Impact of Esketamine on Delayed Neurocognitive Recovery in Older Patients Undergoing Non-cardiac Surgery: a Two-center, Dose-exploring Pilot Trial
试验速览
- 阶段
- 4 期
- 状态
- 尚未招募
- 入组人数
- 120
- 试验地点
- 2
- 主要终点
- Incidence of dissociative symptoms
研究概览
简要总结
Esketamine is frequently used during the perioperative period for supplemental analgesia. Small sample size trials showed that subanesthetic dose esketamine may decrease postoperative neurocognitive complications. However, conflicting results exist and optimal dose of esketamine remains to be determined. This dose-exploring pilot trial is designed to evaluate the safety and efficacy of three different perioperative esketamine dosing regimens in older patients undergoing major non-cardiac surgery. The primary purpose is to explore the optimal dosing strategy that produce maximal neurocognitive benefits with minimal adverse neuropsychiatric symptoms.
详细描述
Postoperative neurocognitive complications including delirium and delayed neurocognitive recovery are common in older patients after major surgery and associated with worse early and long-term outcomes. Risk factors of neurocognitive complications are multiple. Predisposing factors include older age, low education, and cognitive decline. Precipitating factors include major surgery, high dose opioids, severe pain, and sleep disturbances. The underlying mechanisms are not totally clear but may include surgery-related stress response and inflammation.
Ketamine is a noncompetitive N-Methyl-D-aspartic acid (NMDA) receptor antagonist and has been used as an anesthetic and analgesic for decades. Esketamine is the S-enantiomer of ketamine and has an analgesic potent of approximately 2 times of that of ketamine. Available studies showed that subanesthetic dose ketamine/esketamine may reduce delirium and/or delayed neurocognitive recovery. However, conflicting results exist. Furthermore, even subanesthetic dose ketamine/esketamine may produce neuropsychiatric symptoms which are harmful for neurocognitive recovery.
This dose-exploring pilot trial is designed to evaluate the safety and efficacy of three different perioperative esketamine dosing regimens in older patients undergoing major non-cardiac surgery. The primary purpose is to explore the optimal dosing strategy that produce maximal neurocognitive benefits with minimal adverse neuropsychiatric symptoms.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 65 Years 至 90 Years（Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Aged >=65 but <= 90 years;
- •Scheduled to undergo non-cardiac surgery with an expected duration of >= 2 hours under general anesthesia;
- •Requiring patient-controlled intravenous analgesia (PCIA) after surgery.
排除标准
- •Unable to communicate preoperatively due to visual or auditory impairment, language barrier, or severe dementia;
- •Comorbid with schizophrenia, epilepsy, Parkinson's disease, or myasthenia gravis;
- •Traumatic brain injury or neurosurgery;
- •Severe hepatic dysfunction (Child-Pugh Class C), severe renal dysfunction (receiving dialysis preoperatively), or American Society of Anesthesiologists physical status classification >= Ⅳ;
- •Expected admission to the Intensive Care Unit with endotracheal intubation after surgery;
- •Anaphylaxis to esketamine;
- •Participation in other clinical studies, or any other conditions that are considered unsuitable to be involved in the study.
研究组 & 干预措施
Esketamine dose 1
During anesthesia, a loading dose esketamine (0.5 mg/ml) 0.4 ml/kg will be infused over 30 minutes (0.1 mg/kg) after anesthesia induction, followed by a continuous infusion at 0.1 ml/kg/h (0.05 mg/kg/h) until 1 hour before the expected end of surgery.
After surgery, patient-controlled intravenous analgesia will be established with esketamine (0.25 mg/ml) and sufentanil (1 ug/ml), programmed to deliver 2-ml bolus (0.5 mg esketamine) with a 8-10-minute lock-out time and a 1-ml/h (0.25 mg/h esketamine) background infusion, and used for up to 48 hours.
干预措施: Esketamine 1 (Drug)
Esketamine dose 2
During anesthesia, a loading dose esketamine (1 mg/ml) 0.4 ml/kg will be infused over 30 minutes (0.2 mg/kg) after anesthesia induction, followed by a continuous infusion at 0.1 ml/kg/h (0.1 mg/kg/h) until 1 hour before the expected end of surgery.
After surgery, patient-controlled intravenous analgesia will be established with esketamine (0.5 mg/ml) and sufentanil (1 ug/ml), programmed to deliver 2-ml bolus (1 mg esketamine) with a 8-10-minute lock-out time and a 1-ml/h (0.5 mg/h esketamine) background infusion, and used for up to 48 hours.
干预措施: Esketamine 2 (Drug)
Esketamine dose 3
During anesthesia, a loading dose esketamine (1.5 mg/ml) 0.4 ml/kg will be infused over 30 minutes (0.3 mg/kg) after anesthesia induction, followed by a continuous infusion at 0.1 ml/kg/h (0.15 mg/kg/h) until 1 hour before the expected end of surgery.
After surgery, patient-controlled intravenous analgesia will be established with esketamine (0.75 mg/ml) and sufentanil (1 ug/ml), programmed to deliver 2-ml bolus (1.5 mg esketamine) with a 8-10-minute lock-out time and a 1-ml/h (0.75 mg/h esketamine) background infusion, and used for up to 48 hours.
干预措施: Esketamine 3 (Drug)
Placebo
During anesthesia, a loading dose placebo (normal saline) 0.4 ml/kg will be infused over 30 minutes after anesthesia induction, followed by a continuous infusion at 0.1 ml/kg/h until 1 hour before the expected end of surgery.
After surgery, patient-controlled intravenous analgesia will be established with sufentanil (1 ug/ml), programmed to deliver 2-ml bolus with a 8-10-minute lock-out time and a 1-ml/h background infusion, and used for up to 48 hours.
干预措施: Normal saline (Drug)
结局指标
主要结局
Incidence of dissociative symptoms
时间窗: Up to 4 days after surgery
Dissociative symptoms will be assessed at 30 minutes after extubation and then twice daily (8:00-10:00, 18:00-20:00) during the first 4 days after surgery, using the 6-item Clinician Administered Dissociative State Scale (CADSS-6; scores range frrom 0 to 24 with higher scores indicating more severe dissociative symptoms; a score \>=3 indicates presence of dissociative symptoms).
次要结局
- Incidence of emergence delirium(At 30 minutes after extubation)
- Incidence of postoperative delirium(Up to 4 days after surgery)
- Incidence of delayed neurocognitive recovery(Up to 5 days after surgery)
研究者
Dong-Xin Wang
Professor and Chairman, Department of Anaesthesiology
Peking University First Hospital