Sleep and Breathing

, Volume 23, Issue 4, pp 1059–1070 | Cite as

Prophylactic use of exogenous melatonin and melatonin receptor agonists to improve sleep and delirium in the intensive care units: a systematic review and meta-analysis of randomized controlled trials

  • Qingyu Zhang
  • Fuqiang Gao
  • Shuai Zhang
  • Wei SunEmail author
  • Zirong Li
Sleep Breathing Physiology and Disorders • Review


To investigate the efficacy of exogenous administration of melatonin and melatonin receptor agonists for the improvement of delirium, sleep, and other clinical outcomes of subjects in the intensive care unit (ICU). We carefully searched three electronic databases, i.e., Pubmed/Medline, Embase, and Cochrane library, to retrieve randomized controlled trials (RCTs) administrating melatonin or melatonin receptor agonists to adult subjects admitted to the ICU. Useful data such as the prevalence of delirium, duration of sleep, number of awakenings per night, duration of mechanical ventilation, and ICU stay as well as in-ICU mortality were extracted and pooled by using a random effect model. Eight RCTs were included in the qualitative analysis. Administration of exogenous melatonin and melatonin receptor agonists was associated with a trend towards elongated duration of sleep (pooled weighted mean difference/WMD = 0.43; 95% confidence intervals/CIs, − 0.02~0.88, p = 0.063) and could decrease the number of awakenings per night (pooled WMD = − 2.03; 95% CIs, − 3.83~− 0.22, p = 0.028). Meanwhile, participants in the treatment group showed a significantly reduced prevalence of delirium (pooled risk ratio/RR = 0.49; 95% CIs, 0.28~0.88, p = 0.017) and duration of ICU stay (pooled WMD = − 0.32; 95% CI, − 0.56~− 0.07, p = 0.002) in comparison with those in the control group. Exogenous administration of melatonin and melatonin receptor agonists could improve the sleep of subjects in the intensive care units, which may play an important role in decreasing the prevalence of delirium and shortening duration of ICU stay.


Intensive care unit Delirium Melatonin Circadian rhythms Sleep deprivation Meta-analysis 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

For this study, ethical approval is not required.

Informed consent

For this type of study, formal consent is not required.

Supplementary material

11325_2019_1831_Fig5_ESM.png (1.2 mb)
Figure S1

Forest plot and sensitivity analysis of the comparison about sleep duration by using data from secondary analysis of Bourne et al’ study. As depicted, the diamond intersecting the central vertical line represents no differences between the treatment group and the control group (a & c & e). These results were stable in sensitivity analysis when omitting studies one by one (b & d). CI, confidence interval; WMD, weighted mean difference; SD, standard deviation (PNG 1185 kb)

11325_2019_1831_MOESM1_ESM.tif (1.7 mb)
High Resolution Images (TIF 1764 kb)


