A placebo controlled double-blind randomized clinical trial to study the effect of melatonin in prevention of post-operative delirium in patients undergoing reperfusion surgery for chronic limb ischaemia.

Post-operative delirium (POD), as a phenotype of delirium, occurs in approximately 10-50% of patients after major surgery. Post-operative delirium is a common, serious, under-recognized adverse event and is associated with significant morbidity and mortality in elderly patients. While delirium may occur in every patient after surgery, the incidence is higher in the elderly patient. Post- operative delirium in the elderly occurs in 10% to 61% of those aged 65 or older.ost-operative delirium and the associated risk factors have been studied quite extensively in patients having orthopaedic or cardiac surgery and recent studies report incidence of delirium of up to 24% in patients with critical limb ischemia. The identified risk factors of postoperative delirium in lower limb ischemia are age, end-stage renal failure, multiple occlusive lesions, cognitive impairment, and critical limb ischemia. Critical limb ischemia (CLI) is the term used to delineate the condition in which arterial disease has resulted in pain in the foot even at rest or in a breakdown of the skin (ulcer or gangrene), and it is the most advanced form among peripheral artery disease. Despite such high incidence, the treatment and prevention of POD remain elusive in these sub-group patients.

Melatonin (N-acetyl-5-methoxytryptamine) is a hormone produced in the brain by the pineal gland from the amino acid tryptophan. Synthetic melatonin supplements have been used for various medical conditions, most notably sleep-related disorders. It has been used successfully  when  used  as  a  premedication  to  decrease  anxiety  and  sedate  patients preoperatively with an excellent cognitive profile. Moreover, it has been found that melatonin levels drop after the surgery. Sleep disturbances result in serious physiological consequences such as delirium, which may negatively influence the patients outcomes. The use of melatonin to prevent delirium in clinical studies is promising, and the reported decrease in delirium incidence in elderly patients hospitalized in medical wards was up to 50%. Concerning the perioperative period, only a few small studies with conflicting results are available, and there is a paucity of literature and data to support or refute its role in vascular surgery patients specifically in patients undergoing reperfusion surgery for chronic limb ischaemia. Given the inconsistencies in the previous studies concerning the prevention of post operative delirium, as well as the limited studies in this area and to test the hypothesis that short-term administration of oral melatonin will reduce the incidence of postoperative delirium in patients undergoing elective reperfusion surgeries, this placebo controlled, double blind, randomized clinical trial will be carried out. The research question for this study is to determine the effect of melatonin on prevention of postoperative delirium in patients aged 40 -75 years of age undergoing reperfusion surgery for chronic lower limb ischemia.

All patients who will be undergoing bypass surgery for chronic limb ischemia will be approached within 24 hours of admission by the researcher. Patients will be screened for eligibility, and proper consent will be taken. After randomization, the patient will receive the study medication on two consecutive evenings, on the evening before surgery and one day prior to the day before surgery (at seven p.m.).

At baseline, we will record demographic data, medical history, medication use, and surgery related characteristics. We will also observe intraoperatively for any general and specific complications, drugs used for anaesthesia, any infusion applied, and lab and hemodynamic data. All patients enrolled in the study will be screened at least once daily using the 4AT assessment method administered by the investigator. The development of delirium will be observed from post-op day 1 to post-op day 5. We will not protocolize the administration of any co-interventions in this study. Pain, agitation, sedation, delirium, and sleep management will be performed according to institutional practice.

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