Abstract
Background
Opioid-free anesthesia (OFA) protocols using esketamine and dexmedetomidine have shown potential benefits for perioperative pain control with fewer side effects. We explored whether an esketamine–dexmedetomidine OFA regimen accelerates bowel recovery and preserves cognitive function after laparoscopic total hysterectomy.
Methods
In this prospective observational cohort study, we enrolled 114 women undergoing elective total laparoscopic hysterectomy (TLH). Anesthesia technique—esketamine–dexmedetomidine–based OFA (OFA group) versus standard opioid-based anesthesia (OBA group)—was chosen by the attending anesthesiologist. Key perioperative variables, including drug dosages and rescue analgesics, were recorded. The primary outcome was the time to first bowel movement. Secondary endpoints included incidence of postoperative ileus, pain scores, opioid consumption, and postoperative cognitive function assessed by the Montreal Cognitive Assessment (MoCA) at baseline and postoperative Days 1 and 3.
Results
Among the 114 participants (OFA group n = 59; OBA group n = 55), median time to first bowel movement was significantly shorter in the OFA group (42 h [IQR 38–48]) compared with the OBA group (49 h [IQR 42–56]; p < 0.01). Postoperative ileus occurred in 6% of OFA patients versus 15% of OBA patients (p = 0.07). Postoperative MoCA scores showed a smaller decline from baseline in the OFA group (mean difference − 1.2 ± 1.0) compared with the OBA group (− 2.3 ± 1.5; p < 0.05). Use of rescue opioids was lower in the OFA group (23% vs. 42%; p = 0.02).
Conclusions
Esketamine–dexmedetomidine–based OFA approach was associated with faster return of bowel function and reduced cognitive decline compared to standard opioid-based anesthesia in women undergoing TLH, without compromising analgesia or safety. These observational findings warrant confirmation in randomized trials.
Keywords: Esketamine, Dexmedetomidine, Opioid-Free anesthesia, Postoperative bowel function, Cognitive function
Introduction
Total laparoscopic hysterectomy (TLH) is a widely performed surgical procedure for benign gynecological conditions, offering advantages such as reduced hospital stay, minimal blood loss, and fewer complications compared to traditional abdominal hysterectomy [1, 2]. TLH is one of the most common gynecological surgeries [3, 4]. The procedure is particularly beneficial for conditions like adenomyosis, fibroids, and endometriosis [5, 6]. However, postoperative complications, although generally low, are clinically significant and include issues such as bowel dysfunction and cognitive decline [1, 6, 7]. Bowel injuries can occur during surgery, leading to significant postoperative morbidity [1, 7], while cognitive decline can be a concern due to anesthesia and the stress of surgery [4]. The incidence of complications varies, with some studies reporting minor complications like postoperative fever as the most common, while others note more severe issues such as ureteric fistulas and bowel obstructions [5, 7]. The rate of conversion to open surgery is low, underscoring the procedure’s safety and efficacy [8, 9]. Overall, TLH is a safe and effective option for many patients, but awareness and management of potential complications are crucial for optimizing patient outcomes [2, 8].
Opioid-Free Anesthesia (OFA) is increasingly being explored as a viable alternative to traditional opioid-based anesthesia due to the adverse effects associated with opioids [10, 11]. The rationale for OFA is to mitigate these opioid-related complications while maintaining hemodynamic stability during surgery [10, 12]. OFA regimens typically involve a multimodal approach using non-opioid agents like lidocaine, ketamine, magnesium, and alpha-2 agonists such as dexmedetomidine [11, 13]. These regimens aim to provide effective analgesia and reduce the incidence of postoperative nausea and vomiting (PONV) and other opioid-related side effects [14, 15]. However, the results of OFA regimens have been mixed. Some studies have shown promising outcomes, such as reduced pain scores and lower opioid consumption postoperatively, particularly in high-risk patients like those with obstructive sleep apnea or obesity [16, 17]. Conversely, other studies have not demonstrated significant clinical benefits in terms of pain management compared to opioid-based anesthesia [14, 15]. Despite the potential benefits, the adoption of OFA is hindered by the lack of standardized protocols and the need for more high-quality evidence to support its efficacy across different surgical procedures [12, 18].
