The Median Effective Infusion Rate of Ciprofol with Different Doses of Esketamine During Gastrointestinal Endoscopy: A Randomized Controlled Trial

Abstract

Purpose

To quantify the dose-dependent ciprofol-sparing effect of adjunctive esketamine and determine its optimal infusion rate regimen in adult patients undergoing gastrointestinal endoscopy.

Methods

In this randomized, double-blind trial, 90 ASA I–III patients (aged 18–65 years) received ciprofol with esketamine (0.25 mg/kg [SK0.25], 0.5 mg/kg [SK0.5]) or saline (SK0) during combined gastroscopy/colonoscopy. The median effective infusion rate of ciprofol was determined using the modified Dixon’s up-and-down method. Hemodynamic parameters and adverse events were systematically assessed.

Results

Adjunctive esketamine significantly reduced ciprofol median effective infusion rate in dose-dependent manner: 0.75 mg/kg/h (95% CI: 0.66–0.85) with saline versus 0.70 mg/kg/h (0.66–0.76; adjusted p < 0.0167) at 0.25 mg/kg esketamine and 0.62 mg/kg/h (0.54–0.70; adjusted p < 0.0167) at 0.5 mg/kg. The esketamine-ciprofol regimen reduced hypotension by 56.7% (16.67% vs 73.33% in controls; adjusted p < 0.0167). Mean arterial pressure (MAP) decline attenuated at 0.5 mg/kg esketamine (ΔMAP: −8.2% vs −14.7% in controls). No severe adverse events occurred. Equivalent sedation (MOAA/S ≤1) was maintained with 45% ciprofol reduction at optimal 0.5 mg/kg esketamine dose.

Conclusion

Esketamine (0.5 mg/kg) significantly reduces the ciprofol maintenance infusion rate while enhancing hemodynamic stability during gastrointestinal endoscopy. Under standard monitoring, no hypoxemia occurred in any group. However, specific esketamine-related adverse events, such as neuropsychiatric symptoms and increased secretions, were not systematically assessed, which should be considered when interpreting the clinical safety profile. These findings are based on specific procedural and monitoring protocols; their application to different clinical settings should consider local contexts.

Introduction

The rising global burden of complex gastrointestinal diseases has driven the expansion of endoscopic applications in diagnostic evaluation, therapeutic intervention, and early cancer screening.1 While essential for clinical management, conventional endoscopy frequently induces patient distress through gag reflexes, visceral pain, and anxiety—adverse effects that impair procedural efficacy and compromise long-term compliance. To optimize patient tolerance and clinical outcomes, procedural sedation has emerged as a standard adjunct, with epidemiological data revealing near-universal acceptance (>98% adoption rates) of analgesic-enhanced endoscopy across diverse populations.2 This paradigm shift underscores the critical interplay between patient-centered care and technological advancement in modern gastroenterology.

The 2024 British Society of Gastroenterology guidelines advocate a standardized pharmacologic regimen for sedation in gastrointestinal endoscopy, prioritizing rapid-onset agents with titratable effects and minimal recovery time.3 First-line recommendations include propofol (intravenous hypnotic), fentanyl (μ-opioid analgesic), and remimazolam (ultra-short-acting benzodiazepine), supplemented by nitrous oxide (inhaled anxiolytic) or pethidine (synthetic opioid) in specific clinical contexts to optimize procedural efficiency and patient safety.3 Propofol and fentanyl remain the primary sedative agents for gastrointestinal endoscopy; however, their clinical utility is constrained by dose-dependent risks of respiratory depression, systemic hypotension, and localized injection-site discomfort.4

Ciprofol, designed via cyclopropyl moiety substitution on the propofol pharmacophore, mitigates the suboptimal hemodynamic and respiratory profiles intrinsic to the parent compound’s molecular scaffold.5 While ciprofol—as monotherapy or combined with opioid analgesics—demonstrates superior sedation efficacy to propofol in gastrointestinal endoscopy, its clinical utility remains restricted by dose-dependent oxygen desaturation and hypotension.6,7 A multicenter, single-blind, randomized, Phase III trial demonstrated that propofol infusion (0.8–1.5 mg/kg) during anesthetic maintenance achieved 100% efficacy with a low incidence of adverse drug reactions.8 This study demonstrated that ciprofol produced little injection pain during the induction period and exhibited comparable intraoperative hemodynamic characteristics compared with propofol.

