The role of melatonin and melatonin receptor agonist in the prevention of sleep disturbances and delirium in intensive care unit - a clinical review.

AIM: The intensive care unit (ICU) environment contributes to the development of sleep disturbances. Sleep disturbances, sleep fragmentation, and multiple awakening episodes lead to the circadian rhythm disorder, which increases the risk of delirium. Melatonin and melatonin receptor agonist is widely used agent in the therapy of sleep disturbances. However, there is also some for its efficacy in ICU delirium. Enteral melatonin and ramelteon supplementation eliminates (partially) the delirium inducing factors. METHODS: PubMed/MEDLINE, OVID, Embase, Cochrane Library, and Web of Science databases were searched using adequate key words. We reviewed the literature on the role of melatonin and ramelteon in the prevention of sleep disturbances and delirium in intensive care units and analysed the methods of melatonin therapy in an ICU setting. Review followed the PRISMA statement. A review written protocol was not drafted. RESULTS: Originally 380 studies were searched in five scientific databases. After rejecting the duplicate results, 125 results were obtained. Finally, 10 scientific studies were included in the review. In selected articles, the leading topics analysed were the role of melatonin and ramelteon in the prevention of delirium and sleep disorders. In addition, the noted effect of therapy with these agents on reducing the ventilation time of mechanical time and the demand for psychoactive substances in the ICU environment. CONCLUSION: Reduction of either the incidence or the severity of delirium course is possible by eliminating its risk factors. Risk factors are directly related to sleep disorders. To reduce the problem, therefore, a holistic approach to the source is necessary. The efficacy of melatonin therapy in an ICU setting requires confirmation in studies including a greater number of participants as the impact of melatonin on these factors is yet to be fully elucidated. However, the prognosis is predictive because this concept provides patients with a minimally invasive and natural form of therapy.

Internal clock and the surgical ICU patient.

PURPOSE OF REVIEW: The alteration of circadian rhythms in the postoperative period has been demonstrated to influence the outcomes. With this narrative review we would revise how anesthesia, surgery and intensive care can interfere with the circadian clock, how this could impact on the postsurgical period and how to limit the disruption of the internal clock. RECENT FINDINGS: Anesthesia affects the clock in relation to the day-time administration and the type of anesthetics, N-methyl-D-aspartate receptor antagonists or gamma-aminobutyric acid receptors agonists. Surgery causes stress and trauma with consequent alteration in the circadian release of cortisol, cytokines and melatonin. ICU represents a further challenge for the patient internal clock because of sedation, immobility, mechanical ventilation and alarms noise. SUMMARY: The synergic effect of anesthesia, surgery and postoperative intensive care on circadian rhythms require a careful approach to the patient considering a role for therapies and interventions aimed to re-establish the normal circadian rhythms. Over time, approach like the Awakening and Breathing Coordination, Delirium Monitoring and Management, Early Mobility and Family engagement and empowerment bundle can implement the clinical practice.

The protective effect of cycloastragenol on aging mouse circadian rhythmic disorder induced by d-galactose.

Aging process in mammals is associated with a decline in amplitude and a long period of circadian behaviors which are regulated by a central circadian regulator in the suprachiasmatic nucleus (SCN) and local oscillators in peripheral tissues. It is unclear whether enhancing clock function can retard aging. Using fibroblasts expressing per2::lucSV and senescent cells, we revealed cycloastragenol (CAG), a natural aglycone derivative from astragaloside IV, as a clock amplitude enhancing small molecule. CAG could activate telomerase to antiaging, but no reports focused on its effects on circadian rhythm disorders in aging mice. Here we analyze the potential effects of CAG on d-galactose-induced aging mice on the circadian behavior and expression of clock genes. For this purpose, CAG (20 mg/kg orally), was administered daily to d-galactose (150 mg/kg, subcutaneous) mice model of aging for 6 weeks. An actogram analysis of free-running activity of these mice showed that CAG significantly enhances the locomotor activity. We further found that CAG increase expressions of per2 and bmal1 genes in liver and kidney of aging mouse. Furthermore, CAG enhanced clock protein BMAL1 and PER2 levels in aging mouse liver and SCN. Our results indicated that the CAG could restore the behavior of circadian rhythm in aging mice induced by d-galactose. These data of present study suggested that CAG could be used as a novel therapeutic strategy for the treatment of age-related circadian rhythm disruption.

