Cervical dilation-induced somatic responses remain a critical challenge in ambulatory hysteroscopic surgery. Esketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, exhibits unique analgesic and sedative properties that may enhance perioperative somatic response inhibition. However, the effective dose of esketamine under dexmedetomidine-remifentanil based monitored anesthesia care (MAC) during ambulatory hysteroscopic surgery remains to be determined. This prospective dose-finding study aimed to establish the median effective dose (ED50) and 95% effective dose (ED95) of esketamine for cervical response suppression. Afterwards, the investigators will conduct an RCT study to evaluate the safety of the dose of esketamine ED95 through the incidence of respiratory depression.

This research will be divided into two stages. (i) In Phase one, a prospective dose discovery study using the Dixon sequential method will be conducted, aiming to determine the median effective dose (ED50) and 95% effective dose (ED95) of esketamine in inhibiting cervical response. Esketamine will be initiated by intravenous infusion at 0.3 mg∙kg-1, followed by somatic response based on cervical dilation (positive: any exercise; negative: no movement). Dose adjustment will be carried out, with a dose fluctuation step of 0.02 mg∙kg-1 up and down. All patients will receive a standardized anesthesia regimen, including continuous infusion of remifentanil at a dose of 5 μg∙kg∙h-1, combined with dexmedetomidine (infusion at a loading dose of 0.6 μg∙kg-1 for 10 minutes, followed by maintenance infusion at 0.4 μg∙kg-1∙h-1). The test will continue until six cross-pairings are obtained. Probabilistic regression analysis will be used to calculate the ED50 and ED95 of esketamine with a 95% confidence interval.

(ii) The investigators will conduct a single-center, randomized, double-blind controlled trial in Phase Two to evaluate the safety of the esketamine ED95 dose under the monitoring anesthesia care program based on the incidence of respiratory depression. The intervention group will be injected with the dose of esketamine ED95; the control group will be injected with remifentanil 1μg∙kg-1. Both groups of patients will receive the same sedation regimen, namely remifentanil will be continuously pumped at a rate of 5μg∙kg∙h-1 combined with dexmedetomidine (pumped at a loading dose of 0.6 μg∙kg-1 for 10 minutes, followed by maintenance pumping at 0.4 μg∙kg-1∙h-1). Intravenous injection of 100 mg of flurbiprofen axetil for auxiliary analgesia. Intravenous injection of 4 mg of ondansetron to prevent nausea and vomiting.

Inclusion Criteria:

• Aged 18 - 55 years;
• ASA physical status Ⅰ or Ⅱ;
• Body mass index (BMI) 18 - 28 kg∙m-2;
• Scheduled for elective diagnostic/therapeutic hysteroscopy.

Exclusion Criteria:

(i) Pharmacological contraindications:

• Known hypersensitivity to study medications (esketamine, remifentanil, dexmedetomidine);
• Opioid or benzodiazepine medications dependence;
• Analgesic/psychotropic medication use within 48 hours preoperatively;
• Participation in any other drug clinical trial within the preceding three months.

(ii) Comorbidities:

• Significant cardiopulmonary dysfunction (NYHA III-IV, FEV₁/FVC <70%);
• Hepatic impairment (Child-Pugh B/C);
• Uncontrolled hypertension, intracranial hypertension, intraocular hypertension or hyperthyroidism;
• Neurological/psychiatric conditions (epilepsy, schizophrenia, depression);
• Active gastroesophageal reflux disease (GERD-Q score ≥8). (iii) Airway/Perioperative Risks:
• Anticipated difficult airway (Mallampati III-IV, thyromental distance <6 cm) or airway stenosis;
• Non-fasted status (solids <8h, clear fluids <2h preoperatively).