Study on the Effective Dose and Safety of Esketamine in Hysteroscopic Surgery Under Monitored Anesthesia Care

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Intrauterine Synechiae; Intrauterine Polyp
• Intervention / Treatment: Drug: Determine the ED50 and ED95 of esketamine; Drug: Intravenous the dose of esketamine ED95; Drug: Intravenous remifentanil 1μg∙kg-1

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 95
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• China
  • Fujian
    • Xiamen, Fujian, China, 361000
      • Department of Anesthesiology, The First Affiliated Hospital of Xiamen University, 55 Zhenhai Road, Xiamen, China

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Determine the ED50 and ED95 of esketamine by Dixon's up-and-down method; According to Dixon's up-and-down sequential design, esketamine will be initiated at 0.3 mg∙kg-1 intravenously, followed by dose adjustments (0.02 mg∙kg-1 increments/decrements) based on somatic responses to cervical dilation (positive: any movement; negative: no movement). The tests will continue until six crossover pairs are achieved.	Drug: Determine the ED50 and ED95 of esketamine; According to Dixon's up-and-down sequential design, esketamine will be initiated at 0.3 mg∙kg-1 intravenously, followed by dose adjustments (0.02 mg∙kg-1 increments/decrements) based on somatic responses to cervical dilation (positive: any movement; negative: no movement). The tests will continued until six crossover pairs are achieved.; Other Names: Remifentanil will be continuously pumped at a rate of 5μg∙kg∙h-1 combined with dexmedetomidine (a loading dose of 0.6 μg∙kg-1 for 10 minutes, followed by maintenance dose of 0.4 μg∙kg-1∙h-1).
Active Comparator: Evaluate the safety of the dose of esketamine ED95 by 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 Monitoring Anesthesia Care (MAC) regimen, namely, remifentanil will be continuously pumped at a rate of 5μg∙kg∙h-1 combined with dexmedetomidine (a loading dose of 0.6 μg∙kg-1 for 10 minutes, followed by maintenance dose of 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. The study at this stage will evaluate the safety of the dose of esketamine ED95 through the incidence of respiratory depression.	Drug: Intravenous the dose of esketamine ED95; The intervention group will be injected with the dose of esketamine ED95.; Other Names: Remifentanil will be continuously pumped at a rate of 5μg∙kg∙h-1 combined with dexmedetomidine (a loading dose of 0.6 μg∙kg-1 for 10 minutes, followed by maintenance dose of 0.4 μg∙kg-1∙h-1).; Drug: Intravenous remifentanil 1μg∙kg-1; The control group will be injected with remifentanil 1μg∙kg-1.; Other Names: Remifentanil will be continuously pumped at a rate of 5μg∙kg∙h-1 combined with dexmedetomidine (a loading dose of 0.6 μg∙kg-1 for 10 minutes, followed by maintenance dose of 0.4 μg∙kg-1∙h-1).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cervical dilation-induced somatic responses	Positive: Body movement or complaint of pain. Negative: No body movement or no reported pain. This scale will be administered during the surgery at the first stage of the research.	Day 1 (During the surgery at the first stage of the research)
Incidence of respiratory depression	The primary outcome is the incidence of respiratory depression, which is defined as SpO2 <90% or EtCO2 >55 mmHg. By comparing with the control group, evaluate the safety of ED95 of esketamine by the incidence of respiratory depression at T2-T6 of the second stage of the research. T2: 60 seconds after esketamine injection; T3: During vaginal disinfection; T4: During cervical dilation; T5: During intrauterine operations; T6: In the PACU.	Day 1 (T2-T6 of the second stage of the research)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HR	HR: heart rate. T1: Prior to anesthesia (10 minutes after positioning); T2: 60 seconds after esketamine injection; T3: During vaginal disinfection; T4: During cervical dilation; T5: During intrauterine operations; T6: In the PACU.	Day 1 (T1-T6 of the first and second stages of the research)
MAP	MAP: Mean Arterial Pressure. T1: Prior to anesthesia (10 minutes after positioning); T2: 60 seconds after esketamine injection; T3: During vaginal disinfection; T4: During cervical dilation; T5: During intrauterine operations; T6: In the PACU.	Day 1 (T1-T6 of the first and second stages of the research)
RR	RR: respiratory rate. T1: Prior to anesthesia (10 minutes after positioning); T2: 60 seconds after esketamine injection; T3: During vaginal disinfection; T4: During cervical dilation; T5: During intrauterine operations; T6: In the PACU.	Day 1 (T1-T6 of the first and second stages of the research)