Circadian rhythms and the molecular clock in cardiovascular biology and disease.

The Earth turns on its axis every 24 h; almost all life on the planet has a mechanism - circadian rhythmicity - to anticipate the daily changes caused by this rotation. The molecular clocks that control circadian rhythms are being revealed as important regulators of physiology and disease. In humans, circadian rhythms have been studied extensively in the cardiovascular system. Many cardiovascular functions, such as endothelial function, thrombus formation, blood pressure and heart rate, are now known to be regulated by the circadian clock. Additionally, the onset of acute myocardial infarction, stroke, arrhythmias and other adverse cardiovascular events show circadian rhythmicity. In this Review, we summarize the role of the circadian clock in all major cardiovascular cell types and organs. Second, we discuss the role of circadian rhythms in cardiovascular physiology and disease. Finally, we postulate how circadian rhythms can serve as a therapeutic target by exploiting or altering molecular time to improve existing therapies and develop novel ones.

[Surgery and circadian disturbances].

Circadian disturbances in relation to surgery have been extensively researched through the latest couple of decades. Surgery has been shown to affect melatonin rhythm, core body temperature, cortisol rhythm, activity rhythm and sleep in the perioperative period. The changes translate into both subjective patients' discomfort, prolonging convalescence and clinical effects on morbidity and mortality. Future research should be performed to show effect across different surgical procedures and to investigate potential interventions to alleviate harmful effects of circadian disturbances.

Dietary supplementation with essence of chicken enhances daily oscillations in plasma glucocorticoid levels and behavioral adaptation to the phase-shifted environmental light-dark cycle in mice.

Maintenance of circadian rhythms is essential to many aspects of human health, including metabolism and neurological and psychiatric well-being. Chronic disruption of circadian clock function is implicated in increasing the risk of metabolic syndrome, cardiovascular events and development of cancers. However, there are little approaches to reinforce the function of circadian clock for prevention of these diseases. Essence of Chicken (EC) is a nutritional supplement that is traditionally made by extracting water soluble substances derived from cooking the whole chicken. In this study, we found that dietary supplementation with EC enhanced circadian oscillation of glucocorticoid secretion in mice, and this was accompanied by enhancement of circadian oscillation in the adrenal expression of steroidogenic acute regulatory (StAR) protein that mediates the rate-limiting step of glucocorticoid synthesis. Furthermore, EC facilitated re-entrainment of behavioral rhythm in mice when phase of the light-dark cycle was suddenly advanced. These results suggest that intake of EC has enhancement effect on circadian clock function in mice, which may contribute to sustain health and also offer new preventive strategies against circadian-related diseases.

Food in synchrony with melatonin and corticosterone relieves constant light disturbed metabolism.

Circadian disruption is associated with metabolic disturbances such as hepatic steatosis (HS), obesity and type 2 diabetes. We hypothesized that HS, resulting from constant light (LL) exposure is due to an inconsistency between signals related to food intake and endocrine-driven suprachiasmatic nucleus (SCN) outputs. Indeed, exposing rats to LL induced locomotor, food intake and hormone arrhythmicity together with the development of HS. We investigated whether providing temporal signals such as 12-h food availability or driving a corticosterone plus melatonin rhythm could restore rhythmicity and prevent the metabolic disturbances under LL conditions in male rats. Discrete metabolic improvements under these separate treatments stimulated us to investigate whether the combination of hormone treatment together with mealtime restriction (12-h food during four weeks) could prevent the metabolic alterations. LL exposed arrhythmic rats, received daily administration of corticosterone (2.5 µg/kg) and melatonin (2.5 mg/kg) in synchrony or out of synchrony with their 12-h meal. HS and other metabolic alterations were importantly ameliorated in LL-exposed rats receiving hormonal treatment in synchrony with 12-h restricted mealtime, while treatment out of phase with meal time did not. Interestingly, liver bile acids, a major indication for HS, were only normalized when animals received hormones in synchrony with food indicating that disrupted bile acid metabolism might be an important mechanism for the HS induction under LL conditions. We conclude that food-elicited signals, as well as hormonal signals, are necessary for liver synchronization and that HS arises when there is conflict between food intake and the normal pattern of melatonin and corticosterone.

