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Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial.

ABSTRACT: 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 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. CONCLUSION: 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. TRIAL REGISTRATION: Current Controlled Trials ISRCTN47578325.

SUBMITTER: Bourne RS

PROVIDER: S-EPMC2447606 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial.

Bourne Richard S RS Mills Gary H GH Minelli Cosetta C

Critical care (London, England) 20080418 2

<h4>Introduction</h4>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 ...[more]

PMID: 18423009

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Project description:IntroductionSleep deprivation, which is a common complication in the intensive care unit (ICU), is associated with delirium and increased mortality. Sedation with gamma-aminobutyric acid agonists (propofol, benzodiazepine) results in significant disturbance of the sleep architecture. Dexmedetomidine is a lipophilic imidazole with an affinity for α2-adrenoceptors and it has sedative and analgesic properties. It has been reported to enhance sleep efficiency, thus sedate while preserving sleep architecture.Methods and analysisThirty consecutive patients are planned to be included, at the Department of Anesthesia and Intensive Care at the Hospital of Southwest Jutland, Denmark. The study is a double-blinded, randomised, controlled trial with two parallel groups (2:1 allocation ratio). Screening and inclusion will be done on day 1 from 8:00 to 16:00. Two 16 hours PSG (polysomnography) recording will be done starting at 16:00 on day 1 and day 2. Randomisation is performed if the first recording is of acceptable quality, otherwise the patient is excluded before randomisation. Dexmedetomidine/placebo will be administered during the second recording from 18:00 on day 2 to 6:00 on day 3.Primary endpointImprovement of total sleep time and sleep quality of clinical significance determined by PSG.Secondary endpointsSleep phases determined by PSG. Daytime function and delirium determined by Confusion Assessment Method-ICU. Alertness and wakefulness determined by Richmonde Agitation Sedation Scale. The objective is to compare the effect of dexmedetomidine versus placebo on sleep quality in critical ill mechanically ventilated patients.Ethics and disseminationThe trial investigate the potential benefit of dexmedetomidine on clinically relevant endpoints. If a beneficial effect is shown, this would have a large impact on future treatment of mechanically ventilated critically ill patients. Publication in peer-reviewed journal are plannedand the study has been approved by the National Committee on Health Research Ethics (ID:S-20180214).Trial registration numberEudraCT (2017-001612-11DK) and Danish National Committee on Health Research Ethics (ID:S-20180214). The study related to pre-results.

Project description:Background Abolished circadian rhythm is associated with altered cognitive function, delirium, and as a result increased mortality in critically ill patients, especially in those who are mechanically ventilated. The causes are multifactorial, of which changes in circadian rhythmicity may play a role. Melatonin plays a crucial role as part of the circadian and sleep/wake cycle. Whether sedation effects circadian regulation is unknown. Hence, the objective of this study was to evaluate the melatonin concentration in critically ill patients randomized to sedation or non-sedation and to investigate the correlation with delirium. Methods All patients were included and randomized at the intensive care unit at the hospital of southwest Jutland, Denmark. Seventy-nine patients completed the study (41 sedated and 38 non-sedated). S-melatonin was measured 3 times per day, (03.00, 14.00, and 22.00), for 4 consecutive days in total, starting on the second day upon randomization/intubation. The study was conducted as a sub-study to the NON-SEDA study in which one hundred consecutive patients were randomized to sedation or non-sedation with a daily wake-up call (50 in each arm). Primary outcome: melatonin concentration in sedated vs. non-sedated patients (analyzed using linear regression). Secondary outcome: risk of developing delirium or non-medically induced (NMI) coma in sedated vs. non-sedated patients, assessed by CAM-ICU (Confusion Assessment Method for the Intensive Care Unit) analyzed using logistic regression. Results Melatonin concentration was suppressed in sedated patients compared to the non-sedated. All patients experienced an elevated peak melatonin level early on in the course of their critical illness (p?=?0.01). The risk of delirium or coma (NMI) was significantly lower in the non-sedated group (OR 0.42 CI 0.27; 0.66 p?<?0.0001). No significant relationship between delirium development and suppressed melatonin concentration was established in this study (OR 1.004 p?=?0.29 95% CI 0.997; 1.010). Conclusion Melatonin concentration was suppressed in sedated, critically ill patients, when compared to non-sedated controls and the frequency of delirium was elevated in sedated patients. Trail registration Clinicaltrials.gov (NCT01967680) on October 23, 2013.

