title: Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial.
abstract: BACKGROUND
  Sleep disturbances are common in critically ill patients and when sleep does occur it traverses the day-night periods. The reduction in plasma melatonin levels and loss of circadian rhythm observed in critically ill patients receiving mechanical ventilation may contribute to this irregular sleep-wake pattern. We sought to evaluate the effect of exogenous melatonin on nocturnal sleep quantity in these patients and, furthermore, to describe the kinetics of melatonin after oral administration in this patient population, thereby guiding future dosing schedules.
  
  
  METHODS
  We conducted a randomised double-blind placebo-controlled trial in 24 patients who had undergone a tracheostomy to aid weaning from mechanical ventilation. Oral melatonin 10 mg or placebo was administered at 9 p.m. for four nights. Nocturnal sleep was monitored using the bispectral index (BIS) and was expressed in terms of sleep efficiency index (SEI) and area under the curve (AUC). Secondary endpoints were SEI measured by actigraphy and nurse and patient assessments. Plasma melatonin concentrations were measured in nine patients in the melatonin group on the first night.
  
  
  RESULTS
  Nocturnal sleep time was 2.5 hours in the placebo group (mean SEI = 0.26, 95% confidence interval [CI] 0.17 to 0.36). Melatonin use was associated with a 1-hour increase in nocturnal sleep (SEI difference = 0.12, 95% CI -0.02 to 0.27; P = 0.09) and a decrease in BIS AUC indicating 'better' sleep (AUC difference = -54.23, 95% CI -104.47 to -3.98; P = 0.04). Results from the additional sleep measurement methods were inconclusive. Melatonin appeared to be rapidly absorbed from the oral solution, producing higher plasma concentrations relative to similar doses reported in healthy individuals. Plasma concentrations declined biexponentially, but morning (8 a.m.) plasma levels remained supraphysiological.
  
  
  CONCLUSIONS
  In our patients, nocturnal sleep quantity was severely compromised and melatonin use was associated with increased nocturnal sleep efficiency. Although these promising findings need to be confirmed by a larger randomised clinical trial, they do suggest a possible future role for melatonin in the routine care of critically ill patients. Our pharmacokinetic analysis suggests that the 10-mg dose used in this study is too high in these patients and may lead to carryover of effects into the next morning. Reduced doses of 1 to 2 mg could be used in future studies.
  
  
  BACKGROUND
  Current Controlled Trials ISRCTN47578325.
authors.affiliation: Sheffield Teaching Hospitals, Critical Care Department, Northern General Hospital, Herries Road, Sheffield, UK. richard.bourne@sth.nhs.uk
authors.forename: Richard S
authors.initials: RS
authors.lastname: Bourne
authors.forename: Gary H
authors.initials: GH
authors.lastname: Mills
authors.forename: Cosetta
authors.initials: C
authors.lastname: Minelli
mesh_terms: D000284:Administration, Oral; D000368:Aged; D019540:Area Under Curve; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D016638:Critical Illness; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D016014:Linear Models; D008297:Male; D008550:Melatonin / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D008875:Middle Aged; D010919:Placebos; D012893:Sleep Wake Disorders / Q000188:drug therapy*; D014139:Tracheostomy; D016896:Treatment Outcome
chemical_list: D002492:Central Nervous System Depressants; D010919:Placebos; D008550:Melatonin