Esketamine, the S-enantiomer of ketamine, exhibits higher NMDA receptor affinity and fewer psychomimetic effects compared to its racemic counterpart [19, 20]. Its combination with dexmedetomidine is theoretically beneficial but remains untested in TLH settings [19]. While esketamine has demonstrated effective analgesic properties and comparable gastrointestinal recovery in burn patients, there is a significant knowledge gap regarding its combined use with dexmedetomidine in Asian populations [19, 21]. Further research is essential to explore these combinations and their implications for clinical practice.
The present prospective cohort study therefore sought to determine whether an esketamine–dexmedetomidine OFA regimen is associated with earlier postoperative bowel recovery than standard opioidbased anaesthesia (OBA) in women undergoing total laparoscopic hysterectomy. Time from skin closure to the first documented passage of stool constituted the prespecified primary outcome, while key secondary outcomes included time to first flatus, pain intensity, opioid consumption, postoperative nausea/vomiting, post‑operative cognitive function assessed with the Montreal Cognitive Assessment (MoCA), and length of stay.
Methods
This was a prospective, observational cohort study conducted at Xingtai People’s Hospital. The study aimed to compare two anesthesia strategies—OFA and OBA—in routine clinical practice among patients undergoing TLH. Ethical approval was obtained from the Institutional Review Board of Xingtai People’s Hospital prior to patient enrollment (Approval number: 2024-[082]). Data were de-identified and stored on a secure server. The study was conducted in accordance with the principles of the Declaration of Helsinki and local regulatory requirements.
Inclusion Criteria: 1), Women aged ≥18 years; 2), Scheduled for elective total laparoscopic hysterectomy; 3), international ASA-Physical-Status II–III; 4), Baseline MoCA score ≥18; 5), Ability to provide written informed consent.
Exclusion Criteria: 1), Allergy or contraindication to esketamine, dexmedetomidine, or opioids; 2), Chronic opioid use (>3 months) or opioid dependence; 3), Severe cardiac, renal, or hepatic dysfunction; 4), Significant psychiatric illness interfering with study participation; 5), Inability to complete cognitive testing due to hearing/vision impairment or language barrier. Patients scheduled for TLH were screened by the research team at the pre-anesthesia evaluation clinic. Eligible individuals were approached for consent, and those agreeing to participate signed the approved informed consent form.
Sample‑size calculation
Pilot data (n = 20) showed a mean ± SD time to first bowel movement of 48 ± 10 h after OBA. Detecting a 6‑h reduction with OFA at α = 0.05 (two‑tailed) and 80% power required 45 patients per group (GPower v3.1). Expecting ≤ 10% attrition, we targeted 110 patients; ultimately 114 were analyzed, yielding 89% post‑hoc power for the observed inter‑group difference.
Anesthesia management
Because this study was non-interventional, the choice of anesthesia (OFA or OBA) was at the discretion of the attending anesthesiologist, based on patient factors and clinical judgment. Patients were then observed prospectively according to the group in which they naturally fell.
OFA group
OFA was delivered with a standardized, esketamine-dexmedetomidine regimen. After pre-oxygenation, patients received dexmedetomidine 0.5 µg/kg over 10 min, followed by an intravenous esketamine bolus of 0.25 mg/kg given over 60 s. General anesthesia was induced with propofol 2 mg/kg and rocuronium 0.6 mg/kg, then maintained with propofol target-controlled infusion (BIS 40–60), continuous esketamine 0.20 mg/kg per hour, and dexmedetomidine 0.3 µg/kg per hour, titrated to keep mean arterial pressure within ±20% of baseline. Intra-operative analgesia was supplemented with lidocaine 1.5 mg/kg per hour and ketorolac 30 mg i.v.; no opioids were administered. All infusions were stopped 20 min before skin closure, neuromuscular block was antagonized with sugammadex (2 mg/kg), and standard international ASA monitoring plus invasive arterial pressure were used throughout.