Nutrition, movement and sleep behaviours: their interactions in pathways to obesity and cardiometabolic diseases.

Among the multitude of dietary and lifestyle behaviours that have been proposed to contribute to the obesity epidemic, those that have generated considerable research scrutiny in the past decade are centred upon sleep behaviours, sedentary behaviours (sitting or lying while awake) and diminished low-level physical activities of everyday life, with each category of behaviours apparently presenting an independent risk for obesity and/or cardiometabolic diseases. These behaviours are highly complex, operate in synergy with each other, disrupt the link between regulation of the circadian clock and metabolic physiology and impact on various components of daily energy expenditure and feeding behaviours to promote obesity and hinder the outcome of obesity therapy. As such, this behavioural triad (nutrition, movement and sleep) presents plenty of scope for intervention and optimization in the context of body weight regulation and lifestyle-related disease prevention. It is against this background that recent advances relevant to the theme of 'Nutrition, Movement & Sleep Behaviors: their interactions in pathways to obesity and cardiometabolic diseases' are addressed in this overview and the nine review articles in this supplement reporting the proceedings of the 8th Fribourg Obesity Research Conference.

Dynamic light application therapy to reduce the incidence and duration of delirium in intensive-care patients: a randomised controlled trial.

BACKGROUND: Disturbed circadian rhythm is a potentially modifiable cause of delirium among patients in intensive-care units (ICUs). Bright-light therapy in the daytime can realign circadian rhythm and reduce the incidence of delirium. We investigated whether a high-intensity dynamic light application (DLA) would reduce ICU-acquired delirium. METHODS: This was a randomised, controlled, single-centre trial of medical and surgical patients admitted to the ICU of a teaching hospital in the Netherlands. Patients older than 18 years, expected to stay in the ICU longer than 24 h and who could be assessed for delirium were randomised to DLA or normal lighting (control), according to a computer-generated schedule. The DLA was administered through ceiling-mounted fluorescent tubes that delivered bluish-white light up to 1700 lux between 0900 h and 1600 h, except for 1130-1330 h, when the light was dimmed to 300 lux. The light could only be turned off centrally by investigators. Control light levels were 300 lux and lights could be turned on and off from inside the room. The primary endpoint was the cumulative incidence of ICU-acquired delirium. Analyses were by intention to treat and per protocol. The study was terminated prematurely after an interim analysis for futility. This study is registered with Clinicaltrials.gov, number NCT01274819. FINDINGS: Between July 1, 2011, and Sept 9, 2013, 734 patients were enrolled, 361 in the DLA group and 373 in the control group. Delirium occurred in 137 (38%) of 361 DLA patients and 123 (33%) of 373 control patients (odds ratio 1·24, 95% CI 0·92-1·68, p=0·16). No adverse events were noted in patients or staff. INTERPRETATION: DLA as a single intervention does not reduce the cumulative incidence of delirium. Bright-light therapy should be assessed as part of a multicomponent strategy. FUNDING: None.

Disruption of running activity rhythm following restricted feeding in female mice: Preventive effects of antidepressants.

