Effect of Different Doses of Esketamine on the Propofol Effect-Site Concentration Required to Suppress Cervical Dilation-Associated Movement During Hysteroscopy: A Prospective, Randomised, Controlled, Parallel-Group Dose-Response Trial

Abstract

Background

Operative hysteroscopy is commonly performed under propofol-based intravenous anesthesia, but the relatively high propofol requirement needed to suppress movement during cervical dilation may increase the risk of respiratory and hemodynamic adverse events. Esketamine, the active enantiomer of ketamine, has greater analgesic potency and has been increasingly used as a propofol adjunct; however, its dose-dependent effects on propofol effect-site concentration during hysteroscopy remain unclear.

Objective

To determine whether esketamine dose-dependently reduces the propofol effect-site concentration required to suppress movement during cervical dilation in operative hysteroscopy.

Methods

In this randomised, double-blind, parallel-group dose–response trial, 112 adult women undergoing elective operative hysteroscopy were allocated across five parallel esketamine dose groups (0, 0.1, 0.2, 0.3, or 0.4 mg·kg⁻¹) before anesthesia induction. Propofol was administered using target-controlled infusion, and the effect-site concentration was adjusted using a modified Dixon up-and-down method to estimate the median effective concentration (EC₅₀) for suppressing movement during cervical dilation. Secondary outcomes included total propofol consumption, recovery characteristics, and perioperative adverse events.

Results

Esketamine reduced the propofol effect-site EC₅₀ in a dose-dependent manner, from 3.70 μg·mL⁻¹ in the control group to 2.01 μg·mL⁻¹ in the 0.4 mg·kg⁻¹ group. Esketamine doses of 0.2–0.4 mg·kg⁻¹ significantly reduced total propofol consumption and decreased the incidences of hypoxemia and hypotension compared with propofol alone. Higher esketamine doses were associated with more transient tachycardia. Recovery time was not clinically prolonged across groups.

Conclusion

Esketamine dose-dependently reduced the propofol effect-site concentration required to suppress movement during cervical dilation. In relatively healthy women undergoing short operative hysteroscopy, esketamine 0.2–0.3 mg·kg⁻¹ appears to provide a favorable balance between propofol-sparing efficacy and cardiovascular stability.

Introduction

Operative hysteroscopy is widely used for the minimally invasive management of benign intrauterine disease and is increasingly performed in ambulatory settings. Cervical dilation represents a brief but intense noxious stimulus that often determines whether the initial depth of anesthesia is sufficient to prevent purposeful movement and allow the procedure to proceed smoothly. Because propofol-based total intravenous anaesthesia (TIVA) is commonly administered without a secured airway, suppressing this stimulus may narrow the safety margin for respiratory and haemodynamic stability.1–3

Propofol remains the cornerstone intravenous hypnotic for hysteroscopic procedures because of its rapid onset and favourable recovery profile.3–8 However, its limited intrinsic analgesic activity means that relatively high concentrations may be required to suppress movement when opioids are minimised, resulting in dose-dependent hypoxaemia, hypotension, and bradycardia.1–3 Although several studies have evaluated propofol-based regimens for hysteroscopy, most have focused on total propofol consumption, adverse events, or recovery characteristics rather than effect-site pharmacodynamic dose-response relationships.4–16 Consequently, the propofol effect-site concentration required to suppress cervical dilation–associated movement, and the extent to which adjunctive agents modify this requirement, remain insufficiently characterised.

Esketamine, the active S-enantiomer of ketamine, exerts its principal effects through N-methyl-D-aspartate receptor antagonism and has analgesic, antihyperalgesic, and sympathomimetic properties.17–20 Compared with racemic ketamine, it has greater analgesic potency and is generally used at lower anesthetic and subanaesthetic doses to achieve comparable clinical effects. Its clinical distinction from racemic ketamine appears to be predominantly pharmacodynamic rather than pharmacokinetic. At subanaesthetic doses, esketamine is increasingly used as an adjunct to reduce opioid or hypnotic requirements while helping preserve spontaneous ventilation and cardiovascular stability.17–23 In hysteroscopy and other short procedures, emerging evidence suggests that esketamine may reduce propofol requirements and improve haemodynamic stability.17–27 However, prior studies have mainly reported total propofol dose or clinical outcomes rather than quantifying how esketamine alters the propofol effect-site concentration required to suppress movement during cervical dilation.