Standard OBA group
OBA followed institutional practice. After 3 min of 100% oxygen, anesthesia was induced with fentanyl 2 µg/kg, propofol 2 mg/kg, and rocuronium 0.6 mg/kg. Anesthesia was maintained with sevoflurane (end-tidal 1.5%) in a 50% air–oxygen mixture, supplemented by a continuous remifentanil infusion of 0.15 µg/kg per min; additional fentanyl 0.5 µg/kg i.v. boluses were permitted at the anesthesiologist’s discretion to keep mean arterial pressure and heart rate within ±20% of baseline. Intra-operative analgesia was supplemented with lidocaine 1.5 mg/kg per hour and ketorolac 30 mg i.v. Ventilation, depth of anesthesia (BIS 40–60), and neuromuscular blockade were adjusted per standard international ASA guidelines. All volatile and opioid infusions were discontinued at skin closure, neuromuscular block was reversed with sugammadex (2 mg/kg).
Outcome measurement
The primary outcome was the time (hours) from skin closure to the first documented passage of stool. Ward nurses record bowel movements every four hours and on patient request; the clock time of the first event is entered into the electronic chart and was extracted verbatim for analysis. Secondary outcomes were: (1) time to first flatus, (2) time to first oral intake of clear fluids, (3) pain intensity at 24 h and 48 h measured on a 0–10 numeric‑rating scale, (4) incidence of post‑operative nausea and/or vomiting within 24 h, (5) clinically significant oversedation in the post‑anesthesia care unit, (6) length of hospital stay, (7) surgical complications up to 30 days classified by Clavien–Dindo, and (8) baseline Montreal Cognitive Assessment score.
Post-operative ileus
Post-operative ileus (POI) was diagnosed when patients exhibited persistent abdominal distension without passage of flatus or stool for more than 72 h, required nasogastric decompression or cessation of oral intake because of gastrointestinal intolerance, and showed radiographic evidence of dilated bowel loops in the absence of a mechanical obstruction or other secondary causes such as intra-abdominal sepsis or anastomotic leak; time to first bowel movement (hours from skin closure) was recorded for all participants, and POI was analyzed as a binary endpoint.
Post-operative cognitive dysfunction
Post-operative cognitive dysfunction (POCD) was evaluated with the Montreal Cognitive Assessment (MoCA) performed pre-operatively and on post-operative days (POD) 1 and 3 by a nurse blinded to anesthetic allocation; POCD was predefined as either an absolute MoCA score below 26 or a decline of at least 2 points relative to the individual’s baseline, a dual criterion designed to capture clinically meaningful impairment while accounting for test–retest variability.
Statistical analysis
Primary analysis
Continuous variables were checked for normality using the Shapiro–Wilk test. Normally distributed data were expressed as mean ± standard deviation (SD) and compared using Student’s t-test; skewed data were presented as median with interquartile range (IQR) and analyzed with the Mann–Whitney U test. Categorical variables (counts and percentages) were compared using Chi-square or Fisher’s exact test as appropriate. Time to first bowel movement was compared between the two groups using the Mann–Whitney U test. MoCA changes were examined using paired t-tests and independent t-tests (between-groups). Pain scores over time were compared using repeated-measures ANOVA or nonparametric equivalents. The proportion of patients with postoperative ileus, need for rescue opioids, and adverse events were evaluated using Chi-square tests. A two-sided p-value < 0.05 was considered statistically significant. All analyses were performed with R (Version 4.4).
Pre‑specified subgroup analysis
Pre‑specified subgroup comparisons examined the treatment effect on the primary endpoint (time to first bowel movement) within categories of age (< 70 vs ≥ 70 years), ASA physical‑status class (I–II vs III), and the presence or absence of hypertension or diabetes. Interaction terms were tested in multivariable models.
Sensitivity analyses
Three sensitivity analyses were conducted: (i) multivariable linear or logistic regression adjusted for age, ASA class, hypertension and diabetes; (ii) 1:1 nearest‑neighbor propensity‑score matching with a caliper of 0.20; and (iii) mixed‑effects models with a random intercept for attending anesthesiologist to account for provider‑level clustering. Finally, a mediation analysis assessed whether the association between anesthetic technique and bowel‑recovery time was mediated by earlier oral intake.
Results
A total of 114 women undergoing laparoscopic total hysterectomy were enrolled in this study. Of these, 59 received an OFA regimen (esketamine–dexmedetomidine–based), while 55 underwent Standard Opioid-Based Anesthesia (OBA). All patients completed the study protocol and were included in the final analysis (Fig. 1).