Biological rhythms are critical in the etiology of mood disorders; therefore, effective mood disorder treatments should address rhythm disturbances. Among the variables synchronized with the light-dark cycle, spontaneous activity in rodents is useful for investigating circadian rhythms. However, previous studies have focused only on the increase of wheel-running activity under restricted feeding conditions, while little information is available on circadian rhythm of running activity. In this study, chronometrical analysis was used to assess whether circadian rhythms during wheel-running are altered by restricted feeding and affected by antidepressant drugs. Wheel revolutions were automatically recorded and analyzed using cosinor-rhythmometry in 8-week old ICR albino mice. When feeding was restricted to 1 h per day (21:00-22:00), wheel-running rhythms were reliably disrupted. Female mice exhibited marked alterations in the pattern and extent of wheel-running beginning on day 1. Subchronic treatment with imipramine or paroxetine, as well as tandospirone and (-)-DOI, prevented wheel-running rhythm disruption. Thus, altering the circadian activity rhythms of female mice on a 1-h feeding schedule may be useful for investigating disturbances in biological rhythms.

Chronic consumption of dietary proanthocyanidins modulates peripheral clocks in healthy and obese rats.

Circadian rhythm plays an important role in maintaining homeostasis, and its disruption increases the risk of developing metabolic syndrome. Circadian rhythm is maintained by a central clock in the hypothalamus that is entrained by light, but circadian clocks are also present in peripheral tissues. These peripheral clocks are trained by other cues, such as diet. The aim of this study was to determine whether proanthocyanidins, the most abundant polyphenols in the human diet, modulate the expression of clock and clock-controlled genes in the liver, gut and mesenteric white adipose tissue (mWAT) in healthy and obese rats. Grape seed proanthocyanidin extracts (GSPEs) were administered for 21 days at 5, 25 or 50 mg GSPE/kg body weight in healthy rats and 25 mg GSPE/kg body weight in rats with diet-induced obesity. In healthy animals, GSPE administration led to the overexpression of core clock genes in a positive dose-dependent manner. Moreover, the acetylated BMAL1 protein ratio increased with the same pattern in the liver and mWAT. With regards to clock-controlled genes, Per2 was also overexpressed, whereas Rev-erbα and RORα were repressed in a negative dose-dependent manner. Diet-induced obesity always resulted in the overexpression of some core clock and clock-related genes, although the particular gene affected was tissue specific. GSPE administration counteracted disturbances in the clock genes in the liver and gut but was less effective in normalizing the clock gene disruption in WAT. In conclusion, proanthocyanidins have the capacity to modulate peripheral molecular clocks in both healthy and obese states.

Melatonin and the circadian system: contributions to successful female reproduction.

OBJECTIVE: To summarize the role of melatonin and circadian rhythms in determining optimal female reproductive physiology, especially at the peripheral level. DESIGN: Databases were searched for the related English-language literature published up to March 1, 2014. Only papers in peer-reviewed journals are cited. SETTING: Not applicable. PATIENT(S): Not applicable. INTERVENTION(S): Melatonin treatment, alterations of the normal light:dark cycle and light exposure at night. MAIN OUTCOME MEASURE(S): Melatonin levels in the blood and in the ovarian follicular fluid and melatonin synthesis, oxidative damage and circadian rhythm disturbances in peripheral reproductive organs. RESULT(S): The central circadian regulatory system is located in the suprachiasmatic nucleus (SCN). The output of this master clock is synchronized to 24 hours by the prevailing light-dark cycle. The SCN regulates rhythms in peripheral cells via the autonomic nervous system and it sends a neural message to the pineal gland where it controls the cyclic production of melatonin; after its release, the melatonin rhythm strengthens peripheral oscillators. Melatonin is also produced in the peripheral reproductive organs, including granulosa cells, the cumulus oophorus, and the oocyte. These cells, along with the blood, may contribute melatonin to the follicular fluid, which has melatonin levels higher than those in the blood. Melatonin is a powerful free radical scavenger and protects the oocyte from oxidative stress, especially at the time of ovulation. The cyclic levels of melatonin in the blood pass through the placenta and aid in the organization of the fetal SCN. In the absence of this synchronizing effect, the offspring may exhibit neurobehavioral deficits. Also, melatonin protects the developing fetus from oxidative stress. Melatonin produced in the placenta likewise may preserve the optimal function of this organ. CONCLUSION(S): Both stable circadian rhythms and cyclic melatonin availability are critical for optimal ovarian physiology and placental function. Because light exposure after darkness onset at night disrupts the master circadian clock and suppresses elevated nocturnal melatonin levels, light at night should be avoided.

