) antagonism and increased chemosensitivity to CO2, reducing the likelihood of respiratory depression [22,23]. This mechanism may explain the reduced incidence of transient hypoxemia observed with the CK regimen in our cohort. Furthermore, a systematic review and a multicenter randomized controlled trial demonstrated that subclinical doses of esketamine (<0.5 mg/kg) provide a favorable safety and efficacy profile, characterized by reduced apnea and intraoperative asphyxia, effective analgesia, and a low incidence of neuropsychiatric adverse effects [18,24]. Based on a dose-response analysis that established the dose expected to produce 95% block (ED95) of esketamine as 0.254 mg/kg when co-administered with propofol for hysteroscopy [13], an intravenous dose of 0.25 mg/kg was selected for the present study.

Although our data suggested a trend toward shorter awakening time in the CR group despite similar ciprofol consumption, this difference was not statistically significant. In contrast, a previous randomized controlled trial indicated that esketamine reduced propofol requirements relative to remifentanil without affecting recovery [17]. This discrepancy may be attributed to differences in pharmacokinetic and pharmacodynamic profiles between the 2 agents, particularly the short half-life of remifentanil and potent analgesic effects of esketamine.

The most common adverse events associated with ketamine – delirium and hallucinations – predominantly occur when it is used as the sole sedative [17]. Although ketamine is often associated with neuropsychiatric effects, particularly when used alone [17], no such events were observed in the CK group. This favorable profile may be attributable to the low dose of esketamine (0.25 mg/kg) utilized in the present study, as well as a potential modulatory effect of ciprofol in mitigating these side effects. Our findings align with multiple studies demonstrating that esketamine, particularly at low doses, does not increase the overall burden of adverse events and maintains a favorable safety profile without exacerbating neuropsychiatric or common side effects [22,24]. Although postoperative nausea and vomiting is frequently attributed to opioid use [25], its incidence was particularly low in the CR group in this study, which may be explained by the relatively small total dose of remifentanil administered. Gynecologist satisfaction is closely linked to optimal surgical conditions – namely, the absence of patient movement and maintenance of procedural workflow – which are, in turn, influenced by the speed and quality of patient recovery. The comparable gynecologist satisfaction between groups may be attributed to effective suppression of procedure-related body movement by both esketamine and remifentanil, given that gynecologists primarily focus on the hysteroscopic procedure rather than the patient’s intraoperative respiratory or hemodynamic status. Factors influencing postoperative pain after hysteroscopic surgery include surgical trauma, intrauterine pressure during the procedure, postoperative uterine contractions, and the use of analgesic medications. A study evaluating intracavitary pressure during hysteroscopy showed that, compared with standard intracavitary pressure (60–100 mmHg), higher intrauterine pressure (110–150 mmHg) may reduce postoperative pain [26]. Although intracavitary pressure was not directly compared between groups in the present study, there was no significant difference in operative time, suggesting that intracavitary pressure was similar between groups and unlikely to have influenced postoperative pain. Furthermore, the VAS score at 10 minutes postoperatively was higher in the CR group than in the CK group; however, no significant difference was observed at 6 hours postoperatively. These findings may be related to the shorter elimination half-life of remifentanil compared with esketamine. Future studies of anesthesia and pain outcomes in hysteroscopy may benefit from including intracavitary pressure as a covariate in the analysis.

This study has some limitations. The relatively small sample size may have limited statistical power and generalizability. Notably, observations were restricted to the peri-procedural period (from sedation to PACU discharge), and no long-term follow-up data were collected. Furthermore, only a single dose of esketamine (0.25 mg/kg) in combination with ciprofol was evaluated, and the optimal dosing regimen requires further investigation. The absence of pharmacokinetic data also precludes definitive characterization of the dose-exposure-response relationship. Large-scale, multicenter prospective studies are warranted to validate our findings.

Conclusions

The CK combination offers a clear clinical advantage over the CR combination for HEP. By reducing the risk of hypoxemia and providing superior short-term postoperative analgesia, the CK combination represents a promising and potentially safer sedation regimen.