Esketamine, the S-enantiomer of ketamine and an NMDA receptor antagonist, emerges as a superior analgesic agent. Recent clinical evidence demonstrates that esketamine-propofol coadministration preserves hemodynamic stability and attenuates respiratory depression during gastrointestinal endoscopic procedures.9

Ciprofol and esketamine represent promising agents for procedural sedation; however, evidence for ciprofol combined with single-dose esketamine in gastrointestinal endoscopic procedures remains limited. The doses of 0.25 mg/kg and 0.5 mg/kg were selected based on their common subanesthetic analgesic/sedative dosing ranges, aiming to explore their dose-dependent effects on circulatory stability and ciprofol requirement while providing effective adjunctive analgesia. Compared to traditional propofol-opioid regimens, the ciprofol-esketamine strategy aims to reduce opioid-related risks such as respiratory depression and nausea/vomiting, which is particularly relevant for patients with higher demands on cardiorespiratory function. The EC50 (median effective infusion rate) estimated in this study directly corresponds to the ciprofol rate required to suppress movement during the most stimulating phase of endoscopic manipulation, providing a quantitative reference for bedside titration. Motivated by these findings, we assessed low-dose esketamine as a ciprofol adjunct to refine the sedation-analgesia equilibrium during gastrointestinal endoscopy. We postulated that esketamine-ciprofol coadministration would achieve sedation efficacy comparable to ciprofol monotherapy while maintaining hemodynamic stability and attenuating respiratory compromise. To validate this, a randomized controlled trial was conducted to examine adjunctive low-dose esketamine’s impact on safety and efficacy in ciprofol-based endoscopic sedation. Current evidence on ciprofol-esketamine coadministration for gastrointestinal endoscopic sedation remains limited, with optimal infusion rate regimens undefined. To establish evidence-based dosing guidelines, this study determined the median effective infusion rate of ciprofol combined with esketamine for achieving procedural sedation efficacy while minimizing cardiorespiratory adverse events.

Materials and Methods

Study Design

This randomized, double-blind, controlled trial, approved by the Ethics Committee of Biomedicine Research at Shidong Hospital (Shanghai) and prospectively registered (ChiCTR2400093995), enrolled 90 ASA I–III patients aged 18–65 undergoing gastrointestinal endoscopy (December 2024-March 2025) with written informed consent. This study protocol complied with the principles of the Declaration of Helsinki. All patients received combined gastroscopy and colonoscopy under a single anesthetic administration per institutional protocol.

Inclusion Criteria

Patients scheduled for elective gastrointestinal endoscopy; (1) age 18–65 years; (2) ASA class I–III; (3) BMI 19–27 kg/m².

Exclusion Criteria

(1) Allergy to ciprofol or esketamine; (2) Chronic analgesic use; (3) Alcohol use disorder; (4) Neurological disorders or schizophrenia; (5) Advanced hepatic/renal disease; (6) Obstructive sleep apnea syndrome; (7) Uncontrolled hypertension (blood pressure >180/120 mmHg); (8) Psychoactive medication use.

Screening and Group Assignment

Allocation concealment was maintained using identical sealed opaque envelopes. Pre-procedurally, an independent nurse, blinded to group assignments, opened envelopes and allocated eligible patients to esketamine dose groups or control group. The nurse prepared identical syringes containing esketamine or saline (indistinguishable due to matching clarity and color). All study personnel (including anesthesiologists, endoscopists, and outcome assessors) and participants remained blinded throughout.

Interventions

A standardized anesthesia protocol was used. All patients fasted for 6 hours and were prohibited from drinking for more than 2 hours. After the patients entered the operating room, antecubital venous access was established, and then lactated Ringer’s solution was given. Oxygen was inhaled through a nasal oxygen cannula at a flow rate of 3 L/min. Heart rate (HR), blood pressure (BP), electrocardiogram (ECG), and pulse oximetry (SpO2) were routinely monitored continuously throughout the anesthesia period. Ciprofol injection was used at 5 mg/mL. Rescue boluses of 2–3 mL corresponded approximately to 0.2–0.3 mg/kg (based on an average body weight of 60 kg).

After preoxygenation, patients were injected with different doses of esketamine: SK0.25 group (0.25 mg/kg esketamine, n = 30), SK0.5 group (0.5 mg/kg esketamine, n = 30), or saline control group (saline, n = 30). Then, the ciprofol was infused at a constant rate (6 mg/kg/h) until the patient lost consciousness and the Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) score was 1/0, and then entered the anesthesia maintenance stage: the maintenance infusion rate of the first patient in the three groups was 0.6 mg/kg/h.

