Study on the Effective Dose and Safety of Esketamine During Ultrasound-guided Hepatic Tumor Thermal Ablation Under Hilar Nerve Blockade
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 79
- 试验地点
- 1
- 主要终点
- thermal ablation-induced somatic responses to pain
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Supportive Care
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •(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).
研究组 & 干预措施
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.
干预措施: Intravenous esketamine using Dixon's up-and-down sequential method (Drug)
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.
干预措施: Intravenous the dose of esketamine ED95 (Drug)
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.
干预措施: Intravenous fentanyl 1 μg∙kg-1 (Drug)
结局指标
主要结局
thermal ablation-induced somatic responses to pain
时间窗: Day 1 (During the surgery at the first stage of the research)
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.
Incidence of respiratory depression
时间窗: Day 1 (T2-T5 of the second stage of the research)
By comparing with the control group, evaluate the safety of ED95 of esketamine by the incidence of respiratory depression at T2-T5 of the second stage of the research. The primary outcome is the incidence of respiratory depression, which is defined as SpO2 \<90% or EtCO2 \>55 mmHg. T2: 60 seconds after esketamine injection; T3: 5 minutes after HHNB; T4: During thermal ablation of liver tumors; and T5: In the PACU.
次要结局
- HR(Day 1 (T1-T5 of the first and second stages of the research))
- MAP(Day 1 (T1-T5 of the first and second stages of the research))
- SPO2(Day 1 (T1-T5 of the first and second stages of the research))
- EtCO2(Day 1 (T2-T5 of the first and second stages of the research))
- Adverse events(Day 1 (T2-T8 of the first and second stages of the research))
- The need for remedial analgesia(Day 1 (T6-T8 of the first and second stages of the research))
- Duration of stay in the hospital(Day 1 and Day 2 of the second stage of the research)
- The satisfaction of the sonographer(Day 1 of the second stage of the research)
- The satisfaction of patients(Day 2 of the second stage of the research)
- RR(Day 1 (T1-T5 of the first and second stages of the research))
- NRS(Day 1 (T6-T8 of the first and second stages of the research))
- Success rate of anesthesia(Day 1 (T2-T4 of the second stage of the research))
- Induction duration(Day 1 of the second stage of the research)
- Duration of awakening(Day 1 of the second stage of the research)
研究者
Lijuan Yan
Scientific Research Secretary of the Anesthesiology Department
The First Affiliated Hospital of Xiamen University