Fig. 1.
Flow diagram of participant enrollment, allocation, and analysis. A total of 127 women scheduled for total laparoscopic hysterectomy were assessed for eligibility. Thirteen were excluded—eight for not meeting inclusion criteria and five who declined to participate—leaving 114 patients enrolled in the observational cohort. Of these, 59 received an esketamine + dexmedetomidine opioid-free anesthesia regimen (OFA) and 55 received standard opioid-based anesthesia (OBA). All participants completed follow-up and were included in the final analysis
The two groups were similar with regard to age, BMI, and comorbidities (Table 1). The mean age (± SD) was 65.2 ± 5.4 years in the OFA group and 64.8 ± 5.6 years in the OBA group (p = 0.62) (Table 1). A comparable proportion of participants had hypertension (30.5% vs. 29.1%; p = 0.80), diabetes (16.9% vs. 16.4%; p = 0.88), and coronary artery disease (10.2% vs. 9.1%; p = 0.91) (Table 1). Baseline MoCA scores were also similar between groups (25.0 ± 2.0 vs. 24.7 ± 2.3; p = 0.70), indicating no significant preoperative cognitive differences (Table 1).
Table 1.
Baseline characteristics
| Variable | OFA Group (n = 59) | OBA Group (n = 55) | p-value |
|---|---|---|---|
| Age (years), mean ± SD | 65.2 ± 5.4 | 64.8 ± 5.6 | 0.62 |
| BMI (kg/m2), mean ± SD | 26.8 ± 3.5 | 27.1 ± 4.0 | 0.54 |
| ASA Physical Status, n (%) | 0.93 | ||
| II | 32 (54.2%) | 30 (54.5%) | |
| III | 27 (45.8%) | 25 (45.5%) | |
| Baseline MoCA Score, mean ± SD | 25.0 ± 2.0 | 24.7 ± 2.3 | 0.70 |
| Preoperative Opioid Use, n (%) | 2 (3.4%) | 3 (5.5%) | 0.69 |
| Hypertension, n (%) | 18 (30.5%) | 16 (29.1%) | 0.80 |
| Diabetes, n (%) | 10 (16.9%) | 9 (16.4%) | 0.88 |
| Coronary Artery Disease, n (%) | 6 (10.2%) | 5 (9.1%) | 0.91 |
| Smoking Status, n (%) | |||
| Current | 5 (8.5%) | 6 (10.9%) | 0.58 |
| Former | 12 (20.3%) | 10 (18.2%) | 0.79 |
| Never | 42 (71.2%) | 39 (70.9%) | — |
| Previous Abdominal Surgery, n (%) | 14 (23.7%) | 12 (21.8%) | 0.81 |
Legend: Values are mean ± SD, median (IQR), or n (%). Continuous variables with normal distribution were compared with independent‑samples Student t tests; skewed continuous variables with the Mann–Whitney U test; categorical variables with the χ² test or Fisher’s exact test, as appropriate
Abbreviations: ASA American Society of Anesthesiologists, BMI Body‑mass index, IQR Inter‑quartile range, MoCA Montreal Cognitive Assessment, OFA Opioid‑free anesthesia, OBA Opioid‑based anesthesia, SD Standard deviation
The median duration of surgery was 135 min (IQR 120–155) in the OFA group compared with 140 min (125–160) in the OBA group (p = 0.42) (Table 2). There were no significant differences in total crystalloid administration (1200 mL vs. 1300 mL; p = 0.70) or estimated blood loss (80 mL vs. 85 mL; p = 0.58) (Table 2). Mean arterial pressure remained stable in both groups (82 ± 9 vs. 85 ± 10 mmHg; p = 0.10), but patients in the OFA group had a significantly lower mean heart rate (68 ± 6 vs. 73 ± 7 bpm; p < 0.01) (Table 2). As expected, the OFA group did not receive intraoperative opioids, whereas the OBA group received an average of 20 ± 5 mg morphine equivalents (p < 0.001).
Table 2.