The sequential method measured the half effective infusion rate of ciprofol for maintaining anesthesia when combined with different doses of esketamine during gastrointestinal endoscopy. The starting infusion rate was 0.6 mg/kg/h. The ratio between successive infusion rates was 1:1.2. The full dosing ladder included: 0.6, 0.72, 0.86, 1.03, 1.24, 1.49, 1.79, 2.15 mg/kg/h. (subsequent rates calculated accordingly). The EC50 and its confidence interval were calculated using the Dixon’s up-and-down method, supplemented by probit regression modeling for verification. If a ‘positive body movement reaction” (clinically significant trunk/limb movement that disrupts the procedure) occurs during the most stimulating phase of endoscopy (endoscope passage through pharynx-esophagus or anus-rectum), 2–3 mL of ciprofol is immediately administered for rescue, if no such positive body movement reaction occurs (defined as “negative body movement reaction”; minor, non-disruptive movements are excluded), the next patient’s ciprofol maintenance infusion rate is adjusted down one level; conversely, if no body movement reaction occurs (defined as “negative body movement reaction”), the next patient is adjusted down one level, and a lower ciprofol infusion rate will be used with an adjacent gradient ratio of 1:1.2.

Sample Size

For the modified Dixon’s up-and-down method, the sample size is primarily determined by obtaining a sufficient number of effective-ineffective response crossovers (typically 6–8), rather than conventional power-based calculation. Enrolling 30 patients per group ensured adequate sequence length for stable EC50 estimation (over 7 crossovers were obtained in each group). Consequently, 90 participants were randomly allocated in this three-group design. Existing studies demonstrate that 20–40 patients per group are sufficient for this methodology.10–12 Consequently, 90 participants were randomly allocated in this three-group design.

Outcomes and Measurements

An independent anesthesiologist assessed sedation depth using MOAA/S scores during anesthesia induction. The primary outcome was the EC50 of ciprofol for successful sedation, with secondary outcomes including induction time, awakening time, cumulative ciprofol dose, and adverse event incidence. Vital signs—MAP, HR, SpO2, and respiratory rate (RR)—were recorded at baseline (T0), 1 minute post-induction (T1), immediately after gastroscope insertion (T2), and every 3 minutes intraprocedurally (T4-X). Adverse events were managed as follows: hypoxemia (SpO2 <95% for >15 s) prompted jaw thrust and increased O2 flow; respiratory depression (RR <10 breaths/min) required continuous monitoring; respiratory arrest (RR <5 breaths/min with concurrent SpO2 <90%) necessitated mask ventilation; hypotension (MAP decrease >20% from baseline) was treated with fluid bolus or vasopressors; and bradycardia (HR <60 bpm) warranted intravenous atropine (0.1–0.3 mg). Secondary outcomes included onset time (interval from ciprofol administration to MOAA/S ≤1) and recovery time (interval from procedure completion to MOAA/S ≥5), assessed every 5 minutes postoperatively until spontaneous awakening. Hemodynamic comparisons across groups evaluated mean percentage changes in MAP and HR relative to baseline, calculated as: ΔMAP = [(MAPT_1-X − MAP_T0)/MAP_T0] × 100.

Statistical Analysis and Data Management

Statistical analyses were conducted in SPSS (v26.0) and GraphPad Prism 9.0.0. Data normality was evaluated via Shapiro–Wilk testing. Normally distributed continuous variables are presented as mean ± SD and compared using one-way analysis of variance (ANOVA) with Bonferroni correction for pairwise comparisons if data were normally distributed with homogeneous variances; otherwise, the Kruskal–Wallis H-test with Dunn’s test was employed. Non-normal data were expressed as median (IQR) and analyzed with Wilcoxon signed-rank test for paired data or Kruskal–Wallis H-test for multiple groups. Categorical variables were reported as frequencies (%) and assessed via Fisher’s exact test with Bonferroni correction for multiple comparisons. The EC50 of ciprofol was calculated using the Dixon’s up-and-down method. The 95% confidence intervals (CI) were determined by probit regression modeling based on the dose-response data, which also served to validate the robustness of the Dixon-derived values. Dose-response relationships were modeled through probit regression to estimate EC50 and CI, with sensitivity analyses validating robustness. Repeated measures analysis of variance (RM-ANOVA) was used to assess the effects of time and group on hemodynamic data. If a significant interaction was found, a simple-effect analysis was performed to compare inter-group differences at specific time points, with a Bonferroni correction applied to adjust for multiple comparisons. Statistical significance was defined as p < 0.05.

