Melatonin for Prevention of Postoperative Delirium After Lower Limb Fracture Surgery in Elderly Patients: a Randomized Controlled Trial
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 357
- 试验地点
- 1
- 主要终点
- Postoperative delirium incidence
研究概览
简要总结
Postoperative delirium (POD) is one of the most frequent complications after surgery in elderly patients, affecting between 20 and 40% of patients older than 60 after major surgery. This complication has huge consequences for the patients, families and society: increase of morbidity and mortality, prolonged length of stay, cognitive and functional decline leading to loss of autonomy, and important additional healthcare costs.
Among numerous risk factors identified, perioperative inflammatory stress is a key element in delirium genesis: surgical trauma releases danger signals in systemic circulation, activating immune cells and leading to neuroinflammation.
Melatonin is a neurohormone regulating circadian rhythm. But it also exhibits antioxidant and free radical scavenger properties, and regulates energy metabolism and immune function. It has already demonstrated a neuroprotective potential in various animal models. Its use against delirium is promising: it decreases delirium incidence in elderly patients hospitalized in medical ward, and several studies are now recruiting in ICU.
The hypothesis of the trial is that in a high-risk population, perioperative melatonin can reduce the incidence of POD.
The main objective is to evaluate the effect of perioperative melatonin administration on postoperative delirium incidence in the first 10 days after surgery, in elderly patients (over 70 years old) being hospitalized and scheduled for acute surgery of fractured lower limb (from femoral head to tibial plateau).
This is a prospective, national multicentric (24 centers), phase III, superiority, comparative randomized (1:1) double-blinded clinical trial with two parallel arms:
Experimental group: melatonin 4mg per os every night, starting the evening before surgery (or 2 hours before emergency surgery) and until day 5 after surgery.
Control group: placebo of this drug with the same schedule, during the same period of time.
The patients are aged 70 or older, hospitalized and scheduled for surgery of a severe fracture of a lower limb (from femoral head to tibial plateau).
详细描述
Postoperative delirium (POD) is one of the most frequent complications after surgery in elderly patients, affecting between 20 and 40% of patients older than 60 after major surgery. This complication has huge consequences for the patients, families and society: increase of morbidity and mortality, prolonged length of stay, cognitive and functional decline leading to loss of autonomy, and important additional healthcare costs.
Among numerous risk factors identified, perioperative inflammatory stress is a key element in delirium genesis: surgical trauma releases danger signals in systemic circulation, activating immune cells and leading to neuroinflammation. In the brain, especially in hippocampus, proinflammatory cytokines, immune cells recruitment and microglial activation alter synaptic plasticity and lead to acute cognitive dysfunction. Moreover, with aging, an increase in initial neuroinflammatory response and a decrease in subsequent resolution phase are observed.
Melatonin is a neurohormone regulating circadian rhythm. But it also exhibits antioxidant and free radical scavenger properties, and regulates energy metabolism and immune function. It has already demonstrated a neuroprotective potential in various animal models. Its use against delirium is promising: it decreases delirium incidence in elderly patients hospitalized in medical ward, and several studies are now recruiting in ICU. Concerning the perioperative period, only two studies with conflicting results are available. The first one (Sultan, 2010), that has shown that melatonin decreases POD incidence, has strong methodological limitations (no calculated sample size, only 53 patients in melatonin group, all patients, even in the control group received melatonin if they developed POD, etc). In the second one (deJonghe, 2014), melatonin had no effect on POD incidence, but showed a reduction in the proportion of patients with POD exceeding 2 days. These conflicting results emphasize the need for a third RCT, with optimized methodology.
The hypothesis of the trial is that in a high-risk population, perioperative melatonin can reduce the incidence of POD.
The main objective is to evaluate the effect of perioperative melatonin administration on postoperative delirium incidence in the first 10 days after surgery, in elderly patients (over 70 years old) being hospitalized and scheduled for acute surgery of fractured lower limb (from femoral head to tibial plateau).
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
- 70 Years 至 —（Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Demographic criteria: patient 70 years old or older
- •Diagnostic criteria: isolated fracture of a lower limb
- •Proximal femoral fractures: head, cervical, or trochanteric fractures
- •Periprosthetic hip fracture
- •Femoral shaft fracture
- •Distal femoral fractures: supracondylar or condylar
- •Periprosthetic knee fracture
- •Tibial plateau fracture
- •Treatments/strategies/procedures: scheduled orthopedic surgery (osteosynthesis or arthroplasty)
- •proxy or care giver knowing baseline cognitive status of the patient present or reachable by phone for an interview
排除标准
- •Patient already taking Melatonin
- •Contraindications and precaution for use of Melatonin administration:
- •Hypersensitivity to the active substance or to any of the excipients of Circadin©
- •Liver failure (presence of some of the following clinical and biological symptoms: icterus, asterixis, ascites, known esophageal varices, total bilirubin >20 micromol/L, FV <70%),
- •Cirrhosis (known histological liver fibrosis)
- •Renal failure with clearance <30 ml/min O Autoimmune disease O Hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome
- •Patients taking fluvoxamine, 5- or 8-methoxypsoralen, cimetidine, oestrogenotherapy, quinolones, carbamazepine, rifampicin
- •Other concomitant trauma than lower limb fracture(s)
- •Surgery scheduled in more than 5 days
- •Patient under mechanical ventilation
- •Patient refusing to participate
- •Patient not talking / understanding French (delirium assessment impossible)
- •Patient already participating to another interventional study
- •No signed informed consent,
- •No affiliation to a social security regime
- •Secondary Exclusion Criteria:
- •Secondary exclusion (before randomization): diagnosis of delirium at the CAM assessment at inclusion, or creatinin clearance <30 ml / min and /or biological signs of hepatocellular insufficiency (bilirubin> 20 umol/l and factor V <70%) if samples not available during the anesthesiologist consultation and so performed after inclusion.
研究组 & 干预措施
Experimental group
melatonin 4mg per os every night, starting the evening before surgery (or 2 hours before emergency surgery) and until day 5 after surgery
干预措施: Melatonin 4 mg (Drug)
Control group
placebo of this drug with the same schedule, during the same period of time.
干预措施: Placebo oral tablet (Drug)
结局指标
主要结局
Postoperative delirium incidence
时间窗: 10 days after surgery
The Confusion Assessment Method (CAM) score, for patients hospitalized in surgery, or CAM-ICU score, for patients hospitalized in ICU will be applied daily during the first 10 days after surgery or end of hospital stay if shorter
次要结局
- 30 days postoperative mortality(30 days after surgery)
- Incremental cost effectiveness(30 days after surgery)
- Occurrence of side effects(30 days after surgery)
- Total hospital costs at 30 days(30 days after surgery)
- Number of days CAM positive(10 days after surgery)
- Incidence of postoperative sedative or antipsychotic drugs administration from(10 days after surgery)
- Incidence of postoperative physical restrain prescription(10 days after surgery)
- Incidence of postoperative falls(10 days after surgery)
- Mini Mental State Examination(10 days (or end of hospital stay if shorter))
- Duration of hospital stay(30 days after surgery)
- 30 days postoperative QALYs (quality-adjusted life year)(30 days after surgery)
- 30 days postoperative patient autonomy(30 days after surgery)
- 30 days postoperative Quality of life(30 days after surgery)
- cost utility ratios(30 days after surgery)