Intraoperative data
| Variable | OFA | 95% CI | OBA | 95% CI | p |
|---|---|---|---|---|---|
| Durations | |||||
| Surgery, min (median [IQR]) | 135 (120–155) | 128–142 | 140 (125–160) | 133–147 | 0.42 |
| Anesthesia, min (mean ± SD) | 160 ± 25 | 154–166 | 165 ± 28 | 158–172 | 0.35 |
| Fluid & blood loss | |||||
| Crystalloid, mL (median [IQR]) | 1,200 (1,000–1,500) | 1,098–1,302 | 1,300 (1,000–1,500) | 1,194–1,406 | 0.70 |
| Estimated blood loss, mL (median [IQR]) | 80 (50–120) | 66–94 | 85 (50–130) | 68–102 | 0.58 |
| Hemodynamics | |||||
| MAP, mmHg (mean ± SD) | 82 ± 9 | 80–84 | 85 ± 10 | 83–87 | 0.10 |
| Heart rate, bpm (mean ± SD) | 68 ± 6 | 67–69 | 73 ± 7 | 72–75 | < 0.01 |
| Analgesic/adjunct doses | |||||
| Esketamine, mg (mean ± SD) | 75 ± 15 | 71–79 | 0 | — | — |
| Dexmedetomidine, µg | 70 ± 20 | 65–75 | 0 | — | — |
| Opioids, mg morphine equiv. | 0 | — | 20 ± 5 | 19–21 | < 0.001 |
| Adjunct medications, n (%) | |||||
| Nonopioid analgesic | 49 (83.1) | 72–91 | 45 (81.8) | 70–90 | 0.90 |
| Antiemetic | 45 (76.3) | 64–86 | 40 (72.7) | 60–83 | 0.72 |
| Vasopressor used | 12 (20.3) | 11–32 | 8 (14.5) | 6–26 | 0.47 |
Data are presented as mean ± SD, median (IQR), or n (%). Means were compared with independent‑samples Student t tests and medians with the Mann–Whitney U test; categorical variables were analyzed with the χ² or Fisher’s exact test. 95% CIs accompany all non‑zero group means, medians (Harrell–Davis), and proportions (Wilson). CI is not shown for variables that were structurally zero by study design (e.g., esketamine dose in the OBA group)
Abbreviations: bpm Beats per minute, CI Confidence interval, HR Heart rate, IQR Inter‑quartile range, MAP Mean arterial pressure, ME Morphine equivalents, OFA Opioid‑free anesthesia, OBA Opioid‑based anesthesia, SD Standard deviation
The median time to first bowel movement was significantly shorter in the OFA group (42 h [IQR 38–48]) compared with the OBA group (49 h [42–56]; p < 0.01) (Table 3). After propensity‑score matching (OFA n = 48; OBA n = 48) the median time to first bowel movement remained significantly shorter with OFA (43 [IQR 39–49] h vs. 50 [44–56] h; p = 0.01) (Supplementary Table S1). While the incidence of postoperative ileus was numerically lower in OFA patients (6.8% vs. 14.5%), this difference did not reach statistical significance (p = 0.07) (Table 3). Similarly, the time to passage of flatus was shorter in the OFA group (30 [25–35] hours vs. 35 [30–40]; p = 0.02) (Table 3).
Table 3.