  1. 1.
    Brzezinski A (1997) Melatonin in humans. N Engl J Med 336(3):186–195. CrossRefPubMedGoogle Scholar
  2. 2.
    Weinhouse GL (2014) Delirium and sleep disturbances in the intensive care unit: can we do better? Curr Opin Anaesthesiol 27(4):403–408. CrossRefPubMedGoogle Scholar
  3. 3.
    Maldonado JR (2008) Pathoetiological model of delirium: a comprehensive understanding of the neurobiology of delirium and an evidence-based approach to prevention and treatment. Crit Care Clin 24(4):789–856. CrossRefPubMedGoogle Scholar
  4. 4.
    Vijayakumar HN, Ramya K, Duggappa DR, Veeranna Gowda KM, Sudheesh K, Nethra SS, Raghavendra Rao RS (2016) Effect of melatonin on duration of delirium in organophosphorus compound poisoning patients: a double-blind randomised placebo controlled trial. Indian J Anaesth 60(11):814–820. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Dessap AM, Roche-Campo F, Launay JM, Charles-Nelson A, Katsahian S, Brun-Buisson C, Brochard L (2015) Delirium and circadian rhythm of melatonin during weaning from mechanical ventilation: an ancillary study of a weaning trial. Chest 148(5):1231–1241. CrossRefPubMedGoogle Scholar
  6. 6.
    Mehta S, Cook D, Devlin JW, Skrobik Y, Meade M, Fergusson D, Herridge M, Steinberg M, Granton J, Ferguson N, Tanios M, Dodek P, Fowler R, Burns K, Jacka M, Olafson K, Mallick R, Reynolds S, Keenan S, Burry L, SLEAP Investigators, Canadian Critical Care Trials Group (2015) Prevalence, risk factors, and outcomes of delirium in mechanically ventilated adults. Crit Care Med 43(3):557–566. CrossRefPubMedGoogle Scholar
  7. 7.
    Harrison Y, Horne JA, Rothwell A (2000) Prefrontal neuropsychological effects of sleep deprivation in young adults--a model for healthy aging? Sleep 23(8):1067–1073CrossRefGoogle Scholar
  8. 8.
    Walker CK, Gales MA (2017) Melatonin receptor agonists for delirium prevention. Ann Pharmacother 51(1):72–78. CrossRefPubMedGoogle Scholar
  9. 9.
    Macleod MR, O’Collins T, Horky LL, Howells DW, Donnan GA (2005) Systematic review and meta-analysis of the efficacy of melatonin in experimental stroke. J Pineal Res 38(1):35–41. CrossRefPubMedGoogle Scholar
  10. 10.
    Maitra S, Baidya DK, Khanna P (2013) Melatonin in perioperative medicine: current perspective. Saudi J Anaesth 7(3):315–321. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Dianatkhah M, Ghaeli P, Hajhossein TA et al (2015) Evaluating the potential effect of melatonin on the post-cardiac surgery sleep disorder. J Tehran Heart Cent 10(3):122–128PubMedPubMedCentralGoogle Scholar
  12. 12.
    Lewis SR, Pritchard MW, Schofield-Robinson OJ, Alderson P, Smith AF (2018) Melatonin for the promotion of sleep in adults in the intensive care unit. Cochrane Database Syst Rev 5:D12455. CrossRefGoogle Scholar
  13. 13.
    Mo Y, Scheer CE, Abdallah GT (2016) Emerging role of melatonin and melatonin receptor agonists in sleep and delirium in intensive care unit patients. J Intensive Care Med 31(7):451–455. CrossRefPubMedGoogle Scholar
  14. 14.
    Foreman B, Westwood AJ, Claassen J, Bazil CW (2015) Sleep in the neurological intensive care unit: feasibility of quantifying sleep after melatonin supplementation with environmental light and noise reduction. J Clin Neurophysiol 32(1):66–74. CrossRefPubMedGoogle Scholar
  15. 15.
    Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JPA, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339:b2700CrossRefGoogle Scholar
  16. 16.
    Luo D, Wan X, Liu J, Tong T (2018) Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res 27(6):1785–1805. CrossRefPubMedGoogle Scholar
  17. 17.
    Wan X, Wang W, Liu J, Tong T (2014) Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 14(135).
  18. 18.
    Higgins JPT, Green S (editors) (2011) Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated March 2011]. The Cochrane Collaboration. Available from
  19. 19.
    Nishikimi M, Numaguchi A, Takahashi K, Miyagawa Y, Matsui K, Higashi M, Makishi G, Matsui S, Matsuda N (2018) 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 46(7):1099–1105. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Dianatkhah M, Najafi A, Sharifzadeh M, Ahmadi A, Sharifnia H, Mojtahedzadeh M, Najmeddin F, Moghaddas A (2017) Melatonin supplementation may improve the outcome of patients with hemorrhagic stroke in the intensive care unit. J Res Pharm Pract 6(3):173–177. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Mistraletti G, Umbrello M, Sabbatini G et al (2015) Melatonin reduces the need for sedation in ICU patients: a randomized controlled trial. Minerva Anestesiol 81(12):1298–1310PubMedGoogle Scholar
