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Published in: Trials 1/2016

Open Access 01-12-2016 | Study protocol

The Healthy Heart-Mind trial: melatonin for prevention of delirium following cardiac surgery: study protocol for a randomized controlled trial

Authors: Andrew H. Ford, Leon Flicker, Jurgen Passage, Bradley Wibrow, Matthew Anstey, Mark Edwards, Osvaldo P. Almeida

Published in: Trials | Issue 1/2016

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Abstract

Background

Delirium is a common occurrence in patients undergoing major cardiac surgery and is associated with a number of adverse consequences for the individual, their family and the health system. Current approaches to the prevention of delirium include identifying those at risk together with various non-pharmacological and pharmacological strategies, although the efficacy of these is often modest. Emerging evidence suggests that melatonin may be biologically implicated in the development of delirium and that melatonin supplementation may be beneficial in reducing the incidence of delirium in medical and surgical patients. We designed this trial to determine whether melatonin reduces the incidence of delirium following cardiac surgery compared with placebo.

Methods/Design

The Healthy Heart-Mind trial is a randomized, double-blind, placebo-controlled clinical trial of 3 mg melatonin or matching placebo administered on seven consecutive days for the prevention of delirium following cardiac surgery. We will recruit 210 adult participants, aged 50 and older, undergoing elective or semi-elective cardiac surgery with the primary outcome of interest for this study being the difference in the incidence of delirium between the groups within 7 days of surgery. Secondary outcomes of interest include the difference between groups in the severity and duration of delirious episodes, hospital length of stay and referrals to mental health services during admission. In addition, we will assess differences in depressive and anxiety symptoms, as well as cognitive performance, at discharge and 3 months after surgery.

Discussion

The results of this trial will clarify whether melatonin reduces the incidence of delirium following cardiac surgery.

