An impaired sleep-wake cycle may be one factor that affects the development of delirium in critically ill patients. Several small studies suggest that exogenous melatonin or ramelteon may decrease the incidence and/or duration of delirium.
Objective:
To compare the effect of prophylactic administration of melatonin, ramelteon, or no melatonin receptor agonist on the development of delirium in the intensive care unit (ICU).
Methods:
This was a single-center, retrospective, observational cohort study of nondelirious patients in the ICU who received melatonin, ramelteon, or no melatonin receptor agonist. The primary end point was the incidence of delirium. Secondary end points included assessments of daily level of sedation and daily utilization of antipsychotic, sedative, and opioid agents.
Results:
No difference was observed in the incidence of delirium among the melatonin, ramelteon, and placebo cohorts (18.7% vs 14.3% vs 13.8%; P = 0.77). A difference was observed in the rate of agitation and sedation among the 3 groups, with the greatest observed in the melatonin cohort. Additionally, there was a difference in the use of propofol, dexmedetomidine, and opioids. Overall, there was no difference in clinical outcomes, including duration of mechanical ventilation and ICU or hospital length of stay.
Conclusion and Relevance:
Therapy with melatonin, ramelteon, and no melatonin receptor agonist resulted in similar rates of delirium in a mixed ICU population. Despite significant differences in agitation, sedation, and medication utilization, there was no differences in the clinical outcomes evaluated.
DevlinJWSkrobikYGélinasC, et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018;46:e825-e873. doi:10.1097/CCM.0000000000003299
2.
PandharipandePPElyEWAroraRC, et al. The intensive care delirium research agenda: a multinational, interprofessional perspective. Intensive Care Med. 2017;43:1329-1339. doi:10.1007/s00134-017-4860-7
3.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. American Psychiatric Association; 2013.
4.
ThomasonJWShintaniAPetersonJFPunBTJacksonJCElyEW.Intensive care unit delirium is an independent predictor of longer hospital stay: a prospective analysis of 261 non-ventilated patients. Crit Care. 2005;9:R375-R381. doi:10.1186/cc3729
5.
ElyEWGautamSMargolinR, et al. The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care Med. 2001;27:1892-1900. doi:10.1007/s00134-001-1132-2
6.
ElyEWShintaniATrumanB, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004;291:1753-1762. doi:10.1001/jama.291.14.1753
7.
PisaniMAKongSYKaslSVMurphyTEAraujoKLVan nessPH.Days of delirium are associated with 1-year mortality in an older intensive care unit population. Am J Respir Crit Care Med. 2009;180:1092-1097. doi:10.1164/rccm.200904-0537OC
8.
GirardTDJacksonJCPandharipandePP, et al. Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Crit Care Med. 2010;38:1513-1520. doi:10.1097/CCM.0b013e3181e47be1
9.
WeinhouseGLSchwabRJWatsonPL, et al. Bench-to-bedside review: delirium in ICU patients—importance of sleep deprivation. Crit Care. 2009;13:234. doi:10.1186/cc8131
10.
BillingsMEWatsonNF.Circadian dysrhythmias in the intensive care unit. Crit Care Clin. 2015;31:393-402. doi:10.1016/j.ccc.2015.03.006
11.
OlofssonKAllingCLundbergDMalmrosC.Abolished circadian rhythm of melatonin secretion in sedated and artificially ventilated intensive care patients. Acta Anaesthesiol Scand. 2004;48:679-684. doi:10.1111/j.0001-5172.2004.00401.x
12.
MundiglerGDelle-karthGKorenyM, et al. Impaired circadian rhythm of melatonin secretion in sedated critically ill patients with severe sepsis. Crit Care Med. 2002;30:536-540. doi:10.1097/00003246-200203000-00007
13.
YoshitakaSEgiMMorimatsuHKanazawaTTodaYMoritaK.Perioperative plasma melatonin concentration in postoperative critically ill patients: its association with delirium. J Crit Care. 2013;28:236-242. doi:10.1016/j.jcrc.2012.11.004
14.
MiyazakiTKuwanoHKatoH, et al. Correlation between serum melatonin circadian rhythm and intensive care unit psychosis after thoracic esophagectomy. Surgery. 2003;133:662-668. doi:10.1067/msy.2003.149
15.