Therefore, we conducted a randomised, double-blind, parallel-group dose-finding trial in women undergoing operative hysteroscopy. Using five esketamine dose groups and a modified Dixon up-and-down design within each group, we aimed to determine the median effective concentration (EC₅₀) of propofol required to suppress cervical dilation–associated movement and to characterise the dose-dependent propofol-sparing effect of esketamine.28–31 We hypothesised that esketamine would reduce the propofol effect-site EC₅₀ in a dose-dependent manner, with intermediate doses providing a more favourable balance between procedural efficacy and cardiopulmonary safety.

Materials and Methods

Study Design and Ethics

This prospective, randomised, double-blind, dose-finding clinical trial was designed to characterise the dose–response effects of adjunctive esketamine on the propofol effect-site concentration required to suppress movement during cervical dilation. Five parallel esketamine dose groups were studied, and within each group propofol titration followed a modified Dixon up-and-down sequential allocation design to estimate the median effective concentration (EC₅₀).28–31

The study protocol was approved by the Ethics Committee of the Affiliated Women and Children’s Hospital of Ningbo University (approval no. NBFE-2025-KY-011) and conducted in accordance with the Declaration of Helsinki. The trial was prospectively registered in the Chinese Clinical Trial Registry (ChiCTR2500104602). Written informed consent was obtained from all participants. The study was reported in accordance with the CONSORT statement for randomised parallel-group trials.32

Participants

Women aged 18–55 years with American Society of Anesthesiologists (ASA) physical status I–II who were scheduled for elective operative hysteroscopy under intravenous anaesthesia were eligible for inclusion. Additional inclusion criteria were a body mass index of 19–26 kg·m⁻² and a Mallampati airway classification of I–II.

Exclusion criteria included poorly controlled hypertension; increased intracranial or intraocular pressure; pregnancy; hyperthyroidism; neurological or psychiatric disorders; increased risk of aspiration; known hypersensitivity or contraindications to propofol or ketamine; and a history of opioid misuse or other substance abuse. These criteria were selected to minimise pharmacokinetic variability and airway-related confounding during propofol effect-site titration.

Randomization and Blinding

Participants were randomly assigned according to a computer-generated sequence created using IBM SPSS Statistics version 25.0 (IBM Corp., Armonk, NY, USA), with allocation concealment ensured by sequentially numbered, opaque, sealed envelopes. Study medication was prepared immediately before anaesthesia induction by an independent anaesthesiologist who was not involved in intraoperative management or outcome assessment.

Esketamine was diluted with 0.9% saline to a total volume of 10 mL and presented in identical 10-mL syringes labelled only with the study number. Participants were allocated to receive intravenous esketamine at doses of 0, 0.1, 0.2, 0.3, or 0.4 mg·kg⁻¹ according to group assignment. Throughout the study, participants, attending anaesthesiologists, surgeons, and investigators responsible for data collection and outcome assessment remained blinded to treatment allocation.

Anaesthetic Management

All participants adhered to standard preoperative fasting guidelines and did not receive premedication, in accordance with current recommendations for ambulatory anaesthesia.1,2 Standard monitoring was applied throughout the procedure, including electrocardiography, non-invasive arterial blood pressure, peripheral oxygen saturation (SpO₂), and end-tidal carbon dioxide. Supplemental oxygen was administered via facemask at a flow rate of 5 L·min⁻¹.

After establishment of intravenous access, esketamine was administered as a slow intravenous bolus over 30 seconds, followed by intravenous flurbiprofen axetil 50 mg. Anaesthesia was then induced using propofol delivered by effect-site target-controlled infusion (TCI) based on the Schnider pharmacokinetic model. For the first participant in each esketamine dose group, the initial propofol effect-site concentration (Ce_prop) was set at 3.5 μg·mL⁻¹.

Cervical dilation was initiated 4 minutes after the target Ce_prop had been reached and once the Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) score was ≤ 1. The MOAA/S score was assessed by the attending anaesthesiologist immediately before cervical dilation. Adequate sedation was defined as the absence of purposeful movement during cervical dilation with a maintained MOAA/S score ≤ 1. Sedation was considered inadequate if any purposeful movement occurred and/or the MOAA/S score exceeded 1.