SPO2	SPO2: peripheral oxygen saturation. T1: Prior to anesthesia (10 minutes after positioning); T2: 60 seconds after esketamine injection; T3: During vaginal disinfection; T4: During cervical dilation; T5: During intrauterine operations; T6: In the PACU.	Day 1 (T1-T6 of the first and second stages of the research)
EtCO2	EtCO2: End-expiratory carbon dioxide. SPO2: peripheral oxygen saturation. T2: 60 seconds after esketamine injection; T3: During vaginal disinfection; T4: During cervical dilation; T5: During intrauterine operations; T6: In the PACU.	Day 1 (T2-T6 of the first and second stages of the research)
Adverse events	Adverse events will encompass a range of systems, including the cardiovascular system (eg. high/low blood pressure and sinus tachycardia/bradycardia), as well as symptoms such as nausea, vomiting, dizziness, and mental symptoms. T2: 60 seconds after esketamine injection; T3: During vaginal disinfection; T4: During cervical dilation; T5: During intrauterine operations; T6: In the PACU. T7 to T9: 2, 6, and 24 hours after the procedure.	Day 1 (T2-T9 of the first and second stages of the research)
NRS	The Numeric Rating Scale (NRS) will be utilized to assess postoperative pain, with a range of 0 representing no pain and 10 representing severe pain. This scale will be administered at 2, 6, and 24 hours following the procedure. T7 to T9: 2, 6, and 24 hours after the procedure.	Day 1 (T7-T9 of the first and second stages of the research)
The need for remedial analgesia	The consumption of remedial analgesia will be the total consumption of acetaminophen documented at 2, 6, and 24 hours after the procedure. T7 to T9: 2, 6, and 24 hours after the procedure.	Day 1 (T7-T9 of the first and second stages of the research)
Induction duration	Induction duration is defined as the period from the start of anaesthetic drug injection to the commencement of the surgical procedure at the first and second stages of the research.	Day 1 of the first and second stages of the research
Duration of awakening	Duration of awakening is defined as the period from the conclusion of the surgical procedure to the moment of eye-opening.	Day 1 of the first and second stages of the research
Success rate of anesthesia	Anesthesia success will be defined as inadequate analgesia requiring ≤3 rescue doses of remifentanil within 10 min throughout the procedure. The success rate of anesthesia will be calculated by dividing the number of successful anesthesia cases by the total number of cases. T2: 60 seconds after esketamine injection; T3: During vaginal disinfection; T4: During cervical dilation; T5: During intrauterine operations.	Day 1 (T2-T5 of the second stage of the research)
The satisfaction of gynecologists	The satisfaction score of gynecologists will be collected postoperatively on Day 1, using a scale ranging from 0 to 10, with 0 representing dissatisfaction and 10 representing very satisfied.	Day 1 of the second stage of the research
The satisfaction of patients	The satisfaction of patients will be collected postoperatively on Day 2, using a scale ranging from 0 to 10, with 0 representing dissatisfaction and 10 representing very satisfied.	Day 2 of the second stage of the research
PACU time	The time from patient admission to the PACU until the fulfillment of the criteria for PACU discharge.	Day 1 of the first and second stages of the research
Discharge time	The interval between patient admission to the operating room and the fulfillment of the criteria for hospital discharge.	Day 1 of the first and second stages of the research

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital of Xiamen University
• Investigators: Principal Investigator: Lijuan Yan, Department of Anesthesiology, The First Affiliated Hospital of Xiamen University

Study record dates

Study Major Dates

• Study Start (Actual): June 26, 2025
• Primary Completion (Estimated): June 30, 2028
• Study Completion (Estimated): June 30, 2028

Study Registration Dates

• First Submitted: May 29, 2025
• First Submitted That Met QC Criteria: June 20, 2025
• First Posted (Actual): June 24, 2025

Study Record Updates

• Last Update Posted (Actual): July 24, 2025
• Last Update Submitted That Met QC Criteria: July 21, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: esketamine; monitored anesthesia care; ambulatory hysteroscopic surgery; cervical dilation response; Intrauterine lesion
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Genital Diseases, Female; Gynatresia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Central Nervous System Depressants; Sensory System Agents; Analgesics, Non-Narcotic; Analgesics; Analgesics, Opioid; Narcotics; Neurotransmitter Agents; Hypnotics and Sedatives; Psychotropic Drugs; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Adrenergic Agents; Antidepressive Agents; Remifentanil; Esketamine; Dexmedetomidine
• Other Study ID Numbers: XMFHIIT-2025SL092

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No