Background:
Cardiovascular diseases remain the leading cause of death worldwide, and reperfusion (with its accompanying reperfusion injury) continues to be the most effective method to limit the detrimental effects associated with ischemia. This, combined with convincing experimental data showing reversal of the harmful effects of reperfusion injury by melatonin, as well as the lack of conclusive human studies, highlights the need for new clinical trials evaluating the protective effect of melatonin in human ischemia–reperfusion (I/R) injury. Melatonin’s favourable safety profile, affordability, and accessibility further add to its potential clinical importance.
Study Design:
This is a multi-centre, prospective, randomized, double-blind, placebo-controlled, phase 2 study investigating the once-off, sublingual, preoperative administration of melatonin.
Hypotheses:
We hypothesize that preoperative, sublingual melatonin will have cardioprotective properties during ischemia–reperfusion injury, and that this cardioprotection will result from the antioxidant and anti-inflammatory effects associated with melatonin supplementation.
The primary aim of this study is to test the hypothesis that preoperative melatonin has cardioprotective properties (as reflected by high-sensitivity troponin T [hsTnT] levels) during ischemia–reperfusion injury.
The secondary aims are to investigate:
- The variation in plasma melatonin levels associated with two different preoperative melatonin dosages.
- The relationship between absolute changes in melatonin levels and the anti-inflammatory marker (as reflected by C-reactive protein [CRP] levels).
- The melatonin dose–response in terms ofcardioprotection(and thushsTnTlevels).
- The relationship betweencardioprotectionand inflammation, as reflected by the association betweenhsTnTand inflammatory markers.
Patient Selection:
To be eligible for enrolment in this study, patients must be aged between 18 and 90 years and scheduled for elective cardiac surgery requiring cardiopulmonary bypass for coronary artery bypass grafting (CABG) at Sir Charles Gairdner Hospital or Fiona Stanley Hospital.
Intervention:
Participants will be allocated into three study groups: the control group (receiving placebo), the low-dose melatonin group (10 mg), and the high-dose melatonin group (30 mg). The dissolvable melatonin wafers will be an immediate-release formulation placed under the patient’s tongue. The wafer will be administered within 20 minutes peri-induction, after baseline blood samples have been drawn.
Biomarkers:
Serum melatonin, hsTnT, and CRP levels will be measured preoperatively (to determine individual baseline values), intraoperatively, and at 6, 12, and 24 hours postoperatively.
Human melatonin receptors
MT1 and MT2 are membrane bound, MT3 a cytoplasmic receptor, and RZR a nuclear receptor. Abbreviations: MT, melatonin; RZR, Retinoid-related orphan nuclear hormone receptor
Dr Marli Smit, Dr Dale Currigan, Sir Charles Gairdner Hospital, Western Australia.
The project was awarded A$12,153 funding through the ANZCA research grants program for 2026.