MIND After Surgery (MIND)

Melatonin for Preventing Postoperative Delirium in Elderly Patients; a Multi-centre Randomized Placebo Controlled Pilot Study

Delirium is the most common neurological adverse outcome in elderly surgical patients. It is associated with an increased mortality and morbidity, including need for prolonged hospital stay and institutional care. Despite this, there are no effective preventive strategies. Melatonin is a hormone released from the pineal gland. It is used to improve sleep quality and to treat jet lag. Small studies have suggested that it can decrease the chances of delirium. Since the existing literature is small and uncertain, it is important to test its benefit in a large sample to help guide clinicians. This proposed trial is aimed at testing assessing the feasibility of a large, multi-center, randomized control trial to decrease the incidence of postoperative delirium.

Study Overview

• Status: Active, not recruiting
• Conditions: Post-operative Delirium; Major Non-cardiac Surgery
• Intervention / Treatment: Other: Liquid Melatonin; Other: Placebo

Detailed Description

Delirium is defined as an acute and fluctuating disturbance in cognition characterized by alterations in the level of attention and awareness, which develops over a relative short period of time and represents a change from the subject's baseline. Its incidence increases with age and occurs in nearly 50% of elderly inpatients. Postoperative delirium (POD) increases the risk of patient morbidity and mortality and thereby increasing the cost for the health care system. Increased risk of mortality persists even three years after hospitalization, and is an independent risk factor for urinary incontinence, falls, and decubitus ulcers.

A large prospective study of 1341 patients having non-cardiac surgery with a postoperative stay of at least 48 hours, reported an overall incidence of 9% in >50 years and 15% in >70 years. Another recent study involving 566 patients of similar surgical cohort reported an incidence of 24%.

With no current effective treatment, there is a greater focus on prevention of delirium. Approximately 15% of all POD could be preventable. Preventive strategies can be pharmacological and non-pharmacological. Non-pharmacological strategies are multifaceted and involve different interventions. Among attempted pharmacological options, none have really shown much promise and many suffer from associated adverse effects.

Melatonin is a pineal gland hormone that regulates the sleep-wake rhythm. Disruption of the sleep-wake cycle is observed in delirium. Abnormal tryptophan metabolism is hypothesized as a cause for delirium and melatonin supplementation is observed to decrease the breakdown of tryptophan and serotonin through positive feedback. In patients who develop POD, low tryptophan and serum melatonin levels were observed. Other advantages of melatonin, being a natural supplement, include improved sleep, sparing of sedatives, minimal potential for abuse, or hangover effects.

Systematic reviews done with the existing literature specific to melatonin by a literature search of MEDLINE, EMBASE and Cochrane databases for combination of terms "melatonin" and "delirium", restricted to clinical trials and up to October 25, 2017 found one relevant systematic review: this systematic review looked at the use of melatonin for delirium prevention and found four randomized control trials (RCT), out of which three showed positive results and one showed a negative result. Presently, despite its potential to reduce POD and improve sleep, the role of melatonin in the elderly surgical population is uncertain. There is a clear need for a large, well-designed study to establish definitive evidence.

• Study Type: Interventional
• Enrollment (Actual): 88
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Harsha Shanthanna, MD; Phone Number: 33853 905-522-1155; Email: shanthh@mcmaster.ca
• Study Contact Backup: Name: Toni Tidy, BHSc; Phone Number: 21737 905-525-9140; Email: tonitidy@mcmaster.ca

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 4A6
      • St. Joseph's Healthcare Hamilton
    • Hamilton, Ontario, Canada, L8V 1C3
      • Hamilton Health Sciences-Juravinski Hospital Location

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years and older (Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age >65 years
• having a major non-cardiac surgery (which involve major vascular, thoracic, orthopedic, gynecological, otolaryngeal, general and gastrointestinal surgeries) with an expected hospital stay of 2 days or more, and
• ability to provide informed consent

Exclusion Criteria:

• active delirium or dementia
• ongoing melatonin treatment
• unable to take oral medications
• planned postoperative ventilation
• previous study participation
• allergy to melatonin
• hepatic impairment defined as alanine aminotransferase greater than 500 IU/L
• previous liver transplant or liver cirrhosis of Child-Pugh classes B and C
• not willing to participate
• language barrier