  22. 22.
    Huang HW, Zheng BL, Jiang L, Lin ZT, Zhang GB, Shen L, Xi XM (2015) Effect of oral melatonin and wearing earplugs and eye masks on nocturnal sleep in healthy subjects in a simulated intensive care unit environment: which might be a more promising strategy for ICU sleep deprivation? Crit Care 19:124. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Hatta K, Kishi Y, Wada K, Takeuchi T, Odawara T, Usui C, Nakamura H (2014) Preventive effects of ramelteon on delirium: a randomized placebo-controlled trial. JAMA Psychiat 71(4):397–403. CrossRefGoogle Scholar
  24. 24.
    Bourne RS, Mills GH, Minelli C (2008) Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial. Crit Care 12(2):R52. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Ibrahim MG, Bellomo R, Hart GK et al (2006) A double-blind placebo-controlled randomised pilot study of nocturnal melatonin in tracheostomized patients. Crit Care Resusc 8(3):187–191PubMedGoogle Scholar
  26. 26.
    Hori T, Sugita Y, Koga E et al (2001) Proposed supplements and amendments to ‘A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects’, the Rechtschaffen & Kales (1968) standard. Psychiatry Clin Neurosci 55(3):305–310. CrossRefPubMedGoogle Scholar
  27. 27.
    Devlin JW, Skrobik Y, Gelinas C et al (2018) 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 46(9):e825–e873. CrossRefPubMedGoogle Scholar
  28. 28.
    Neufeld KJ, Yue J, Robinson TN, Inouye SK, Needham DM (2016) Antipsychotic medication for prevention and treatment of delirium in hospitalized adults: a systematic review and meta-analysis. J Am Geriatr Soc 64(4):705–714. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Jarman A, Duke G, Reade M, Casamento A (2013) The association between sedation practices and duration of mechanical ventilation in intensive care. Anaesth Intensive Care 41(3):311–315CrossRefGoogle Scholar
  30. 30.
    Jaiswal SJ, McCarthy TJ, Wineinger NE et al (2018) Melatonin and sleep in preventing hospitalized delirium: a randomized clinical trial. Am J Med 131(9):1110–1117. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Mousavi SS, Shohrati M, Vahedi E, Abdollahpour-Alitappeh M, Panahi Y (2018) Effect of melatonin administration on sleep quality in sulfur mustard exposed patients with sleep disorders. Iran J Pharm Res 17(Suppl):136–144PubMedPubMedCentralGoogle Scholar
  32. 32.
    Watson N, Diamandis T, Gonzales-Portillo C, Reyes S, Borlongan CV (2016) Melatonin as an antioxidant for stroke neuroprotection. Cell Transplant 25(5):883–891. CrossRefPubMedGoogle Scholar
  33. 33.
    Ely EW, Inouye SK, Bernard GR, Gordon S, Francis J, May L, Truman B, Speroff T, Gautam S, Margolin R, Hart RP, Dittus R (2001) Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA 286(21):2703–2710CrossRefGoogle Scholar
  34. 34.
    Elliott R, McKinley S, Cistulli P, Fien M (2013) Characterisation of sleep in intensive care using 24-hour polysomnography: an observational study. Crit Care 17(2):R46. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Ward D, Fulbrook P (2016) Nursing strategies for effective weaning of the critically ill mechanically ventilated patient. Crit Care Nurs Clin North Am 28(4):499–512. CrossRefPubMedGoogle Scholar
  36. 36.
    Johnsa JD, Neville MW (2014) Tasimelteon: a melatonin receptor agonist for non-24-hour sleep-wake disorder. Ann Pharmacother 48(12):1636–1641. CrossRefPubMedGoogle Scholar
  37. 37.
    Miyamoto M (2009) Pharmacology of ramelteon, a selective MT1/MT2 receptor agonist: a novel therapeutic drug for sleep disorders. CNS Neurosci Ther 15(1):32–51. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Wu YH, Zhou JN, Van Heerikhuize J, Jockers R, Swaab DF (2007) Decreased MT1 melatonin receptor expression in the suprachiasmatic nucleus in aging and Alzheimer’s disease. Neurobiol Aging 28(8):1239–1247. CrossRefPubMedGoogle Scholar
  39. 39.
    Osier ND, Pham L, Pugh BJ, Puccio A, Ren D, Conley YP, Alexander S, Dixon CE (2017) Brain injury results in lower levels of melatonin receptors subtypes MT1 and MT2. Neurosci Lett 650:18–24. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of OrthopedicsShandong Provincial Hospital affiliated to Shandong UniversityJinanChina
  2. 2.Beijing Key Laboratory of Immune Inflammatory DiseaseChina-Japan Friendship HospitalBeijingChina
  3. 3.Department of Neurology, Affiliated Hospital of Yangzhou UniversityYangzhou UniversityYangzhouChina
  4. 4.Beijing Key Laboratory of Immune Inflammatory Disease, China-Japan Friendship HospitalPeking Union Medical CollegeBeijingChina

Personalised recommendations