Project description:Tailoring interventions to address identified barriers to change may be an effective strategy to implement guidelines and improve practice. However, there is inadequate data to inform the optimal method or level of tailoring. Consequently, we conducted the PERFormance Enhancement of the Canadian nutrition guidelines by a Tailored Implementation Strategy (PERFECTIS) study to determine the feasibility of a multifaceted, interdisciplinary, tailored intervention aimed at improving adherence to critical care nutrition guidelines for the provision of enteral nutrition.A before-after study was conducted in seven ICUs from five hospitals in North America. During a 3-month pre-implementation phase, each ICU completed a nutrition practice audit to identify guideline-practice gaps and a barriers assessment to identify obstacles to practice change. During a one day meeting, the results of the audit and barriers assessment were reviewed and used to develop a site-specific tailored action plan. The tailored action plan was then implemented over a 12-month period that included bi-monthly progress meetings. Compliance with the tailored action plan was determined by the proportion of items in the action plan that was completely implemented. We examined acceptability of the intervention through staff responses to an evaluation questionnaire. In addition, the nutrition practice audit and barriers survey were repeated at the end of the implementation phase to determine changes in barriers and nutrition practices.All five sites successfully completed all aspects of the study. However, their ability to fully implement all of their developed action plans varied from 14% to 75% compliance. Nurses, on average, rated the study-related activities and resources as 'somewhat useful' and a third of respondents 'agreed' or 'strongly agreed' that their nutrition practice had changed as a result of the intervention. We observed a statistically significant 10% (Site range -4.3% to -26.0%) decrease in overall barriers score, and a non-significant 6% (Site range -1.5% to 17.9%) and 4% (-8.3% to 18.2%) increase in the adequacy of total nutrition from calories and protein, respectively.The multifaceted tailored intervention appears to be feasible but further refinement is warranted prior to testing the effectiveness of the approach on a larger scale.ClinicalTrials.gov NCT01168128. Registered 21 July 2010.

Project description:Sleep is a biological mandate with an integral role in optimizing functions that maintain psychological and physical health. During critical illness, however, sleep may be disrupted at best and elusive at worst. Sleep improvement efforts and research endeavors evaluating interventions to improve sleep in critically ill adults are hampered by limited methods available to measure sleep in this setting. This narrative review summarizes available modalities for sleep assessment in the ICU, describes new ICU sleep assessment methods under development, and highlights features of the ideal ICU sleep measurement tool.Data sourcesThe most relevant literature and author experiences were assessed for inclusion from PubMed and textbooks.Study selectionThe authors selected studies for inclusion by consensus.Data extractionThe authors reviewed each study and selected appropriate data for inclusion by consensus.Data synthesisCurrently available tools to measure sleep in critically ill adults have important flaws. Subjective measurements are limited by recall bias, the inability of many patients to communicate, and poorly correlate with objective measures when completed by surrogates. Actigraphy does not consider the effects of sedating medications or myopathy leading to an over estimation of sleep time. Polysomnography, the gold standard for sleep assessment, is limited by interpretation issues and practical application concerns. Single and multiple channel electroencephalogram devices offer real-time physiologic data and are more practical to use than polysomnography but are limited by the scope of sleep-specific information they can measure and poorly characterize the circadian system.ConclusionsA measurement tool that offers real-time sleep and circadian assessment and is practical for broad application in the ICU does not exist. Newer sleep assessment devices have shown promise in measuring physiologic data in real time; when used in combination with other assessment modalities, and analyzed by computational techniques, they may revolutionize sleep monitoring in the ICU.

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Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial.

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Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial.

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