In cases of inadequate sedation, Ce_prop was increased in increments of 0.5 μg·mL⁻¹ at 2-minute intervals until movement was abolished. For subsequent participants within the same esketamine dose group, the initial Ce_prop was adjusted according to the response of the preceding participant, decreasing by 0.5 μg·mL⁻¹ following a successful response and increasing by 0.5 μg·mL⁻¹ following a failure, in accordance with the standard up-and-down methodology.28–31

To minimise operator-related variability, all hysteroscopic procedures were performed by the same senior gynaecologist, and anaesthesia was managed throughout by a single experienced anaesthesiologist. Following cervical dilation, propofol dosing was adjusted at the discretion of the anaesthesiologist to maintain adequate anaesthesia for the remainder of the procedure. The propofol infusion was discontinued approximately 4–5 minutes before the anticipated end of surgery, after which patients were transferred to the post-anaesthesia care unit. Postoperative analgesia and prophylactic antiemetic therapy were standardised according to institutional protocols, with rescue treatment administered as clinically indicated.

Outcome Measures

The primary outcome was the propofol effect-site concentration (EC₅₀) required to prevent purposeful movement during cervical dilation, consistent with the dose-finding objective of the modified Dixon design. Secondary outcomes included haemodynamic variables, propofol consumption, anaesthetic emergence time, and the incidence of adverse events.

Physiological variables were recorded at baseline and reassessed at 2.5-minute intervals after induction of anaesthesia to evaluate haemodynamic stability and safety. These variables included heart rate, non-invasive arterial blood pressure, and peripheral oxygen saturation (SpO₂). Propofol consumption was quantified as the total administered dose normalised to body weight (mg·kg⁻¹). Anaesthetic emergence time was defined as the interval from cessation of the propofol infusion to spontaneous eye opening.3,4,7,8,15,16

Predefined adverse events included hypoxaemia (SpO₂ < 95%), hypotension (defined as systolic arterial pressure < 90 mmHg or a reduction exceeding 20% from baseline), tachycardia (heart rate > 100 beats·min⁻¹), bradycardia (heart rate < 50 beats·min⁻¹), postoperative nausea and vomiting, and hallucinations or delirium during recovery.

Statistical Analysis

Within each randomised esketamine dose group, propofol titration followed a modified Dixon up-and-down sequence to estimate the median effective concentration (EC₅₀) required to prevent purposeful movement during cervical dilation.28–31 Participant enrolment in each group continued until at least seven crossover pairs had been obtained, in accordance with the methodological requirements of the up-and-down design.

The EC₅₀ was calculated by averaging the midpoints of all crossover pairs,28–31 with corresponding 95% confidence intervals derived using Choi’s method.33 To further characterise the dose–response relationship, complementary analyses were performed using probit regression and isotonic regression models.

Continuous variables were summarised according to their distributional characteristics and are presented as the mean with standard deviation or the median with interquartile range, as appropriate. Distributional assumptions were assessed using the Kolmogorov–Smirnov test. For between-group comparisons, parametric statistical tests were applied to normally distributed data, whereas non-parametric methods were used when normality assumptions were not satisfied. Categorical variables were expressed as proportions and compared across groups using the chi-square test.

All hypothesis testing was conducted on a two-sided basis, with statistical significance defined as a P value < 0.05. When applicable, adjustment for multiple comparisons was performed using the Bonferroni method, resulting in a corrected significance threshold of P < 0.005. Statistical analyses were conducted using SPSS version 29.0 (IBM Corp., Armonk, NY, USA) and GraphPad Prism version 10.0 (GraphPad Software Inc., San Diego, CA, USA). Group sample sizes were determined by the prespecified stopping rule of the modified Dixon up-and-down design rather than by a formal power calculation.

Results

Patient Characteristics

Of the 125 patients assessed for eligibility, 112 met the inclusion criteria and were randomised to one of the five esketamine dose groups. All randomised participants completed the study protocol and were included in the final analysis (Figure 1). Baseline demographic characteristics and procedural duration were comparable across groups, with no clinically meaningful differences observed (Table 1).

Figure 1.

CONSORT flow diagram of patient enrollment, allocation, and analysis. Following the assessment of 125 patients, 112 were enrolled and randomised into five esketamine dose groups. All randomised patients completed the study and were analyzed, with no loss to follow-up.

Abbreviation: CONSORT, Consolidated Standards of Reporting Trials.

Table 1.