Result

Study flow is detailed in Figure 1 (a CONSORT-compliant flow diagram); preoperative laboratory parameters and baseline patient characteristics showed no significant differences (Table 1).

Figure 1.

Study flow diagram.

Table 1.

Patient Characteristics (n=30 for Each Group)

	Control	SK0.25	SK0.5	p-value
Age (years)	51.47 ± 10.98	48.87 ± 10.03	48.63 ± 12.23	0.55
Gender (Male/Female)	13/17	10/20	11/19	0.62
Weight (kg)	64.70 ± 9.94	64.03 ± 13.47	67.20 ± 22.66	0.73
Height (m)	167.03 ± 7.48	165.36 ± 8.43	162.53 ± 17.24	0.24
BMI (kg/m2)	22.93 ± 2.65	23.19 ± 3.04	23.26 ± 2.68	0.89
TBL (μmol/L)	16.47 ± 9.99	12.73 ± 2.99	15.64 ± 3.67	0.51
Albumin (g/L)	44.16 ± 3.55	43.69 ± 1.52	46.32 ± 0.36	0.41
ALT (U/L)	21.85 ± 7.70	21.75 ± 6.74	17.52 ± 11.03	0.62
AST (U/L)	41.77 ± 59.67	25.13 ± 6.22	23.67 ± 3.79	0.66
SCR (μmol/L)	70.09 ± 15.60	71.36 ± 19.21	71.67 ± 7.06	0.99
BUN (mmol/L)	5.27 ± 1.11	4.77 ± 0.16	4.90 ± 0.71	0.73
INR	0.98 ± 0.07	1.03 ± 0.14	0.99 ± 0.06	0.59

Notes: Data are mean (standard deviation), median [range] or n.

Abbreviations: BMI, body mass index; TBL, serum total bilirubin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; SCR, serum creatinine; BUN, blood urea nitrogen; INR, international normalized ratio.

The EC50 of ciprofol (95% CI) in the Group control, SK0.25, and SK0.5 groups demonstrated dose-dependent reductions: 0.75 (0.66–0.85), 0.70 (0.66–0.76), and 0.62 (0.54–0.70) mg/kg/h, respectively (Table 2). Relative to SK0, EC50 decreased by 6.67% and 17.33% in the SK0.25 and SK0.5 groups. The ciprofol maintenance infusion rate and endoscopic response trajectories are detailed in Figures 2–4. Rescue medication was required in n=14, 13, and 13 patients across group control, SK0.25, and SK0.5 groups, respectively.

Table 2.

Ciprofol Median Effective Infusion Rate (EC50, mg/kg/h) and Its 95% Confidence Interval (CI)

	Control	SK0.25	SK0.5
EC50 (mg/kg/h)	0.75	0.70	0.62
95% CI	[0.66, 0.85]	[0.66, 0.76]	[0.54, 0.70]
Relative reduction vs Control	–	6.67%	17.33%

Notes: EC50 Definition: Median ciprofol infusion rate required for effective sedation (no significant body movement during endoscope insertion), calculated via the modified Dixon’s up-and-down method with 7–8 effective-ineffective cross-over points per group. Dose Ladder Details: Starting rate = 0.6 mg/kg/h; successive rates (1:1.2 ratio): 0.6, 0.72, 0.86, 1.03, 1.24 mg/kg/h. Statistical Validation: “Probit regression-validated EC50” denotes independent verification via dose-response curve fitting, confirming consistency with Dixon-derived values. Group Definitions: Control = ciprofol + normal saline; SK0.25 = ciprofol + esketamine 0.25 mg/kg; SK0.5 = ciprofol + esketamine 0.5 mg/kg.

Figure 2.

Modified Dixon’s up-and-down sequence of ciprofol median effective infusion rate (EC50) in the Control group. This plot displays the sequential adjustment of ciprofol infusion rates (mg/kg/h) across 30 patients in the Control group. The x-axis represents the patient sequence, and the y-axis represents the ciprofol infusion rate administered. Open circles represent ineffective sedation (body movement during the most stimulating endoscopic phase), while solid circles represent effective sedation (no body movement). The horizontal line denotes the median effective infusion rate (EC50 = 0.75 mg/kg/h) of ciprofol in this group, calculated via the modified Dixon-Massey method. The calculated ciprofol EC50 with 95% confidence interval was 0.75 (0.66–0.85)mg/kg/h.

