The Healthy Heart‐Mind Trial: Randomized Controlled Trial of Melatonin for Prevention of Delirium

Abstract

OBJECTIVES Delirium is a serious medical condition with increased incidence in at‐risk surgical populations. We sought to determine if melatonin use reduces the incidence of delirium in individuals undergoing major cardiac surgery. DESIGN Randomized double‐blind placebo‐controlled clinical trial (two arms, 1:1 allocation, parallel design). SETTING The trial took place in two metropolitan hospitals (public tertiary and private) in Perth, Western Australia. PARTICIPANTS We recruited 210 adults aged 50 years or older who were due to undergo coronary artery bypass grafting or valve replacement surgery. INTERVENTION Participants were randomly assigned (1:1) to 7 days of treatment with melatonin 3 mg at night or matching placebo, starting 2 days before the surgery. MEASUREMENTS The primary outcome of interest was incident delirium within 7 days of surgery as assessed via daily clinical assessment that included the Confusion Assessment Method. Secondary outcomes of interest included duration and severity of delirium, length of hospital stay, cognitive function, and mood and anxiety symptoms at discharge and 3 months after the surgery. RESULTS The groups were well balanced for demographic and clinical parameters. Forty‐two participants developed delirium, but it was evenly distributed between the groups (melatonin 21/98, 21.4%; placebo 21/104, 20.2%; adjusted odds ratio [OR] = .78; 95% confidence interval [CI] = .35‐1.75). The median duration of delirium was 3 (interquartile range [IQR] = 2‐4) and 2 (IQR = 1‐3) days for people treated with melatonin and placebo, respectively (z = −1.03; P = .304). A similar proportion of participants experienced severe episodes of delirium in each group (melatonin 9/21, 42.9% vs placebo 6/21, 28.6%; χ2 = .93; P = .334; adjusted OR = 1.98; 95% CI = .40‐9.78). The groups did not differ in terms of length of stay, mood, anxiety, and cognitive performance. CONCLUSION The findings of this randomized double‐blind placebo‐controlled trial do not support the prophylactic use of melatonin to prevent delirium after major cardiac surgery. J Am Geriatr Soc 68:112–119, 2019

Melatonin and its analogues for the prevention of postoperative delirium: A systematic review and meta‐analysis

“…This study included 4 RCTs in the analysis, including 2 RCTs that were also included in the present study 27,30 . The present meta‐analysis included several most recently published studies and was not limited to RCTs 28‐29,31,33‐35 . Our results indicate that melatonin and its analogue might efficiently prevent postoperative delirium, a finding that is not consistent with the previous analysis 16 .…”

“…From these, 10 records were excluded due to the following reasons: 9 for conference abstracts and 1 for reporting tryptophan supplementation with no difference in the postoperative serum melatonin levels 26 . Finally, 6 randomized controlled trials, 27‐32 2 cohort studies 33,34 and 1 case‐control study 35 were included in the meta‐analysis.…”

“…Six studies compared the effect of melatonin with that of a placebo, 27,29‐33 1 study compared the effect of melatonin with that of oxazepam, 28 and 2 studies compared the effect of ramelteon with that of a placebo 34 or a tranquilizer 35 . Four studies were associated with patients undergoing cardiac surgery, 28‐29,31,33 while the remaining studies were associated with hip surgery, 27,30 liver resection, 32 pulmonary resection 34 and pharyngolaryngectomy with esophagectomy 35 . Melatonin dose was 3 mg in 4 studies, 27‐29,31 5 mg in 2 studies 30,33 and 50 mg/kg in 1 study 32 .…”

“…Four studies were associated with patients undergoing cardiac surgery, 28‐29,31,33 while the remaining studies were associated with hip surgery, 27,30 liver resection, 32 pulmonary resection 34 and pharyngolaryngectomy with esophagectomy 35 . Melatonin dose was 3 mg in 4 studies, 27‐29,31 5 mg in 2 studies 30,33 and 50 mg/kg in 1 study 32 . Ramelteon dose was 8 mg in the remaining 2 studies 34,35 .…”

“…Abbreviated Mental Test (AMT),30 the Intensive Care Delirium Screening Checklist (ICDSC), 29,34 the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM‐IV), 27 the fifth edition of DSM (DSM‐V), 35 Confusion Assessment Method for the Intensive Care Unit (CAM‐ICU) 31,33 and clinical observations 28 were used as diagnostic tools for delirium. In the quality assessment of included RCTs, 3 trials 29,31,32 were judged to be at low risk of bias, 2 28,30 at unclear risk and 1 27 at high risk of bias. Quality assessment of the nonrandomized observational studies showed that all studies 33‐35 were of good quality.…”