Melatonin for Prevention of Postoperative Delirium After Lower Limb Fracture Surgery in Elderly Patients

Phase

Condition

Orthopedic Surgery

Dementia

Orthopedics

Treatment

Melatonin 4 mg

Placebo oral tablet

Clinical Study ID

NCT04335968

APHP180594

Ages > 70
All Genders

Study Summary

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.

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).

Eligibility Criteria

Inclusion

Inclusion Criteria:

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 orarthroplasty)
proxy or care giver knowing baseline cognitive status of the patient present orreachable by phone for an interview

Exclusion

Exclusion Criteria:

Patient already taking Melatonin
Contraindications and precaution for use of Melatonin administration:
Hypersensitivity to the active substance or to any of the excipients ofCircadin©
Liver failure (presence of some of the following clinical and biologicalsymptoms: icterus, asterixis, ascites, known esophageal varices, totalbilirubin >20 micromol/L, FV <70%),
Cirrhosis (known histological liver fibrosis)
Renal failure with clearance <30 ml/min O Autoimmune disease O Hereditarygalactose intolerance, Lapp lactase deficiency or glucose-galactosemalabsorption 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.

Study Design

Melatonin 4 mg

January 23, 2021

April 18, 2025

Study Description

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.