Melatonin Therapy to Improve Nocturnal Sleep in Critically Ill Patients:Encouraging Results from a Small Randomised Controlled Trial


Richard S Bourne, Gary H Mills, Cosetta Minelli



Critical Care 2008, 12



Introduction: 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. Furthermore to describe the kinetics of melatonin after oral administration in this patient population, thereby guiding future dosing schedules.

Methods: 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 21:00 hours for 4 nights. Nocturnal sleep was monitored using the bispectral index (BIS) and expressed in terms of sleep efficiency index (SEI) and area under the curve (AUC). Secondary endpoints were SEI measured by actigraphy, nurse and patient assessment. Plasma melatonin concentrations were measured in 9 patients in the melatonin group on the first night.

Results: nocturnal sleep time was two and a half hours in the placebo group (mean SEI=0.26; 95%CI: 0.17 to 0.36). Melatonin use was associated with a onehour 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 (08:00) 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 10mg dose used in this study is too high in these patients and may lead to carry over of effects into the next morning. Reduced doses of 1-2 mg could be used in future studies.



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