Demographic Characteristics

	Esketamine 0 mg·kg−1 (n=22)	Esketamine 0.1 mg·kg−1 (n=22)	Esketamine 0.2 mg·kg−1 (n=21)	Esketamine 0.3 mg·kg−1 (n=23)	Esketamine 0.4 mg·kg−1 (n=24)	Effect size (η2)
Age (y)	35.2±7.3	36.3±8.1	33.7±6.9	36.1±7.1	33.3±7.9	0.028
Weight (kg)	55.2±5.4	56.7±6.1	58.3±7.2	55.6±7.8	55.8±6.9	0.027
Height (cm)	161.6±5.4	162.1±6.1	161.7±5.7	161.0±6.8	160.7±6.0	0.007
BMI (kg·m−2)	21.1±1.7	21.6±2.0	22.3±2.1	21.4±1.7	21.5±1.9	0.039
Surgery duration (min)	21.3±3.2	23.3±3.1	21.8±3.5	22.7±2.9	22.5±3.1	0.045

Notes: Data are expressed as mean ± SD. Groups were defined by the assigned esketamine dose. One-way ANOVA was used for comparisons across groups (effect size: η²).

Abbreviation: BMI, body mass index.

Primary Outcome: Propofol EC₅₀ for Cervical Dilation

Co-administration of esketamine was associated with a clear dose-dependent reduction in the propofol effect-site concentration (EC₅₀) required to suppress purposeful movement during cervical dilation (Table 2 and Figure 2). Using the modified Dixon up-and-down method, the estimated propofol EC₅₀ in the control group (0 mg·kg⁻¹ esketamine) was 3.70 μg·mL⁻¹ (95% CI: 3.68–4.10). Corresponding EC₅₀ values progressively declined to 3.61 μg·mL⁻¹ (95% CI: 3.37–4.01), 2.58 μg·mL⁻¹ (95% CI: 2.41–2.81), 2.27 μg·mL⁻¹ (95% CI: 2.03–2.43), and 2.01 μg·mL⁻¹ (95% CI: 1.71–2.17) in the 0.1, 0.2, 0.3, and 0.4 mg·kg⁻¹ esketamine groups, respectively (overall η² = 0.812; P < 0.001).

Table 2.

Propofol Effect-Site EC₅₀ for Suppression of Movement During Cervical Dilation

	Esketamine 0 mg·kg−1 (n=22)	Esketamine 0.1 mg·kg−1 (n=22)	Esketamine 0.2 mg·kg−1 (n=21)	Esketamine 0.3 mg·kg−1 (n=23)	Esketamine 0.4 mg·kg−1 (n=24)	Effect size (η2)
EC50a	3.70 (3.68–4.10)	3.61 (3.37–4.01)	2.58 (2.41–2.81) *,#	2.27 (2.03–2.43) *,#	2.01 (1.71–2.17) *,#	0.812
EC50b	3.84 (3.41–4.11)	3.61 (3.21–3.87)	2.48 (2.07–2.74) *,#	2.23 (1.79–2.50) *,#	1.96 (1.32–2.30) *,#	–
EC50c	3.67 (3.52–3.85)	3.58 (3.41–3.78)	2.50 (2.35–2.68) *,#	2.17 (2.01–2.36) *,#	1.88 (1.69–2.11) *,#	–

Notes: Data are expressed as EC₅₀ (95% CI). EC₅₀ was calculated by a Modified Dixon’s up-and-down method (a), probit regression (b), and isotonic regression (c). *P<0.005 vs. 0 mg·kg⁻¹ group; ^#P<0.005 vs. 0.1 mg·kg⁻¹ group (Bonferroni-corrected). Effect size (η²) is provided for the primary method (a). EC₅₀, effect-site propofol concentration suppressing cervical dilation in 50% of patients.

Figure 2.

Patient response sequences to propofol during esketamine co-administration. The five panels represent sequential data for each esketamine dose group. Individual patient response sequences (connected lines) are shown, with solid circles indicating an effective response (no movement during cervical dilation) and open circles indicating an ineffective response (movement occurred). The solid vertical line in each panel denotes the calculated propofol EC₅₀ for the corresponding group. Ce_prop, effect-site propofol concentration.

Compared with propofol alone, esketamine administered at doses of 0.2–0.4 mg·kg⁻¹ reduced the propofol EC₅₀ by approximately 30–45%, indicating a substantial propofol-sparing effect at clinically relevant dose levels. EC₅₀ estimates and corresponding confidence intervals obtained from probit and isotonic regression analyses were consistent with those derived from the modified Dixon method, supporting the robustness of the primary pharmacodynamic findings (Table 2).