BourneRSMillsGHMinelliC.Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial. Crit Care. 2008;12:R52. doi:10.1186/cc6871
16.
GandolfiJVDi BernardoAPAChanesDAV, et al. The effects of melatonin supplementation on sleep quality and assessment of the serum melatonin in ICU patients: a randomized controlled trial. Crit Care Med. 2020;48:e1286-e1293. doi:10.1097/CCM.0000000000004690
17.
BellapartJBootsR.Potential use of melatonin in sleep and delirium in the critically ill. Br J Anaesth. 2012;108:572-580. doi:10.1093/bja/aes035
18.
HattaKKishiYWadaK, et al. Preventive effects of ramelteon on delirium: a randomized placebo-controlled trial. JAMA Psychiatry. 2014;71:397-403. doi:10.1001/jamapsychiatry.2013.3320
19.
NishikimiMNumaguchiATakahashiK, et al. Effect of administration of ramelteon, a melatonin receptor agonist, on the duration of stay in the ICU: a single-center randomized placebo-controlled trial. Crit Care Med. 2018;46:1099-1105. doi:10.1097/CCM.0000000000003132
20.
BaumgartnerLLamKLaiJ, et al. Effectiveness of melatonin for the prevention of intensive care unit delirium. Pharmacotherapy. 2019;39:280-287. doi:10.1002/phar.2222
21.
ThomRBuiMRosnerB, et al. Ramelteon is not associated with improved outcomes among critically ill delirious patients: a single-center retrospective cohort study. Psychosomatics. 2019;60:289-297. doi:10.1016/j.psym.2018.07.015
22.
DanielsLMNelsonSBFrankRDParkJG.Pharmacologic treatment of intensive care unit delirium and the impact on duration of delirium, length of intensive care unit stay, length of hospitalization, and 28-day mortality. Mayo Clin Proc. 2018;93:1739-1748. doi:10.1016/j.mayocp.2018.06.022
23.
DevlinJWRobertsRJ.Pharmacology of commonly used analgesics and sedatives in the ICU: benzodiazepines, propofol, and opioids. Anesthesiol Clin. 2011;29:567-585. doi:10.1016/j.anclin.2011.09.001
24.
TordjmanSChokronSDelormeR, et al. Melatonin: pharmacology, functions and therapeutic benefits. Curr Neuropharmacol. 2017;15:434-443. doi:10.2174/1570159X14666161228122115
25.
ScottBK.Disruption of circadian rhythms and sleep in critical illness and its impact on the development of delirium. Curr Pharm Des. 2015;21:3443-3452. doi:10.2174/1381612821666150706110656
26.
MarraAMcgraneTJHensonCPPandharipandePP.Melatonin in critical care. Crit Care Clin. 2019;35:329-340. doi:10.1016/j.ccc.2018.11.008
ZaalIJDevlinJWPeelenLMSlooterAJ.A systematic review of risk factors for delirium in the ICU. Crit Care Med. 2015;43:40-47. doi:10.1097/CCM.0000000000000625
29.
SultanSS.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;4:169-173. doi:10.4103/1658-354X.71132
30.
Al-aamaTBrymerCGutmanisIWoolmore-goodwinSMEsbaughJDasguptaM.Melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial. Int J Geriatr Psychiatry. 2011;26:687-694. doi:10.1002/gps.2582
31.
De jongheAvan MunsterBCGoslingsJC, et al. Effect of melatonin on incidence of delirium among patients with hip fracture: a multicentre, double-blind randomized controlled trial. CMAJ. 2014;186:E547-E556. doi:10.1503/cmaj.140495
32.
JaiswalSJMccarthyTJWineingerNE, et al. Melatonin and sleep in preventing hospitalized delirium: a randomized clinical trial. Am J Med. 2018;131:1110-1117.e4. doi:10.1016/j.amjmed.2018.04.009
33.
NgKTTeohWYKhorAJ.The effect of melatonin on delirium in hospitalised patients: a systematic review and meta-analyses with trial sequential analysis. J Clin Anesth. 2020;59:74-81. doi:10.1016/j.jclinane.2019.06.027
34.
TerryKJAngerKESzumitaPM.Prospective evaluation of inappropriate unable-to-assess CAM-ICU documentations of critically ill adult patients. J Intensive Care. 2015;3:52. doi:10.1186/s40560-015-0119-y