Figure 3.

Modified Dixon’s up-and-down sequence of ciprofol median effective infusion rate (EC50) in the SK0.25 group. This plot illustrates the sequential ciprofol infusion rate adjustments (mg/kg/h) for 30 patients in the SK0.25 group (esketamine 0.25 mg/kg). The x-axis denotes the patient sequence, and the y-axis denotes the administered ciprofol infusion rate. Open circles represent ineffective sedation (body movement during the most stimulating endoscopic phase), while solid circles represent effective sedation (no body movement). The horizontal line indicates the EC50 of ciprofol in this group (0.70 mg/kg/h), derived from the modified Dixon-Massey method. The calculated ciprofol EC50 with 95% confidence interval was 0.70 (95% CI: 0.66–0.76)mg/kg/h.

Figure 4.

Modified Dixon’s up-and-down sequence of ciprofol median effective infusion rate (EC50) in the SK0.5 group. This plot depicts the sequential ciprofol infusion rate adjustments (mg/kg/h) for 30 patients in the SK0.5 group (esketamine 0.5 mg/kg). The x-axis denotes the patient sequence, and the y-axis denotes the administered ciprofol infusion rate. Open circles represent ineffective sedation (body movement during the most stimulating endoscopic phase), while solid circles represent effective sedation (no body movement). The horizontal line marks the EC50 of ciprofol in this group (0.62 mg/kg/h), calculated using the Dixon’s up-and-down method. The calculated ciprofol EC50 with 95% confidence interval was 0.62 (95% CI: 0.54–0.70)mg/kg/h.

Figure 2 shows the up-and-down sequences for the Control group; Figure 3 shows the up-and-down sequences for the SK0.25 cohort; Figure 4 shows the up-and-down sequences for the SK0.5 cohort. Non-response events are denoted by open circles and response events by solid circles (solid triangles for SK0.5 group). The EC50 is indicated by a horizontal line. Specific EC50 values are shown in Table 2.

No severe adverse events (SAEs), including endotracheal intubation or procedure termination, were observed. The incidence of hypoxemia was 0% in all three groups. Sedation-associated cardiovascular events are summarized in Table 3. Bonferroni-corrected pairwise comparisons showed that the incidence of hypotension in the SK0.25 group (36.67%) was significantly lower than that in the Control group (73.33%, adjusted p < 0.001), and the incidence in the SK0.5 group (16.67%) was significantly lower than that in both the Control group (adjusted p < 0.001); however, no significant difference was observed compared with the SK0.25 group (adjusted p = 0.126). There were no significant differences in bradycardia incidence among the three groups (overall p = 0.75). RM-ANOVA revealed significant main effects of time, group, and their interaction on mean arterial pressure (overall p < 0.05). Simple-effect analysis showed that MAP in the SK0.5 group was significantly higher than in the Control group at T2 (2 min post-induction) and T3 (at scope insertion) (all adjusted p < 0.0167). For heart rate, there were no significant differences among the three groups at each time point (all adjusted p > 0.0167) (Figures 5 and 6).

Table 3.

Examination-Related Characteristics and Adverse Reactions

Item	Control	SK0.25	SK0.5	Overall p-value
Dosage of Ciprofol (mg)	78.32 ± 16.37	65 ± 15.18***	56.39 ± 10.69***	<0.001
Onset times (s)	277 ± 64.80	232 ± 62.69	203 ± 56.68***	<0.001
Examination time (min)	19.17 ± 7.94	18.17 ± 4.79	16.65 ± 6.22	0.144
Awakening time (s)	315 ± 171.0	242.2 ± 117.1	273.4 ± 141.0	0.154
Hypotension	22(73.33%)	11(36.67%)***	5(16.67%)***	<0.001
Bradycardia	5(16.67%)	3(10.0%)	4(13.33%)	0.677

Notes: Data are presented as n (%) for categorical variables or mean ± SD for continuous variables. Normality was verified by the Shapiro–Wilk test and variance homogeneity by Levene’s test. Single-point continuous variable (e.g., induction time, dosage, and recovery times) were compared using one-way ANOVA, followed by Bonferroni-corrected pairwise comparisons. Categorical variables (hypotension, bradycardia) were analyzed using Fisher’s exact test. To maintain a family-wise error rate of 0.05 across the three study groups, a unified Bonferroni-adjusted significance threshold of α = 0.0167 (0.05/3) was applied for all pairwise comparisons. *** indicates adjusted p < 0.001 compared with the Control group. Regarding the comparison between the two intervention groups (SK0.25 vs SK0.5), a significant difference was observed in the ciprofol infusion rate (adjusted p = 0.006). No significant differences were found between the SK0.25 and SK0.5 groups in onset time (adjusted p = 0.555), awakening time (adjusted p = 0.324), or hypotension incidence (adjusted p = 0.126). For bradycardia and examination time, no significant overall inter-group differences were observed (overall p > 0.05), thus pairwise comparisons were not performed.