Secondary Outcomes

Total propofol consumption decreased progressively with increasing esketamine dose (P < 0.001; Table 3). Compared with the control group, patients receiving esketamine at doses of 0.2–0.4 mg·kg⁻¹ required approximately one-third less median propofol to achieve satisfactory anaesthetic conditions.

Table 3.

Postoperative Outcomes and Adverse Events

	Esketamine 0 mg · kg−1 (n=22)	Esketamine 0.1 mg·kg−1 (n=22)	Esketamine 0.2 mg·kg−1 (n=21)	Esketamine 0.3 mg·kg−1 (n=23)	Esketamine 0.4 mg·kg−1 (n=24)	P value
Propofol requirements (mg·kg−1)	5.69 (4.28–6.45)	5.32 (3.94–6.78)	3.75 (3.18–4.53)*	3.46 (2.83–4.66)*,#	3.22 (2.93–3.82)*,#	<0.001
Time to anaesthesia emergence (min)	8.0 (7.0–9.0)	7.0 (7.0–8.0)	6.0 (5.0–7.0)*	8.0 (7.0–9.0)	8.5 (8.0–9.0)	<0.001
Inpatient days (d)	2.0 (1.0–2.0)	2.0 (1.0–2.0)	2.0 (1.0–2.0)	2.0 (1.0–2.0)	2.0 (1.0–2.0)	0.830
Nausea and vomiting	2 (9.1)	1 (4.5)	2 (9.5)	3 (13.0)	4 (16.7)	0.789
Tachycardia	2 (9.1)	4 (18.2)	5 (23.8)	6 (26.1)	9 (37.5)	0.252
Desaturation (SpO2 <95%)	11 (50.0)	10 (45.5)	3 (14.3)*,#	2 (8.7)*,#	2 (8.3) *,#	<0.001
Hypotension	10 (45.5)	7 (31.8)	1 (4.8) *,#	1 (4.3) *,#	0 (0) *,#	0.001
Hallucinations or delirium	0 (0)	0 (0)	0 (0)	0 (0)	1 (4.2)	1.000

Notes: Data are presented as median (interquartile range) or number (%). Desaturation was defined as SpO₂< 95% and hypotension as systolic blood pressure < 90 mmHg or < 80% of baseline. Continuous variables were compared using the Kruskal–Wallis test and categorical variables using the χ²-test. *P<0.005 vs 0 mg·kg⁻¹ esketamine group; ^#P<0.005 vs 0.1 mg·kg⁻¹ esketamine group (Bonferroni-corrected).

The incidence of hypoxaemia (SpO₂ < 95%) and hypotension was markedly lower in patients treated with esketamine at doses ≥ 0.2 mg·kg⁻¹ compared with controls. Hypoxaemia occurred in 50.0% of patients in the control group, compared with 14.3%, 8.7%, and 8.3% in the 0.2, 0.3, and 0.4 mg·kg⁻¹ esketamine groups, respectively (P < 0.001). Similarly, hypotension was observed in 45.5% of control patients but in only 4.8%, 4.3%, and 0% of patients receiving escalating esketamine doses (P = 0.001).

The incidence of tachycardia increased with higher esketamine doses and was greatest in the 0.4 mg·kg⁻¹ group (Table 3). Although this trend is consistent with enhanced sympathetic activation at higher esketamine doses, the statistical significance of individual pairwise comparisons—particularly after Bonferroni correction—was inconsistent and should therefore be interpreted cautiously. No significant between-group differences were observed in the incidence of postoperative nausea and vomiting or in length of hospital stay. Hallucinations or delirium were uncommon, occurring in only one patient (4.2%) in the 0.4 mg·kg⁻¹ group and in none of the other groups (P = 1.000; Table 3).

Time to anaesthetic emergence differed significantly among the five groups (overall P < 0.001; Table 3). Median times from cessation of propofol infusion to eye opening ranged from 6.0 (5.0–7.0) to 8.5 (8.0–9.0) min. Post hoc analyses demonstrated a shorter emergence time in the 0.2 mg·kg⁻¹ esketamine group compared with the control group (6.0 [5.0–7.0] vs 8.0 [7.0–9.0] min), although absolute between-group differences were modest.