Trial registration

The trial is registered with the Australian Clinical Trials Registry, trial number ACTRN12615000819527 (10 August 2015).
Appendix
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Literature
1.
Saxena S, Lawley D. Delirium in the elderly: a clinical review. Postgrad Med J. 2009;85(1006):405–13.PubMedCrossRef
2.
Bucht G, Gustafson Y, Sandberg O. Epidemiology of delirium. Dement Geriatr Cogn Disord. 1999;10(5):315–8.PubMedCrossRef
3.
Inouye SK. Delirium in hospitalized older patients: recognition and risk factors. J Geriatr Psychiatry Neurol. 1998;11(3):118–25. discussion 57-8.PubMedCrossRef
4.
McKhann GM, Grega MA, Borowicz Jr LM, Bechamps M, Selnes OA, Baumgartner WA, et al. Encephalopathy and stroke after coronary artery bypass grafting: incidence, consequences, and prediction. Arch Neurol. 2002;59(9):1422–8.PubMed
5.
Tan MC, Felde A, Kuskowski M, Ward H, Kelly RF, Adabag AS, et al. Incidence and predictors of post-cardiotomy delirium. Am J Geriatr Psychiatry. 2008;16(7):575–83.PubMedCrossRef
6.
Santos FS, Velasco IT, Fraguas Jr R. Risk factors for delirium in the elderly after coronary artery bypass graft surgery. Int Psychogeriatr. 2004;16(2):175–93.PubMedCrossRef
7.
Bucerius J, Gummert JF, Borger MA, Walther T, Doll N, Falk V, et al. Predictors of delirium after cardiac surgery delirium: effect of beating-heart (off-pump) surgery. J Thorac Cardiovasc Surg. 2004;127(1):57–64.PubMedCrossRef
8.
Witlox J, Eurelings LS, de Jonghe JF, Kalisvaart KJ, Eikelenboom P, van Gool WA. Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and dementia: a meta-analysis. JAMA. 2010;304(4):443–51.PubMedCrossRef
9.
Inouye SK, Rushing JT, Foreman MD, Palmer RM, Pompei P. Does delirium contribute to poor hospital outcomes? A three-site epidemiologic study. J Gen Intern Med. 1998;13(4):234–42.PubMedPubMedCentralCrossRef
10.
McCusker J, Cole MG, Dendukuri N, Belzile E. Does delirium increase hospital stay? J Am Geriatr Soc. 2003;51(11):1539–46.PubMedCrossRef
11.
Leslie DL, Marcantonio ER, Zhang Y, Leo-Summers L, Inouye SK. One-year health care costs associated with delirium in the elderly population. Arch Intern Med. 2008;168(1):27–32.PubMedPubMedCentralCrossRef
12.
Siddiqi N, House AO, Holmes JD. Occurrence and outcome of delirium in medical in-patients: a systematic literature review. Age Ageing. 2006;35(4):350–64.PubMedCrossRef
13.
Rasmussen LS, Larsen K, Houx P, Skovgaard LT, Hanning CD, Moller JT. The assessment of postoperative cognitive function. Acta Anaesthesiol Scand. 2001;45(3):275–89.PubMedCrossRef
14.
Newman MF, Kirchner JL, Phillips-Bute B, Gaver V, Grocott H, Jones RH, et al. Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery. N Engl J Med. 2001;344(6):395–402.PubMedCrossRef
15.
Sanders RD, Pandharipande PP, Davidson AJ, Ma D, Maze M. Anticipating and managing postoperative delirium and cognitive decline in adults. BMJ. 2011;343:d4331.PubMedCrossRef
16.
Schor JD, Levkoff SE, Lipsitz LA, Reilly CH, Cleary PD, Rowe JW, et al. Risk factors for delirium in hospitalized elderly. JAMA. 1992;267(6):827–31.PubMedCrossRef
17.
Siddiqi N, Stockdale R, Britton AM, Holmes J. Interventions for preventing delirium in hospitalised patients. Cochrane Database Syst Rev. 2007;2:CD005563.PubMed
18.
Inouye SK. Prevention of delirium in hospitalized older patients: risk factors and targeted intervention strategies. Ann Med. 2000;32(4):257–63.PubMedCrossRef
19.
Tabet N, Howard R. Pharmacological treatment for the prevention of delirium: review of current evidence. Int J Geriatr Psychiatry. 2009;24(10):1037–44.PubMedCrossRef
20.
Wade A, Downie S. Prolonged-release melatonin for the treatment of insomnia in patients over 55 years. Expert Opin Investig Drugs. 2008;17(10):1567–72.PubMedCrossRef
21.
Lewis MC, Barnett SR. Postoperative delirium: the tryptophan dysregulation model. Med Hypotheses. 2004;63(3):402–6.PubMedCrossRef
22.
Swaab DF, Fliers E, Partiman TS. The suprachiasmatic nucleus of the human brain in relation to sex, age and senile dementia. Brain Res. 1985;342(1):37–44.PubMedCrossRef
23.
Cronin AJ, Keifer JC, Davies MF, King TS, Bixler EO. Melatonin secretion after surgery. Lancet. 2000;356(9237):1244–5.PubMedCrossRef
24.
Lapwood KR, Bhagat L, Simpson MP. Analgesic effects on endogenous melatonin secretion. J Pineal Res. 1997;22(1):20–5.PubMedCrossRef
25.
Shigeta H, Yasui A, Nimura Y, Machida N, Kageyama M, Miura M, et al. Postoperative delirium and melatonin levels in elderly patients. Am J Surg. 2001;182(5):449–54.PubMedCrossRef
26.
Balan S, Leibovitz A, Zila SO, Ruth M, Chana W, Yassica B, et al. The relation between the clinical subtypes of delirium and the urinary level of 6-SMT. J Neuropsychiatry Clin Neurosci. 2003;15(3):363–6.PubMedCrossRef
