The Prevention of Post Operative Cognitive Dysfunction by Ketamine: a Prospective Multicenter Randomized Blinded Placebo-controlled Trial in Elderly Patients Undergoing Elective Orthopaedic Surgery
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 307
- 试验地点
- 1
- 主要终点
- Proportion of early postoperative cognitive dysfunction
研究概览
简要总结
Over 30 million patients require a major surgery annually in the US alone and more than half of them are performed in patients over 60 years of age. Post-operative cognitive dysfunction (POCD) is a keystone complication of these surgeries and affects up to 40% of surgical patients aged over 60 years on discharge from the hospital. Despite controlled longitudinal studies have shown that POCD is transient, it is associated with delirium, higher mortality, earlier retirement, and greater utilization of social financial assistance The pathophysiology of persistent postoperative cognitive dysfunction and causal relationship between POCD and delirium remain incompletely understood. Identified clinical risk factors for both include advanced age, type of surgery, preexisting cognitive impairment, and drug addiction. We and others have provided evidence that the inflammatory response triggered by surgical trauma and pain may contribute to the development of delirium and cognitive impairment after surgery.
Ketamine, a N-methyl-D-aspartic acid receptor antagonist, is commonly used in anaesthesia and postoperative analgesia. By reducing both pain and glutamate excitotoxic effects on neuronal and microglial brain cells, it contributes to tone down the neuroinflammatory process associated with surgery. A recent body of evidence has shown that ketamine reduces the depressive-like behavior induced by inflammatory or stress-induced stimuli in mice. Ketamine was also found to reduce levels of inflammatory biomarkers in cardiac surgical patients.
Orthopaedic surgery is a high-risk situation for developing postoperative cognitive dysfunction. In patients undergoing non-cardiac surgery, the prevalence of POCD is 26% one week after surgery and decreased to 10% at 3 months postoperatively, and a similar prevalence is found 12 months after the operation. Postoperative delirium is associated with an increased risk of POCD. Hundred thousands of patients > 60 years undergo elective orthopaedic procedures per year around the world.
详细描述
The design consists in a prospective multicenter randomized blinded placebo-controlled trial in elderly patients undergoing elective orthopaedic surgery.
Patients will be informed at the pre-anaesthetic consultation, 7 to 30 days before surgery. They will be randomized the day before surgery. Cognitive and depressive status at baseline will be assessed precisely the day pior to surgery with cognitive tests. Self-administered scores will be recorded to evaluate depression, anxiety, and quality of life.
At the day of surgery, patients in the experimental group will receive a bolus of low intravenous dose (sub-anaesthetic) 0.5 mg/kg ketamine following induction of anaesthesia. Patients in the control group will receive a bolus of an intravenous normal saline solution following induction of anaesthesia.
From D0 (2 hours after surgery end) to D7 or discharge from the hospital if earlier, delirium, pain, adverse clinical and psychiatric events will be measured and recorded.
Cognitive functions, neuropathic pain, depression, anxiety and quality of life will be assessed at D7 or discharge from the hospital if earlier and D90.
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
- 60 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients 60 years and older
- •Competent to provide informed consent
- •Undergoing major elective orthopaedic surgery under general anaesthesia
- •Patients with and without pre-existing neurodegenerative disease
排除标准
- •Moribund patient or patient under palliative care
- •Expected length of stay at hospital < 48 hours
- •Patient under tutorship or curatorship
- •Surgical procedure performed under spinal or epidural anaesthesia without general anaesthesia
- •Emergency surgery (i.e. emergency hip fracture)
- •Patients with a known allergy to ketamine
- •Contraindication for ketamine: severe, uncontrolled arterial hypertension or severe heart (FEVG<25%)
- •Patient with glaucoma or history of thyrotoxicosis
- •Severe audition or vision disorder
- •Patients with drug misuse history (e.g., ketamine, cocaine, heroin, amphetamine, methamphetamine, MDMA (methylenedioxymethamphetamine), phencyclidine, lysergic acid, mescaline, psilocybin)
- •Patients taking anti-psychotic medications (e.g., chlorpromazine, clozapine, olanzapine, risperidone, haloperidol, quetiapine, risperidone, paliperidone, amisulpride, sertindole)
- •Patients with severe alcohol liver disease (TP<50% and or bilirubin > 50 µmol/L)
- •Pregnant or breast-feeding woman
- •Patient not speaking French
- •Absence of informed consent or request to not participate to the study
- •Non affiliation to the social security
研究组 & 干预措施
Ketamine
Patients in this experimental group will receive a bolus of low intravenous dose (sub-anaesthetic) 0.5 mg/kg ketamine following induction of anaesthesia.
干预措施: Ketamine (Drug)
Placebo
Patients in this control group will receive a bolus of an intravenous normal saline solution following induction of anaesthesia.
干预措施: Placebo (Drug)
结局指标
主要结局
Proportion of early postoperative cognitive dysfunction
时间窗: Days 7 and 90 after surgery
POCD assessed using MoCA (Montreal Cognitive Assessment) test and others cognitive tests included in the calculation of the combined Z-score
次要结局
- Post-operative cognitive dysfunction type(Days 7 and 90 after surgery)
- Early postoperative delirium(7 days after surgery)
- Pain status: Visual Analog Scale(Day prior to surgery, at days 7 and 90 after surgery)
- Anxiety(Days 7 and 90 after surgery)
- Hospital readmission(Day 90)
- Pre-existing cognitive status(Days 7 and 90 after surgery)
- Cause of death(Day 90)
- Depression(Days 7 and 90 after surgery)
- Intraoperative serious adverse events(Day 7)
- Post-operative cognitive dysfunction severity(Days 7 and 90 after surgery)
- The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU)(Days 7 before surgery or discharge from the hospital)
- Time from surgery to POCD.(Days 7 and 90 after surgery)
- Preoperative Charlson's score for comorbidities(Days 7 and 90 after surgery)
- Postoperative adverse events(Day 7)
- Hospital length of stay(Day 90)
- Inflammatory biomarkers(Day 90)
- Quality of life evaluated thanks to the SF-36 scale(Day 90)