Primary outcome: bowel function
| Outcome | OFA | 95% CI | OBA | 95% CI | p |
|---|---|---|---|---|---|
| Time to first bowel movement, h (median [IQR]) | 42 (38–48) | 40–44 | 49 (42–56) | 46–52 | < 0.01 |
| Postoperative ileus, n (%) | 4 (6.8%) | 2–17 | 8 (14.5%) | 6–26 | 0.07 |
| Time to passage of flatus, h | 30 (25–35) | 28–32 | 35 (30–40) | 33–37 | 0.02 |
| Nasogastric tube required, n (%) | 2 (3.4%) | 0–10 | 5 (9.1%) | 3–19 | 0.21 |
| Prokinetic use, n (%) | 3 (5.1%) | 1–14 | 7 (12.7%) | 5–24 | 0.16 |
Medians (IQR) for time‑to‑event outcomes were compared with the Mann–Whitney U test; categorical endpoints with the χ² or Fisher’s exact test. Ninety‑five percent CIs for medians and median differences were derived with the Harrell–Davis method; CIs for proportions use the Wilson method
CI for medians: Harrell–Davis; CI for proportions: Wald
Abbreviations: CI Confidence interval, IQR Inter‑quartile range, NG Nasogastric, OFA Opioid‑free anesthesia, OBA Opioid‑based anesthesia
Participants in the OFA group exhibited a smaller decrease in MoCA scores from baseline to postoperative Day 3 (− 1.2 ± 1.0) compared to those in the OBA group (− 2.3 ± 1.5; p < 0.05) (Table 4). Pain scores (NRS) at 24 and 48 h were consistently lower in the OFA group (3.2 ± 1.1 vs. 4.0 ± 1.2 at 24 h; p = 0.01 and 2.6 ± 1.0 vs. 3.4 ± 1.1 at 48 h; p = 0.02) (Table 4). Fewer OFA patients required rescue opioids (23.7% vs. 41.8%; p = 0.02), and overall postoperative opioid consumption was significantly lower in the OFA group (4.1 ± 2.5 vs. 9.8 ± 3.0 mg morphine equivalents; p < 0.001) (Table 4). The mean length of hospital stay was shorter in the OFA group (3.5 ± 0.8 vs. 4.1 ± 1.0 days; p = 0.04), and participants in the OFA group tolerated oral intake earlier (8 [6–10] hours vs. 10 [8–12]; p = 0.03) (Table 4). Rates of adverse events, including nausea/vomiting, sedation requiring intervention, and delirium, did not differ significantly between the two groups.
Table 4.
Secondary outcomes
| Outcome | OFA Group (n = 59) | 95% CI | OBA Group (n = 55) | 95% CI | p-Value |
|---|---|---|---|---|---|
| Postoperative Cognitive Function | |||||
| MoCA (Day 1), mean ± SD | 23.8 ± 1.8 | 23.3–24.3 | 22.5 ± 2.2 | 21.9–23.1 | 0.02 |
| MoCA (Day 3), mean ± SD | 24.1 ± 2.0 | 23.6–24.6 | 22.7 ± 2.5 | 22.0–23.4 | 0.03 |
| Change from Baseline (Day 3 – Baseline) | −1.2 ± 1.0 | −1.46 to − 0.94 | −2.3 ± 1.5 | −2.70 to − 1.90 | < 0.05 |
| Pain Scores (NRS) | |||||
| At 24 h | |||||
| Mean ± SD | 3.2 ± 1.1 | 2.9–3.5 | 4.0 ± 1.2 | 3.7–4.3 | 0.01 |
| Median (IQR) | 3 (2–4) | 2.8–3.3 | 4 (3–5) | 3.7–4.3 | 0.01 |
| At 48 h | |||||
| Mean ± SD | 2.6 ± 1.0 | 2.3–2.9 | 3.4 ± 1.1 | 3.1–3.7 | 0.02 |
| Median (IQR) | 2 (2–3) | 1.8–2.3 | 3 (2–4) | 2.7–3.3 | 0.02 |
| Rescue Opioid Use, n (%) | 14 (23.7%) | 13–35 | 23 (41.8%) | 29–55 | 0.02 |
| Total Opioid Consumption, mg morphine equivalents (mean ± SD) | 4.1 ± 2.5 | 3.5–4.7 | 9.8 ± 3.0 | 9.0–10.6 | < 0.001 |
| Other Recovery Indicators | |||||
| Length of Hospital Stay (days), mean ± SD | 3.5 ± 0.8 | 3.3–3.7 | 4.1 ± 1.0 | 3.8–4.4 | 0.04 |
| Time to Oral Intake (hours), median (IQR) | 8 (6–10) | 7.2–8.8 | 10 (8–12) | 9.2–10.9 | 0.03 |
| Adverse Events | |||||
| Nausea/Vomiting, n (%) | 7 (11.9%) | 4–20 | 14 (25.5%) | 14–37 | 0.08 |
| Sedation Requiring Intervention, n (%) | 2 (3.4%) | 0–10 | 6 (10.9%) | 3–19 | 0.15 |
| Delirium (CAM), n (%) | 3 (5.1%) | 1–14 | 5 (9.1%) | 1–17 | 0.48 |
| Serious Adverse Events, n (%) | 1 (1.7%) | 0–8 | 2 (3.6%) | 0–11 | 0.53 |
Mean values are shown ± SD and compared with independent‑samples Student t tests; medians (IQR) were compared with the Mann–Whitney U test. Categorical variables were analyzed with the χ² or Fisher’s exact test. 95% CIs accompany group means, medians (Harrell–Davis), and proportions (Wilson)
Abbreviations: CAM‑ICU Confusion Assessment Method for the ICU, CI Confidence interval, IQR Inter‑quartile range, ME Morphine equivalents, MoCA Montreal Cognitive Assessment, NRS Numeric rating scale, OFA Opioid‑free anesthesia, OBA Opioid‑based anesthesia, SD Standard deviation