The interactive effect of dietary water-soluble vitamin levels on the depression of gonadal development in growing male rats kept under disturbed daily rhythm.

The purpose of this study was to clarify the effects of nutrients on the gonadal development of male rats kept under constant darkness as a model of disturbed daily rhythm. In the present study we examined the effects of nine water-soluble vitamins. We selected 7 water-soluble vitamins (choline, nicotinic acid (NA), pantothenic acid (PA), vitamin B6 (VB6), vitamin B1 (VB1), vitamin B2 (VB2) and folic acid (FA)) as experimental factors for the first experiment (Ex. 1) and biotin and vitamin B12 (VB12) as experimental factors for the second experiment (Ex. 2). The dietary content of these vitamins was normal or six times the normal content. Lighting condition (L.C.) was also added as a factor. Four-week-old male rats (Fischer 344 strain) were kept under constant darkness or normal lighting (12-h light/dark cycle) for 4 wk. The depression of gonadal development in the constant darkness groups (D-groups) was shown. The L.C., PA, VB6 and VB1 influenced testes development, and these three vitamins had interactions with L.C. Among the normal lighting groups (N-groups), the highest value for testes weight was observed under the normal-PA, high-VB6 and high-B1 diet; on the other hand, among the D-groups, it was observed under the high-PA, normal-VB6 and normal-VB1 diet. The results showed that the depression of gonadal development in rats kept under disturbed daily rhythm was improved by getting a high amount of PA and normal amount of VB6 and VB1.

Effectiveness of a red-visor cap for preventing light-induced melatonin suppression during simulated night work.

Bright light at night improves the alertness of night workers. Melatonin suppression induced by light at night is, however, reported to be a possible risk factor for breast cancer. Short-wavelength light has a strong impact on melatonin suppression. A red-visor cap can cut the short-wavelength light from the upper visual field selectively with no adverse effects on visibility. The purpose of this study was to investigate the effects of a red-visor cap on light-induced melatonin suppression, performance, and sleepiness at night. Eleven healthy young male adults (mean age: 21.2±0.9 yr) volunteered to participate in this study. On the first day, the subjects spent time in dim light (<15 lx) from 20:00 to 03:00 to measure baseline data of nocturnal salivary melatonin concentration. On the second day, the subjects were exposed to light for four hours from 23:00 to 03:00 with a nonvisor cap (500 lx), red-visor cap (approx. 160 lx) and blue-visor cap (approx. 160 lx). Subjective sleepiness and performance of a psychomotor vigilance task (PVT) were also measured on the second day. Compared to salivary melatonin concentration under dim light, the decrease in melatonin concentration was significant in a nonvisor cap condition but was not significant in a red-visor cap condition. The percentages of melatonin suppression in the nonvisor cap and red-visor cap conditions at 4 hours after exposure to light were 52.6±22.4% and 7.7±3.3%, respectively. The red-visor cap had no adverse effect on performance of the PVT, brightness and visual comfort, though it tended to increase subjective sleepiness. These results suggest that a red-visor cap is effective in preventing melatonin suppression with no adverse effects on vigilance performance, brightness and visibility.

Is circadian rhythm disruption important in obsessive-compulsive disorder (OCD)? A case of successful augmentation with agomelatine for the treatment of OCD.

The main augmentation strategy in the treatment of obsessive-compulsive disorder (OCD) is the addition of low-dose dopamine antagonists, such as risperidone. However, the development of additional pharmacological therapeutics is necessary because some patients remain refractory to these strategies. In the present report, we describe an adult male patient with clomipramine treatment-resistant OCD who did not respond to augmentation with risperidone and aripiprazole but who showed clinical improvement with agomelatine. The effect of agomelatine in resynchronizing circadian rhythms may demonstrate the importance of the circadian rhythm disruption observed in OCD. Moreover, the regulation of the serotoninergic system is circadian in nature, and the resynchronization of the serotoninergic system may regulate serotoninergic dysfunction, a major factor in OCD.