Figure 5.

Percentage changes in heart rate (ΔHR) from baseline during gastrointestinal endoscopy. Data are presented as mean ±SEM. HR was measured at 12 time points in 30 patients per group (Control: ciprofol monotherapy; SK0.25: ciprofol + esketamine 0.25 mg/kg; SK0.5: ciprofol + esketamine 0.5 mg/kg). The dashed line represents 0% change (no deviation from baseline). Statistical analyses were performed using RM-ANOVA; when a significant interaction was found, simple-effect analysis with Bonferroni correction (α = 0.0167) was used for both inter-group and intra-group comparisons. Significant intra-group HR reductions (vs baseline) were observed in the Control group at T3–T5 (all adjusted p < 0.0167), while no significant deviations were noted in the SK0.25 or SK0.5 groups at any time point (all adjusted p > 0.0167). Significant inter-group differences (Control > SK0.25/SK0.5 in HR reduction) were detected at T3–T5 (all adjusted p < 0.0167). Longitudinal HR percentage changes from baseline were quantified at defined procedural phases: T₀ (baseline); T₁ (1 minute post-induction); T₂ (3 min post-esketamine injection); T₃ (endoscope intubation); T_4-ₓ (3-min intervals during procedure).

Figure 6.

Percentage changes in mean arterial pressure (ΔMAP) from baseline during gastrointestinal endoscopy. Data are presented as mean ± SEM. MAP was measured at 12 time points in 30 patients per group (Control: ciprofol monotherapy; SK0.25: ciprofol + esketamine 0.25 mg/kg; SK0.5: ciprofol + esketamine 0.5 mg/kg). The dashed line represents 0% change (no deviation from baseline). Statistical analyses were performed using RM-ANOVA. When a significant interaction was found, simple-effect analysis with Bonferroni correction (α = 0.0167) was used for both inter-group and intra-group comparisons. Significant intra-group MAP reductions (vs baseline) were observed in the Control group at T8 and T11 (all adjusted p < 0.0167), while no significant deviations were noted in the SK0.25 or SK0.5 groups at any time point (all adjusted p > 0.0167). Significant inter-group differences (Control > SK0.25/SK0.5 in MAP reduction) were detected at 9 time points (T1, T3–T10; all adjusted p < 0.0167). Longitudinal percentage changes in mean arterial pressure (MAP) from baseline were assessed at defined intervals: T₀ (baseline); T₁ (1 minute post-induction); T₂ (3 min post-esketamine injection); T₃ (endoscope intubation); T_4-ₓ (3-min intervals during procedure).

Discussion

In this modified Dixon’s up-and-down dose-finding study, we identified EC50 values of 0.75 (0.66–0.85) mg/kg/h, 0.70 (0.66–0.76) mg/kg/h, and 0.62 (0.54–0.70) mg/kg/h for ciprofol combined with escalating esketamine doses during intravenous sedation in gastrointestinal endoscopic procedures. The median effective infusion rate of ciprofol combined with varying esketamine doses was determined using a modified Dixon’s up-down method, a well-established sequential design. This approach maximizes data utilization from limited samples while ensuring rapid and precise estimation, contingent on two criteria: rapid drug effect discernibility and flexible dose adjustments. Both ciprofol and esketamine met these criteria, validating the methodological feasibility.

Our study demonstrates significant benefits of low-dose esketamine as an adjunct to ciprofol-based sedation. The esketamine-ciprofol regimen in this trial was associated with a reduced incidence of hypotension. No hypoxemia occurred in any group, which may be related to the standardized procedural protocol including routine pre-oxygenation and close monitoring employed in this study. Esketamine supplementation reduced composite and individual outcomes of intraprocedural desaturation and hypotension, while lowering ciprofol dose requirements without increasing adverse effects.