Among patients aged ≥ 70 years, the OFA group continued to show a statistically significant reduction in time to first bowel movement compared with the OBA group (43 [39–49] vs. 50 [44–57] hours; p = 0.02) (Supplementary Table S2). Similar findings were observed for participants aged < 70 years (41 [37–47] vs. 48 [42–55] hours; p = 0.03) (Supplementary Table S2). In the subgroup of patients with hypertension, the decline in MoCA from baseline to Day 3 was smaller in the OFA arm (− 1.3 ± 1.1) than in the OBA arm (− 2.2 ± 1.4; p = 0.05) (Supplementary Table S2). Sensitivity analyses excluding participants with preoperative opioid use and adjusting for potential confounders continued to favor the OFA group, indicating robustness of the primary and secondary outcome findings (Supplementary Table S2).
Discussion
In this prospective cohort, patients who received esketamine–dexmedetomidine OFA experienced markedly faster gastrointestinal recovery, achieving their first postoperative bowel movement significantly earlier than those under opioidbased anesthesia. Our findings indicate a clinically relevant association between opioid avoidance and accelerated bowel function, yet the observational design precludes assigning a causal “effect” to the anesthetic regimen.
Published OFA regimens based on lidocaine plus ketamine have reported substantially smaller gastrointestinal benefits than we observed. In total laparoscopic hysterectomy for uterine fibroids, lidocaineketamine shortened bowelmovement time [22], similarly in laparoscopic cholecystectomy for gallstone disease [23]. Other combinations—lidocaine + magnesium in laparoscopic gastric bypass for morbid obesity [23] and dexmedetomidine + lidocaine in colorectal cancer surgery [24]—either showed no advantage or measured only surrogate endpoints such as time to first flatus. Unlike those protocols, our regimen replaces racemic ketamine with the higheraffinity Senantiomer esketamine and combines it with dexmedetomidine, associated with a numerically larger 7 h median acceleration of stool passage in a homogeneous cohort of patients undergoing total laparoscopic hysterectomy for benign uterine disease. Differences in drug choice, surgical pathology, and outcome definition (first stool vs. flatus) likely explain the disparity in effect size.
Esketamine’s potent NMDAreceptor blockade has been shown in rat models of postoperative ileus after intestinal manipulation to dampen macrophagemediated inflammation and shorten gut dysmotility [25]. Clinically, an esketaminecentered opioidsparing protocol reduced time to first flatus and lowered nausea scores in benign gynecologic laparoscopy [26]. Dexmedetomidine, through presynaptic α2agonism, attenuates sympathetic outflow and has been shown to accelerate colonic transit in irritablebowelsyndrome patients [27]. Coadministration of ketamine and dexmedetomidine also decreases µopioidreceptor activation during gynecologic surgery, reinforcing an opioidsparing environment that favors peristalsis [26]. While these pharmacological pathways offer a plausible explanation for the bowelrecovery association we recorded, the present observational design cannot establish causality; the mechanistic links therefore remain speculative.
EnhancedRecoveryAfterSurgery (ERAS) guidelines for benign gynecologic surgery advocate oral fluids once patients are awake, a practice that independently shortens hospital stay and speeds gut recovery [28–31]. In our cohort, mediation analysis showed that earlier feeding accounted for only 18% of the total association between OFA and faster bowel movement, indicating that most of the benefit is unlikely to be driven by feeding protocols alone. Instead, opioid avoidance combined with the NMDAblocking and sympatholytic properties of esketamine and dexmedetomidine may be an important pathway.