Discussion

This randomised, double-blind, dose-response trial demonstrated that adjunctive esketamine significantly reduced the propofol effect-site EC₅₀ required to suppress movement during cervical dilation in a dose-dependent manner. Compared with propofol alone, co-induction with esketamine decreased hypnotic requirements while improving cardiopulmonary stability, thereby widening the therapeutic window of propofol-based total intravenous anaesthesia (TIVA) for operative hysteroscopy without airway instrumentation. By quantifying this interaction at the effect-site level, the present study provides pharmacodynamic evidence supporting the use of low-to-moderate doses of esketamine as a propofol-sparing adjunct in short, highly stimulating ambulatory procedures.

Our findings extend previous studies of hysteroscopic sedation, most of which have focused on total propofol consumption, adverse events, or recovery characteristics rather than effect-site pharmacodynamic interactions. Propofol remains the cornerstone hypnotic in this setting because of its rapid onset and favourable recovery profile; however, its limited intrinsic analgesic activity often necessitates higher concentrations to suppress movement during cervical dilation, thereby increasing the risks of hypoxaemia and hypotension.3–8,10–16 Within this context, the present study adds to the literature by showing that adjunctive esketamine reduces not only the propofol effect-site EC₅₀, but also total propofol consumption and selected cardiopulmonary adverse events. These findings support the view that esketamine may improve the efficiency of propofol-based sedation in short ambulatory hysteroscopic procedures. A plausible explanation is that esketamine attenuates nociceptive transmission while partially offsetting propofol-related haemodynamic and respiratory depression.17–27,34

The present findings may also be interpreted in the context of prior clinical experience with ketofol, the ketamine-propofol combination used in procedural sedation for more than a decade. Both ketofol and the esketamine-propofol strategy used in our study are based on the same general principle: ketamine-related analgesic and sympathomimetic effects may offset propofol-related hypotension, respiratory depression, and inadequate analgesia. Adult procedural sedation literature suggests that ketofol may improve haemodynamic stability and reduce respiratory adverse events compared with propofol alone, although the evidence is heterogeneous and largely derived from mixed procedural settings rather than hysteroscopy-specific pharmacodynamic endpoints.35,36 In contrast, the present trial evaluated esketamine rather than racemic ketamine and quantified the interaction using propofol effect-site EC₅₀ for suppressing cervical dilation–associated movement rather than a fixed ketamine-propofol mixture with predominantly clinical sedation endpoints. This distinction allowed a more precise characterisation of dose dependence and a more informative basis for dose selection.

By applying a modified Dixon up-and-down design complemented by probit and isotonic regression analyses, the present study further refines the dose–response relationship between esketamine and propofol. Across the investigated dose range (0.1–0.4 mg·kg⁻¹), propofol EC₅₀ values declined progressively, with evidence of a plateau between 0.2 and 0.3 mg·kg⁻¹. From a clinical perspective, the importance of this EC₅₀ reduction lies not merely in the pharmacodynamic shift itself, but in its accompanying pattern of lower propofol consumption and fewer hypoxaemic and hypotensive events. In other words, the observed reduction in estimated propofol requirement appears to translate into clinically meaningful sparing of propofol exposure rather than representing only a mathematical reduction in effect-site concentration. Importantly, this pattern does not simply suggest lighter sedation, but rather a more efficient pharmacodynamic interaction in which acceptable movement suppression was achieved with lower propofol exposure. This interpretation is supported by the concordance between the primary endpoint and the secondary clinical outcomes in the present trial. However, because EC₅₀ reflects median effectiveness rather than the higher success thresholds often targeted in routine practice, these findings are more appropriately interpreted as identifying a favourable dose range than as defining a universally optimal regimen.

Our results are also broadly consistent with recent hysteroscopy-specific studies showing that esketamine can reduce propofol requirements in a dose-dependent manner. For example, Wan et al reported a progressive reduction in propofol EC₅₀ across 0.1–0.3 mg·kg⁻¹ esketamine groups and suggested 0.3 mg·kg⁻¹ as the optimal dose for balancing efficacy and safety.25 By contrast, Sheng et al recommended an ED₉₅-equivalent dose of 0.429 mg·kg⁻¹ esketamine combined with propofol for painless hysteroscopy.26 These results are not necessarily contradictory. Rather, they likely reflect important differences in study design, endpoint definition, and analytic target. Wan et al estimated propofol EC₅₀ under a sequential concentration-adjustment design and focused on body movement suppression, whereas Sheng et al estimated esketamine ED₅₀/ED₉₅ with a different induction sequence and a higher-effectiveness target.25,26 The higher recommended dose in the latter study is therefore unsurprising, because ED₉₅-based targets are expected to exceed doses selected from EC₅₀-oriented pharmacodynamic optimisation. In this context, our finding that 0.2–0.3 mg·kg⁻¹ may provide the best overall balance is more closely aligned with dose-selection logic aimed at improving efficiency and safety during routine short ambulatory procedures rather than maximising success probability at any cost.