The adoption of pain-free gastrointestinal endoscopy in China has increased to approximately 48.3%, reflecting growing emphasis on comfort-oriented medical care.7 Propofol remains the global standard for achieving safe and titratable sedation and anesthesia.13 Previous studies have highlighted ciprofol’s advantages over propofol, including reduced respiratory and circulatory depression, enhanced potency, lower injection pain, and a broader therapeutic index.14,15

The observed hemodynamic stability with esketamine-ciprofol co-administration contrasts starkly with conventional propofol-opioid regimens, where hypotension and bradycardia remain dose-limiting complications.4 Mechanistically, esketamine’s sympathomimetic properties likely counterbalance ciprofol’s intrinsic cardiovascular suppression, as evidenced by attenuated MAP declines (ΔMAP: −8.2% in SK0.5 vs −14.7% in controls; Figure 6). To comprehensively assess hemodynamic stability during the procedure, the percentage changes in HR and MAP relative to baseline (T1) were analyzed across the Control, SK0.25, and SK0.5 groups. Statistical analysis was performed using RM-ANOVA to evaluate group-by-time interaction effects, followed by simple-effects analysis with Bonferroni correction for pairwise comparisons. To account for multiplicity, an adjusted significance level of α = 0.0167 was applied, and all related results are reported as adjusted p-values to ensure consistency with the declared statistical framework. At baseline, neither HR change (−4.5±8.2% [Control], 0.4±6.9% [SK0.25], 3.9±7.5% [SK0.5]; overall p > 0.05) nor MAP change (−4.5±9.1% [Control], 0.4±10.5% [SK0.25], 3.9±9.7% [SK0.5]; overall p > 0.05) differed significantly among the three groups, ensuring baseline homogeneity. Simple-effect analysis of the group-by-time interaction revealed distinct stability patterns: the Control group exhibited significant temporal fluctuations in both parameters—HR decreased markedly at T3 (−8.2%, adjusted p < 0.002), T4 (−12.5%, adjusted p < 0.0167), and T5 (−9.8%, adjusted p = 0.003) (corresponding to endoscope insertion and mid-procedure), while MAP showed a downward trend at T8 (−2.7%, adjusted p = 0.044) and T11 (−9.1%, adjusted p < 0.0167), indicating procedural hypotension risk. In contrast, the SK0.25 and SK0.5 groups maintained stable HR and MAP throughout the procedure, with no significant deviations from baseline at any time point (all adjusted p > 0.0167 for MAP and HR). Inter-group comparisons confirmed the protective effect of esketamine: significant differences were observed at T3–T5 for HR (Control > SK0.25/SK0.5 in HR reduction; all adjusted p < 0.0167) and at 9 time points (T1, T3–T10) for MAP (eg., Control > SK0.5 in MAP reduction at T1, adjusted p < 0.0167; Control > SK0.25 in MAP reduction at T7–T9, all adjusted p < 0.0167). Notably, no significant differences in HR or MAP were detected between the SK0.25 and SK0.5 groups at any time point (all adjusted p > 0.0167), suggesting no dose-dependent effect within the tested esketamine range. Collectively, these findings demonstrate that esketamine coadministration (0.25 and 0.5 mg/kg) effectively mitigates procedural HR and MAP fluctuations, reduces hypotension risk, and enhances overall hemodynamic stability during endoscopic procedures. Data are presented as mean ± standard error of the mean (SEM) in Figures 5 (HR) and 6 (MAP). This dual-action pharmacodynamic synergy—sedative-sparing effects coupled with hemodynamic stabilization—positions esketamine as an ideal adjunct for patients with potential cardiopulmonary comorbidities, particularly those with preexisting cardiopulmonary comorbidities.

While prior studies report 12–18% hypoxemia incidence with propofol monotherapy,8 our protocol’s standardized pre-oxygenation and close monitoring may have contributed to the absence of hypoxemia in all groups. This aligns with Song’s research,9 who demonstrated esketamine’s capacity to preserve respiratory drive during propofol-based sedation, likely via NMDA-mediated modulation of brainstem respiratory nuclei.

