Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trialReportar como inadecuado

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Critical Care

, 12:R52

First Online: 18 April 2008Received: 08 February 2008Revised: 11 April 2008Accepted: 18 April 2008


IntroductionSleep 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.

MethodsWe 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.

ResultsNocturnal 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.

ConclusionIn 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.

Trial registrationCurrent Controlled Trials ISRCTN47578325.

AbbreviationsAUCAUC = area under the curve

AUCAUC0–24 = area under the concentration time curve between time 0 and 24 hours

BISBIS = bispectral index

CCmax = maximum plasma concentration

CYP1A2CYP1A2 = cytochrome P450 1A2

EEGEEG = electroencephalogram

ICUICU = intensive care unit

RCSQRCSQ = Richards Campbell Sleep Questionnaire

REMREM = rapid eye movement

SASSAS = Sedation Agitation Scale

SDSD = standard deviation

SEISEI = sleep efficiency index

SWSSWS = slow-wave sleep.

Electronic supplementary materialThe online version of this article doi:10.1186-cc6871 contains supplementary material, which is available to authorized users.

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Autor: Richard S Bourne - Gary H Mills - Cosetta Minelli


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