The safety profile observed in this trial further supports the clinical applicability of esketamine co-induction, but the dose-related increase in heart rate deserves careful interpretation. Although tachycardia was more frequent at higher esketamine doses, absolute rates remained modest and no serious cardiovascular complications were observed in this relatively low-risk population. This pattern is consistent with the known sympathomimetic effects of ketamine-related agents and suggests that the incremental benefit of escalating the esketamine dose from 0.3 to 0.4 mg·kg⁻¹ may be limited by haemodynamic trade-offs. In relatively healthy women undergoing short hysteroscopic procedures, such transient tachycardia may be clinically acceptable when weighed against the reduction in hypotension and hypoxaemia. However, the balance may differ in patients with limited cardiovascular reserve, poorly controlled hypertension, tachyarrhythmia, ischaemic heart disease, or other clinically relevant cardiovascular comorbidities. In such patients, even modest sympathetic stimulation may be less desirable, and the use of higher esketamine doses should be individualised. This consideration further supports the view that 0.2–0.3 mg·kg⁻¹ may represent a more practical dose range for routine use in relatively healthy women undergoing short operative hysteroscopy.

Recovery characteristics were broadly comparable across groups. Time to eye opening was not prolonged by adjunctive esketamine, with only a modest tendency toward faster emergence in the 0.2 mg·kg⁻¹ group. Neither postoperative nausea and vomiting nor length of hospital stay differed materially between groups, indicating that the esketamine–propofol regimen can be incorporated into ambulatory hysteroscopy pathways without obvious recovery penalties. Beyond the immediate perioperative period, subanaesthetic esketamine has been associated with improved acute pain control, reduced opioid requirements, and potential benefits in quality of recovery,17–23 which merit evaluation in future hysteroscopy studies using patient-centred outcome measures.

Several limitations should be acknowledged. First, this was a single-centre study, and sample size was determined by the stopping rule of the modified Dixon up-and-down design rather than by a conventional a priori power calculation; accordingly, secondary outcomes should be interpreted as supportive rather than definitive. Second, because the modified Dixon design is primarily intended to estimate EC₅₀ rather than higher-effect targets such as EC₉₅, extrapolation to higher clinical effectiveness thresholds should be made with caution, and higher-quantile estimates derived from complementary regression analyses should be considered exploratory. Third, objective depth-of-anaesthesia monitoring such as bispectral index monitoring was not incorporated into the study protocol, and sedation depth was therefore assessed clinically, which may have introduced some variability. Fourth, validated assessments of neuropsychiatric outcomes, postoperative pain, and quality of recovery were not employed. Fifth, the relatively healthy cohort undergoing short elective hysteroscopic procedures limits generalisability to higher-risk populations and more invasive gynaecological surgery. Finally, only a single pre-induction bolus of esketamine in combination with propofol-based TIVA was evaluated; alternative dosing strategies and combinations with newer hypnotics or airway devices warrant further investigation.

Conclusion

Adjunctive esketamine dose-dependently reduced the propofol effect-site EC₅₀ and overall propofol requirement for suppressing movement during cervical dilation during operative hysteroscopy. Among the dose levels evaluated, esketamine 0.2–0.3 mg·kg⁻¹ combined with propofol appeared to provide the most favourable balance between propofol-sparing efficacy and cardiovascular tolerability. In relatively healthy patients undergoing short hysteroscopic procedures, this combination may help widen the safety margin of deep sedation while preserving rapid recovery. Further studies are needed to confirm these findings in larger populations and in patients at higher perioperative risk.

Funding Statement

This research was conducted without external funding.

Data Sharing Statement

The datasets generated and analysed during the current study are available from the corresponding author upon reasonable request.

Ethics Approval and Consent to Participate

The study protocol was reviewed and approved by the Ethics Committee of the Affiliated Women and Children’s Hospital of Ningbo University (approval no. NBFE-2025-KY-011). Written informed consent was obtained from all participants prior to enrolment.

Disclosure

The authors declare that they have no competing interests.