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

Sleep Breath. 2019 Dec;23(4):1059-1070. doi: 10.1007/s11325-019-01831-5. Epub 2019 May 22.


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.

Keywords: Circadian rhythms; Delirium; Intensive care unit; Melatonin; Meta-analysis; Sleep deprivation.

Publication types

  • Comparative Study
  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Adult
  • Benzofurans / administration & dosage
  • Case-Control Studies
  • Correlation of Data
  • Cross-Sectional Studies
  • Cyclopropanes / administration & dosage
  • Delirium / drug therapy*
  • Delirium / mortality
  • Hospital Mortality
  • Humans
  • Indenes / administration & dosage
  • Intensive Care Units*
  • Length of Stay
  • Melatonin / administration & dosage*
  • Randomized Controlled Trials as Topic
  • Receptors, Melatonin / agonists*
  • Respiration, Artificial
  • Risk Factors
  • Sleep / drug effects*
  • Sleep Wake Disorders / drug therapy*
  • Sleep Wake Disorders / mortality
  • Treatment Outcome
  • Wakefulness / drug effects


  • Benzofurans
  • Cyclopropanes
  • Indenes
  • Receptors, Melatonin
  • ramelteon
  • Melatonin
  • tasimelteon