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

Melatonin for Prevention of Postoperative Delirium After Lower Limb Fracture Surgery in Elderly Patients: a Randomized Controlled Trial

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).

Study Overview

• Status: Recruiting
• Conditions: Orthopedic Surgery
• Intervention / Treatment: Drug: Melatonin 4 mg; Drug: Placebo oral tablet

Detailed Description

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).

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).

An ancillary study is also planned in this study with the hypothesise that :

• Patients presenting post-operative delirium may exhibit significant perturbations of phenotypic and transcriptomic features of circulating leukocytes, of plasma levels of cytokines, and of oxidative stress level.
• Administration of melatonin may prevent these perturbations.

Ancillary study concerns Beaujon, Bichat and la Pitié centers.

• Study Type: Interventional
• Enrollment (Estimated): 790
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Stéphanie Sigaut; Phone Number: +33 1 40 87 59 11; Email: stephanie.sigaut@aphp.fr
• Study Contact Backup: Name: Emmanuel Weiss; Phone Number: +33 1 40 87 59 11; Email: emmanuel.weiss@aphp.fr

Study Locations

• France
  • Clichy-sous-Bois, France, 93390
    • Recruiting
    • Hopital Beaujon
    • Contact: stéphanie sigaut; Email: stephanie.sigaut@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 68 years and older (Older Adult)
• Accepts Healthy Volunteers: No

Description

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 or arthroplasty)
• proxy or care giver knowing baseline cognitive status of the patient present or reachable by phone for an interview

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 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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	Drug: Melatonin 4 mg; melatonin 4mg per os every night, starting the evening before surgery (or 2 hours before emergency surgery) and until day 5 after surgery.
Placebo Comparator: Control group; placebo of this drug with the same schedule, during the same period of time.	Drug: Placebo oral tablet; placebo of this drug with the same schedule, during the same period of time.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postoperative delirium incidence	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	10 days after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of days CAM positive	CAM will be applied daily during the first 10 days. the minimum 0 and maximum 4 values, and higher scores mean a worse outcome.	10 days after surgery
Incidence of postoperative sedative or antipsychotic drugs administration from	Daily review of the medical chart and prescriptions looking for any sedative or antipsychotic drug administration	10 days after surgery
Incidence of postoperative physical restrain prescription	Daily review of the medical chart and prescriptions looking for physical restraint prescription.	10 days after surgery
Incidence of postoperative falls	Daily review of the medical chart and prescriptions looking for falls, whichever the gravity	10 days after surgery
Mini Mental State Examination	Cognitive testing interview at bedside using the widely used French validated translation of the Mini Mental State Examination. the minimum 0 and maximum 30 values, and higher scores mean a better outcome.	10 days (or end of hospital stay if shorter)
Duration of hospital stay	Daily review of the medical file	30 days after surgery
30 days postoperative mortality	Phone call (or visit for those who had not left the hospital) to the patient or caregivers	30 days after surgery
30 days postoperative patient autonomy	Phone call (or visit for those who had not left the hospital) to the patient or caregivers and evaluation by the Katz Index of activities of daily living. The minimum and maximum values are respectively 0 and 6, and higher scores mean a better outcome.	30 days after surgery
30 days postoperative Quality of life	evaluated by EQ5D5L (standardized instrument for measuring generic health status : MOBILITY, SELF-CARE, USUAL ACTIVITIES, PAIN/DISCOMFORT and ANXIETY/ DEPRESSION),) Questionnaire. the minimum 5 and maximum 125 values, and higher scores mean a better outcome.	30 days after surgery
30 days postoperative QALYs (quality-adjusted life year)	QALYs (quality-adjusted life year) are the utility weights for the 30 day period x30/365. the minimum and maximum values are respectively 0 and1, and higher scores mean a better outcome.	30 days after surgery
Total hospital costs at 30 days	calculated as the cumulative costs of all admissions (in- and outpatient, home care, rehabilitation) over a 30 day period	30 days after surgery
Incremental cost effectiveness	The incremental cost effectiveness ratio is the difference in total costs divided by the difference in the incidence rate of delirium between the two arms	30 days after surgery
cost utility ratios	the incremental cost utility ratio is the difference in total costs divided by the difference in QALYs (quality-adjusted life year)	30 days after surgery
Occurrence of side effects	During the follow-up, daily interview of the patient and review of the medical chart will be performed, looking for side effects of melatonin.	30 days after surgery

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Stéphanie Sigaut, APHP

Publications and helpful links

General Publications

• Sigaut S, Couffignal C, Esposito-Farese M, Degos V, Molliex S, Boddaert J, Raynaud-Simon A, Durand-Zaleski I, Marcault E, Jacota M, Dahmani S, Paugam-Burtz C, Weiss E. Melatonin for prevention of postoperative delirium after lower limb fracture surgery in elderly patients (DELIRLESS): study protocol for a multicentre randomised controlled trial. BMJ Open. 2021 Dec 24;11(12):e053908. doi: 10.1136/bmjopen-2021-053908.

Study record dates

Study Major Dates

• Study Start (Actual): January 23, 2021
• Primary Completion (Estimated): January 31, 2024
• Study Completion (Estimated): April 30, 2024

Study Registration Dates

• First Submitted: February 28, 2020
• First Submitted That Met QC Criteria: April 2, 2020
• First Posted (Actual): April 7, 2020

Study Record Updates

• Last Update Posted (Actual): May 25, 2023
• Last Update Submitted That Met QC Criteria: May 24, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: delirium; aging; orthopedic surgery; Perioperative neurocognitive disorders; melatonine
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Postoperative Complications; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Delirium; Emergence Delirium; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Protective Agents; Antioxidants; Melatonin
• Other Study ID Numbers: P180594

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No