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.

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.

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).