A 7 h median reduction places bowel movement well inside the 48 h threshold that ERAS program use to justify discharge after laparoscopic hysterectomy, supporting the feasibility of early or even sameday release reported in other cohorts [32, 33]. Patientreported outcomes show that each 6 h delay in stool passage increases nausea and bloating [34]; our timing difference therefore represents a change likely to be felt by patients. Pain scores were statistically lower with OFA, yet the 1point median decrease is slightly below the ~ 1.3point minimal clinically important difference defined for gynecologic laparoscopy [35]. Taken together, the data suggest that an esketamine–dexmedetomidine OFA protocol may enhance functional recovery and patient comfort after total laparoscopic hysterectomy, but confirmation in randomized trials is required before causal inferences can be made.
Our finding that patients receiving esketaminedexmedetomidine OFA showed smaller decline in MoCA compared with the OBA is biologically plausible when several converging neuroprotective pathways are considered. First, eliminating intraoperative µopioids removes a major trigger of surgeryrelated neuroinflammation [36]. Second, esketamine’s highaffinity NMDAreceptor antagonism curbs excitotoxic glutamate release and microglial activation—mechanisms that limit neuronal loss, and clinically correspond to lower IL-6 and S100β levels in elderly surgical patients [37, 38]. Third, dexmedetomidine, via locuscoeruleus α₂agonism, preserves cholinergic tone and mitigates delirium [39, 40]. The two agents combined further blunt systemic cytokine surges and protect blood–brainbarrier integrity [41, 42]. Finally, both drugs independently enhance synaptic plasticity and reduce βamyloid or αsynuclein accumulation, rescuing memory performance in rodent models [43, 44]. Together these complementary actions provide a mechanistic framework that aligns well with the attenuated cognitive decline we observed in our study.
Nevertheless, its observational design precludes definitive causal inference; unmeasured variables—such as subtle differences in surgical technique, intraoperative temperature management or postoperative mobilization—may still confound the results. The investigation was conducted at a single countylevel hospital in China with a moderate sample size, leaving it underpowered for rare adverse events and limiting generalizability to other healthcare settings. Baseline MoCA scores were modestly lower than Western norms, reflecting educational background rather than pathological impairment and showing no relationship with bowelfunction outcomes. Despite these caveats, the findings suggest that esketamine–dexmedetomidine opioidfree anesthesia is both feasible and safe for routine total laparoscopic hysterectomy and could serve as a practical template for centers unable to launch immediate randomized trials. Future work should include multicenter randomized controlled studies to confirm causality, assess longerterm endpoints such as persistent opioid use and quality of recovery, and undertake mechanistic investigations to clarify how NMDA blockade and sympatholytic influence postoperative gut motility.
Esketamine–dexmedetomidine opioidfree anesthesia is associated with shorter bowelrecovery time and reduced opioid consumption compared with standard opioidbased anesthesia. These findings warrant confirmation in adequately powered randomized trials. Because this was an observational cohort, causality cannot be inferred; the results should be interpreted as hypothesisgenerating.
Abbreviations
- ASA
American Society of Anesthesiologists
- BMI
Body‑mass index
- IQR
Inter‑quartile range
- MoCA
Montreal Cognitive Assessment
- OFA
Opioid‑free anesthesia
- OBA
Opioid‑based anesthesia
- SD
Standard deviation
Authors’ contributions
The authors confirm contribution to the paper as follows: study conception and design: X.L.; data collection: G.L., Y.L., S.G., X.Y., S.R., L.D.; analysis and interpretation of results: G.L., Y.L., S.G., X.Y., S.R., L.D.; draft manuscript preparation: G.L., Y.L., S.G., X.Y., S.R., L.D., X.L. All authors reviewed the results and approved the final version of the manuscript.
Funding
This study was supported by Hebei Provincial Health Commission (Grant number: 20251414).
Data availability
Data sets generated during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
The study protocol was reviewed and approved by the Institutional Review Board of Xingtai People’s Hospital prior to patient enrollment (Approval number: 2024- [082]). Written informed consent was obtained from all participants, in accordance with the Declaration of Helsinki.
Consent for publication
Not Applicable.
Competing interests
The authors declare no competing interests.
Clinical trial number
Not applicable.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data sets generated during the current study are available from the corresponding author on reasonable request.