Crying babies, tired mothers: what do we know? A systematic review.

OBJECTIVE: to synthesise the evidence on the interconnectedness of infant crying and maternal tiredness in the postpartum period, both from quantitative as well as from qualitative studies. METHODS: a systematic review was conducted including studies in English, French and German published from 1980 to 2007. Studies were included in the systematic review if they had extractable data on infant crying as well as maternal tiredness in the period of 0-3 months post partum. Of 100 retrieved publications, 10 met these criteria. FINDINGS: evidence from this review indicated that the amount of infant crying during the first three months postpartum is associated with the experience of tiredness and fatigue in new mothers. Significant associations were found in five of six quantitative studies. The four identified qualitative studies describe how infant crying disrupts new mothers' circadian rhythms, reducing opportunities to rest and exacerbating tiredness. Incremental exhaustion diminished parents' ability to concentrate, raising the fear of harming their children, triggering depressive symptoms and burdening parent-child interaction. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: if healthcare professionals are to address the prominent concerns of parents caring for a neonate, it is essential to review current care practices and tailor them to maternal and infant needs. A care strategy alleviating the burden of infant crying and maternal fatigue has the potential to strengthen family health from the earliest stage.

Cronobiología y vuelo transmeridiano: ritmos circadianos y jet lag / No disponible

Este trabajo pretende una aproximación al estudio de los efectos del vuelo transmeridiano en los ritmos circadianos. Se hace una primera introducción a los mismos, describiendo a continuación la alteración circadiana propia de los vuelos que atraviesan varios usos horarios (síndrome del jet lag), distinguiendo entre los viajes hacia el Oeste o hacia el Este, pues estos últimos, a igualdad de cambio horario, producen una alteración de mayor magnitud con respecto a los que se dirigen hacia el Oeste, en los cuales la adaptación se realiza con menor dificultad. Se aborda también muy someramente la prevención y el tratamiento del jet lag. Es un estudio mixto: en parte es una revisión sobre el síndrome del Jet lag pero, fundamentalmente, consiste en una exposición de los conocimientos personales sobre la materia, por lo que la estructura y el fondo de este trabajo se acerca, en parte, al tipo editorial pero sin olvidar del todo la sistemática de las revisiones. Por motivos de espacio se realiza un abordaje muy resumido de la materia a tratar. Dado que sobre el Jet lag se puede aportar una cantidad de información muy extensa, no queda más remedio que obviar algunos temas relacionados con el mismo, así como reducir otros a la mínima expresión. Tal es el caso de la melatonina, hormona cuya intervención en los biorritmos circadianos tiene una destacada importancia, pero que aquí, por los aducidos motivos de espacio, no se procede a dedicarla el apartado especial que merece, sino que sólo se hará mención a ella puntualmente en el apartado de la introducción a los ritmos circadianos, y en el contexto de la prevención y del tratamiento del Jet lag. Por último, se ha intentado ag regar un componente divulgativo, diluido a lo largo de este trabajo - especialmente en los apartados de prevención y tratamiento - pues no olvidemos que el jet lag no es sólo una patología padecida por los profesionales del vuelo transmeridiano, sino también por el pasaje. No es fácil combinar el rigor científico con la actitud divulgadora, pero considero que dicho empeño es, o debería ser, inherente a la profesión médica en todas sus especialidades por el importante papel que el médico representa en la educación sanitaria de la población a través del “día a día” de su labor asistencial. Además, no olvidemos la Ley 41/2002 de autonomía del paciente, en la cual se hace especial énfasis, entre otras muchas cuestiones, en el derecho del paciente a la información (con las salvedades y límites que se recogen y admiten en la propia ley 41/02 y en otras). Una buena medida en Medicina Preventiva Aeronáutica sería repartir entre el pasaje y la tripulación de los vuelos que atraviesan varios usos horarios, folletos con breves consejos sobre cómo afrontar el Jet Lag (prevención, tratamiento, etc.) (AU)

No disponible