MIND After Surgery

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Post-operative Delirium, Major Non-cardiac Surgery

Intervention / Treatment
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* Other: Liquid Melatonin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a randomised, placebo-controlled, two arm parallel design pilot RCT
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Melatonin<br>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<br>* Melatonin is a natural supplement.<br>|
| Placebo Comparator: Placebo Group<br>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<br>* Similar looking/tasting placebo syrup<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Delirium, Elderly patients having non-cardiac surgery, Melatonin, sleep quality, sleep deprivation, sleep-wake cycle