Effective Dose and Safety of Esketamine During Ultrasound-guided Hepatic Tumor Thermal Ablation

NCT ID: NCT07034950

Last Updated: 2025-09-11

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 79 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-06-29
• Study Completion Date: 2028-06-30

Brief Summary

Effective pain management during percutaneous thermal ablation of liver tumors outside the operating room remains a significant challenge. While hepatic hilar nerve block (HHNB) provides partial analgesia, its incomplete efficacy often requires opioid supplementation, potentially increasing perioperative risks. Esketamine, an N-methyl-D-aspartate receptor antagonist, exhibits unique dual analgesic-sedative properties that may address this therapeutic gap, thus obviating the necessity for opioids. This prospective dose-finding study aimed to establish the median effective dose (ED50) and 95% effective dose (ED95) of esketamine for opioid-free analgesia during ultrasound-guided thermal ablation of liver tumors under HHNB. Afterwards, the investigators will conduct an RCT study to evaluate the safety of the dose of esketamine ED95 through the incidence of respiratory depression.

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 during ultrasound-guided thermal ablation of liver tumors under hepatic hilar nerve block (HHNB). Esketamine will be initiated by intravenous drip at 0.3 mg∙kg-1, and then based on the patient's response to pain (positive: body movement or complaint of pain; Negative: No body movement or no reported pain. The dose will be adjusted, with a fluctuation step of 0.02 mg∙kg-1 up and down. All patients will receive a standardized anesthesia regimen, including the administration of midazolam at 0.03 mg∙kg-1 and hepatic portal nerve block (10 ml of 0.5% ropivacaine) under ultrasound guidance. Local anaesthesia will be administered using 10 ml of 1% lidocaine, which will be applied until the liver capsule is reached. The test will continue until six cross-pairings will be 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 first injected with fentanyl at a dose of 1 μg∙kg-1. Both groups of patients will receive the same anesthesia regimen, namely midazolam 0.03 mg∙kg-1, and hepatic portal nerve block (0.5% ropivacaine 10 ml) will be performed under ultrasound guidance. Intravenous injection of 100 mg of flurbiprofen axetil for auxiliary analgesia. Intravenous injection of 4 mg of ondansetron to prevent nausea and vomiting.

Conditions

Hepatic Neoplasm; Hepatic Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: SUPPORTIVE_CARE
• Blinding Strategy: QUADRUPLE

Study Groups

Determine the ED50 and ED95 of esketamine by Dixon's up-and-down method

Using Dixon's up-and-down sequential method, esketamine will be titrated intravenously from an initial 0.3 mg∙kg-1 dose with 0.02 mg∙kg-1 adjustments based on intraprocedural responses to pain (positive: purposeful somatic movement or the complaint of pain; negative: no movement or no complaint of pain). All patients will receive standardized premedication with HHNB. The titration sequence will continue until six crossover inflection points are observed.

Group Type: EXPERIMENTAL

Intravenous esketamine using Dixon's up-and-down sequential method

Intervention Type: DRUG

Using Dixon's up-and-down sequential method, esketamine will be titrated intravenously from an initial 0.3 mg∙kg-1 dose with 0.02 mg∙kg-1 adjustments based on intraprocedural responses to pain (Positive: purposeful somatic movement or the complaint of pain; Negative: no movement or no complaint of pain). The titration sequence will continue until six crossover inflection points are observed.

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 fentanyl 1 μg∙kg-1. The study at this stage will evaluate the safety of the dose of esketamine ED95 through the incidence of respiratory depression.

Group Type: ACTIVE_COMPARATOR

Intravenous the dose of esketamine ED95

Intervention Type: DRUG

The intervention group will be injected with the dose of esketamine ED95.

Intravenous fentanyl 1 μg∙kg-1

Intervention Type: DRUG

The control group will be injected with fentanyl 1 μg∙kg-1.

Interventions

Intravenous esketamine using Dixon's up-and-down sequential method

Using Dixon's up-and-down sequential method, esketamine will be titrated intravenously from an initial 0.3 mg∙kg-1 dose with 0.02 mg∙kg-1 adjustments based on intraprocedural responses to pain (Positive: purposeful somatic movement or the complaint of pain; Negative: no movement or no complaint of pain). The titration sequence will continue until six crossover inflection points are observed.

Intervention Type: DRUG

Intravenous the dose of esketamine ED95

The intervention group will be injected with the dose of esketamine ED95.

Intervention Type: DRUG

Intravenous fentanyl 1 μg∙kg-1

The control group will be injected with fentanyl 1 μg∙kg-1.

Intervention Type: DRUG

Other Intervention Names

Ultrasound-guided hepatic hilar nerve block (HHNB); Standardized premedication (midazolam 0.03 mg∙kg-1); Local anaesthesia using 10 ml of 1% lidocaine; Ultrasound-guided hepatic hilar nerve block (HHNB); Standardized premedication (midazolam 0.03 mg∙kg-1); Local anaesthesia using 10 ml of 1% lidocaine; Ultrasound-guided hepatic hilar nerve block (HHNB); Standardized premedication (midazolam 0.03 mg∙kg-1); Local anaesthesia using 10 ml of 1% lidocaine

Eligibility Criteria

Inclusion Criteria

• Aged 18 - 80 years;
• ASA physical status Ⅰ or Ⅲ;
• Body mass index (BMI) 18 - 28 kg∙m-2;
• Scheduled for elective ultrasound-guided thermal ablation of solitary liver tumors under HHNB.

Exclusion Criteria

(i) Pharmacological contraindications:

• Known hypersensitivity to study medications (esketamine, midazolam);
• Opioid or benzodiazepine dependence;
• Using analgesics within the last 24 h preoperatively;
• Participation in other investigational drug trials within 90 days. (ii) Clinical comorbidities and surgery history:
• Multifocal hepatic lesions requiring concurrent ablation;
• Patients after liver transplantation;
• Active upper respiratory tract infection within 14 days;
• Severe cardiopulmonary diseases (New York Heart Association [NYHA] class Ⅲ-Ⅳ, FEV1/FVC < 70%);
• Decompensated hepatic insufficiency (Child-Pugh C);
• Uncontrolled hypertension (≥180/110 mmHg), elevated intracranial/intraocular pressure, or hyperthyroidism;
• Major neuropsychiatric disorders (epilepsy, schizophrenia, major depressive disorder, cognitive impairment).

(iii) Procedural Risk Factors:

• Anticipated difficult airway (Mallampati Ⅲ-Ⅳ, thyromental distance < 6 cm) or anatomical airway obstruction;
• Inadequate preoperative fasting (solid intake < 8 hours, clear fluids < 2 hours).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

The First Affiliated Hospital of Xiamen University

OTHER

Sponsor Role: lead

Responsible Party

Lijuan Yan

Scientific Research Secretary of the Anesthesiology Department

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Lijuan Yan

Role: PRINCIPAL_INVESTIGATOR

Department of Anesthesiology, The First Affiliated Hospital of Xiamen University

Locations

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

Xiamen, Fujian, China

Countries

China

Other Identifiers

XMFHIIT-2025SL091

Identifier Type: -

Identifier Source: org_study_id