Ciprofol-esketamine coadministration reduces the ciprofol EC50 during gastrointestinal endoscopy. Esketamine demonstrates superior sedative-analgesic efficacy via potent NMDA receptor antagonism, coupled with rapid metabolic clearance, minimal adverse events, and accelerated recovery kinetics.16 Esketamine demonstrates reduced hemodynamic instability and respiratory depression compared to conventional analgesics, attributed to its sympathomimetic properties.17 Esketamine enhances hemodynamic stability through sympathomimetic-driven cardiostimulatory effects that antagonize ciprofol-induced cardiovascular suppression. At low-dose regimens, it achieves ketamine-comparable sedation and analgesia while maintaining hemodynamic equilibrium with minimal adverse event incidence.18 Prior studies demonstrate that esketamine-based sedation protocols during endoscopic retrograde cholangiopancreatography (ERCP) achieve propofol-sparing effects compared to opioid regimens (alfentanil 2ug/kg), while preserving recovery kinetics and adverse event incidence.19 A randomized trial in 114 obese patients undergoing gastroscopy demonstrated that adjunctive esketamine (0.25 mg/kg) to propofol, compared to propofol monotherapy, reduced induction and emergence times, decreased propofol dosage, stabilized hemodynamics, and lowered adverse event incidence.20 This study establishes ciprofol-esketamine dose-response curves for clinical guidance, defining a median effective infusion rate. Co-administration of 0.5 mg/kg esketamine reduced required ciprofol dosage by approximately 17.3% to meet procedural demands for gastrointestinal endoscopy. To our knowledge, this represents the first quantitative assessment of esketamine’s ciprofol-sparing effects.

Despite these advances, our findings must be contextualized within inherent limitations. First, the single-center design and homogeneous ASA I–III cohort limit generalizability to critically ill or morbidly obese patients. Second, while the Dixon’s up-and-down method efficiently estimates EC50, it provides limited insight into extreme dose thresholds (eg., ED95), necessitating probit analyses for complete dose-response characterization. Third, the liver (ALT, AST) and renal (SCR, BUN) function indices of enrolled patients in this study were within clinically acceptable mildly abnormal ranges; severe hepatic or renal impairment could affect drug metabolism, which should be considered in future research. Fourth, while our findings highlight the hemodynamic benefits of adjunctive esketamine, the scope of safety monitoring was primarily centered on cardiorespiratory parameters. Specific esketamine-induced adverse events—including neuropsychiatric symptoms (such as dissociation, vivid dreams, or hallucinations) and secretagogue effects (increased oropharyngeal secretions)—were not systematically quantified using standardized assessment tools, such as the Clinician-Administered Dissociative States Scale (CADSS). Although no severe psychiatric distress or clinical airway obstruction was documented during the recovery period, the lack of structured observation may have led to an underestimation of these transient side effects. This omission limits our ability to provide a comprehensive risk-benefit analysis regarding the neurological and psychological impact of the esketamine-ciprofol combination. Future research should incorporate dedicated scales to rigorously evaluate these specific sub-clinical adverse events.

In conclusion, this trial roffers a potentially optimized pharmacologic approach for gastrointestinal endoscopic sedation. By quantifying esketamine’s ciprofol-sparing effects and establishing evidence-based dosing thresholds, we provide a template for optimizing sedation-analgesia equilibrium inpatients undergoing gastrointestinal endoscopy. Future research should explore esketamine’s role in prolonged procedures (eg., ERCP) and its neuroprotective potential in patients with cerebral hypoperfusion risks. As global endoscopy volumes escalate, protocols balancing efficacy, safety, and cost-effectiveness will prove indispensable—a challenge this study directly addresses.

Conclusion

Under the experimental conditions of this study, low-dose esketamine (0.5 mg/kg) reduced ciprofol requirements for suppressing motor responses and was associated with a reduced incidence of hypotension in patients undergoing gastrointestinal endoscopy. Under standard monitoring, no hypoxemia occurred in any group. The ciprofol-esketamine balanced sedation strategy supported by this study offers a feasible regimen that may optimize hemodynamic stability for patients undergoing gastrointestinal endoscopy. These findings are based on specific procedural and monitoring protocols; their application to different clinical settings should consider local contexts. While this combination appears promising for clinical use, it is important to note that specific esketamine-related adverse events—including dissociative symptoms, vivid dreams, and increased oropharyngeal secretions—were not systematically quantified in our study. Therefore, while our results support the hemodynamic advantages of this regimen, further research with structured neuropsychiatric assessments is required to fully characterize the safety profile of the esketamine-ciprofol combination.

Funding Statement

This work was funded by the Shanghai Yangpu District Medical Key Discipline Construction Fund (22YPZA08) and the Yangpu District Health Committee and Science and Technology Commission (YPM202318).

Data Sharing Statement

The datasets generated and analyzed during this study are not publicly available due to privacy restrictions but can be accessed from Jin-chao Song upon reasonable request (E-mail: sjch2013@163.com).

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 have no competing interests in this work.