27.
Uchida K, Aoki T, Ishizuka B. Postoperative delirium and plasma melatonin. Med Hypotheses. 1999;53(2):103–6.PubMedCrossRef
28.
Waldhauser F, Waldhauser M, Lieberman HR, Deng MH, Lynch HJ, Wurtman RJ. Bioavailability of oral melatonin in humans. Neuroendocrinology. 1984;39(4):307–13.PubMedCrossRef
29.
Lemoine P, Zisapel N. Prolonged-release formulation of melatonin (Circadin) for the treatment of insomnia. Expert Opin Pharmacother. 2012;13(6):895–905.PubMedCrossRef
30.
Sultan SS. Assessment of role of perioperative melatonin in prevention and treatment of postoperative delirium after hip arthroplasty under spinal anesthesia in the elderly. Saudi J Anaesth. 2010;4(3):169–73.PubMedPubMedCentralCrossRef
31.
Al-Aama T, Brymer C, Gutmanis I, Woolmore-Goodwin SM, Esbaugh J, Dasgupta M. Melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial. Int J Geriatr Psychiatry. 2011;26(7):687–94.PubMedCrossRef
32.
Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Ann Intern Med. 1990;113(12):941–8.PubMedCrossRef
33.
de Jonghe A, van Munster BC, Goslings JC, Kloen P, van Rees C, Wolvius R, et al. Effect of melatonin on incidence of delirium among patients with hip fracture: a multicentre, double-blind randomized controlled trial. CMAJ. 2014;186(14):E547–56.PubMedPubMedCentralCrossRef
34.
Hatta K, Kishi Y, Wada K, Takeuchi T, Odawara T, Usui C, et al. Preventive effects of ramelteon on delirium: a randomized placebo-controlled trial. JAMA Psychiatry. 2014;71(4):397–403.PubMedCrossRef
35.
Knopman DS, Roberts RO, Geda YE, Pankratz VS, Christianson TJ, Petersen RC, et al. Validation of the telephone interview for cognitive status-modified in subjects with normal cognition, mild cognitive impairment, or dementia. Neuroepidemiology. 2010;34(1):34–42.PubMedPubMedCentralCrossRef
36.
Bohn MJ, Babor TF, Kranzler HR. The Alcohol Use Disorders Identification Test (AUDIT): validation of a screening instrument for use in medical settings. J Stud Alcohol. 1995;56(4):423–32.PubMedCrossRef
37.
Wei LA, Fearing MA, Sternberg EJ, Inouye SK. The Confusion Assessment Method: a systematic review of current usage. J Am Geriatr Soc. 2008;56(5):823–30.PubMedPubMedCentralCrossRef
38.
Ely EW, Inouye SK, Bernard GR, Gordon S, Francis J, May L, et al. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA. 2001;286(21):2703–10.PubMedCrossRef
39.
Breitbart W, Rosenfeld B, Roth A, Smith MJ, Cohen K, Passik S. The Memorial Delirium Assessment Scale. J Pain Symptom Manage. 1997;13(3):128–37.PubMedCrossRef
40.
de Jager CA, Budge MM, Clarke R. Utility of TICS-M for the assessment of cognitive function in older adults. Int J Geriatr Psychiatry. 2003;18(4):318–24.PubMedCrossRef
41.
Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67(6):361–70.PubMedCrossRef
42.
Ibrahim MG, Bellomo R, Hart GK, Norman TR, Goldsmith D, Bates S, et al. A double-blind placebo-controlled randomised pilot study of nocturnal melatonin in tracheostomised patients. Crit Care Resusc. 2006;8(3):187–91.PubMed
43.
Medeiros CA, Carvalhedo de Bruin PF, Lopes LA, Magalhaes MC, de Lourdes Seabra M, de Bruin VM. Effect of exogenous melatonin on sleep and motor dysfunction in Parkinson’s disease. A randomized, double blind, placebo-controlled study. J Neurol. 2007;254(4):459–64.PubMedCrossRef
44.
Song GH, Leng PH, Gwee KA, Moochhala SM, Ho KY. Melatonin improves abdominal pain in irritable bowel syndrome patients who have sleep disturbances: a randomised, double blind, placebo controlled study. Gut. 2005;54(10):1402–7.PubMedPubMedCentralCrossRef
45.
Asayama K, Yamadera H, Ito T, Suzuki H, Kudo Y, Endo S. Double blind study of melatonin effects on the sleep-wake rhythm, cognitive and non-cognitive functions in Alzheimer type dementia. Journal of Nippon Medical School (Nippon Ika Daigaku Zasshi). 2003;70(4):334–41.CrossRef
46.
Wirojanan J, Jacquemont S, Diaz R, Bacalman S, Anders TF, Hagerman RJ, et al. The efficacy of melatonin for sleep problems in children with autism, fragile X syndrome, or autism and fragile X syndrome. J Clin Sleep Med. 2009;5(2):145–50.PubMedPubMedCentral
Metadata
Title
The Healthy Heart-Mind trial: melatonin for prevention of delirium following cardiac surgery: study protocol for a randomized controlled trial
Authors
Andrew H. Ford
Leon Flicker
Jurgen Passage
Bradley Wibrow
Matthew Anstey
Mark Edwards
Osvaldo P. Almeida
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Trials / Issue 1/2016
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/s13063-016-1163-1

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