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Melatonin; 3 mg of liquid melatonin by oral route for 8 days. The 1st dose will be given 1-2 hours prior to the surgery, followed by bed time doses (between 7-9 pm) given on postoperative day (POD) 1 until discharge or for the first 7 days.	Other: Liquid Melatonin; Melatonin is a natural supplement.
Placebo Comparator: Placebo Group; Similar looking/tasting 3 mg (5 ml) placebo syrup administered preoperatively by oral route and for the next 7 days or until discharge. The 1st dose will be given 1-2 hours prior to the surgery, followed by bed time doses (between 7-9 pm) given on postoperative day (POD) 1 until discharge or for the first 7 days.	Other: Placebo; Similar looking/tasting placebo syrup

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recruitment rate	Recruitment rate: assessed as at least 4-5 patients/week, and completion of recruitment (60 patients/site) in each site over 3-4 months.	6 months
Medication compliance	Proportion of patients who are able to take at least two doses of study medications, assessed as >85% of study patients.	8 days
Follow up to 3 months	Proportion of patients who complete 3 months follow up. For feasibility we expect >90% patients to complete study follow up.	3 months
Proportion of patients recruited from screening	To identify the proportion of screened patients meeting the study inclusion criteria	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Delirium	This will be captured from observing the patient from the time of their discharge from pre-anesthetic care unit (PACU), until the time of discharge. Presence or absence will be captured using the Confusion Assessment Method (CAM)-short form. If patient is mechanically ventilated, the assessment will be performed using Confusion Assessment Method-Intensive Care Unit (CAM-ICU) tool.	8 days
Severity of Delirium	When an episode of post-operative delirium is observed, the severity will be assessed using Confusion Assessment Method (CAM) severity form. We will only record the severity for the first episode of post operative delirium observed.	8 days
Sleep quality	Quality of sleep will be assessed daily using Richards-Campbell Sleep Questionnaire (RCSQ). It is a visual analogue scale 0-100mm; zero indicating the worst possible sleep to 100 indicating the best sleep.	8 days
Incidence of ICU care	Need for ICU or critical care during hospitalization: This will be captured along with the reason and duration of such a stay from hospital records/patient charts	8 days
Prolonged hospital stay	Prolonged hospital stay (beyond anticipated for each patient) will be captured from hospital records/patient charts along with the reason and duration of such a stay	8 days
Institutional discharge	This will be recorded from hospital records.	3 months
Cognitive Status	This will be captured using Mini Mental Status Examination (MMSE)	3 months
Mortality	This outcome will be captured as in-hospital mortality and up to 3 months after discharge.	3 months
Adverse effects	Observe significant sedation using Pasero Opioid-induced Sedation Scale (validated, commonly used) S=Sleep, easy to arouse; Awake and alert; Slightly drowsy, easily aroused(S, 1, 2 all acceptable; no action necessary; may increase opioid dose if needed); Frequently drowsy, arousable, drifts off to sleep during conversation Unacceptable; monitor respiratory status and sedation level closely until sedation level is stable at <3 and respiratory status is satisfactory; decrease opioid dose 25% to 50%, or notifiy prescriber or anesthesiologist for orders; consider a non-sedation, opioid-sparing nonopioid if not contraindicated; Somnolent, minimal or no response to verbal and physical stimulation Unacceptable; stop opioid; consider administering naloxone; notifiy prescriber or anesthesiologist; monitor respiratory status and sedation level closely until sedation level is stable at <3 and respiratory status is acceptable	7 days

Collaborators and Investigators

• Sponsor: McMaster University
• Collaborators: St. Joseph's Healthcare Hamilton

Study record dates

Study Major Dates

• Study Start (Actual): September 14, 2021
• Primary Completion (Estimated): March 31, 2024
• Study Completion (Estimated): March 31, 2024

Study Registration Dates

• First Submitted: December 20, 2018
• First Submitted That Met QC Criteria: December 20, 2018
• First Posted (Actual): December 24, 2018

Study Record Updates

• Last Update Posted (Actual): February 21, 2024
• Last Update Submitted That Met QC Criteria: February 20, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Melatonin; sleep deprivation; sleep quality; Delirium; Elderly patients having non-cardiac surgery; sleep-wake cycle
• 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: 5506

Drug and device information, study documents

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