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Lightman and Conway-Campbell review findings showing that, superimposed on its well-known circadian rhythm, the HPA axis shows ultradian, oscillatory activity. They describe how the resulting pulsatile release of glucocorticoids maintains optimal responsiveness of the HPA axis and the brain processes regulated by these hormones. The classical concept of hypothalamus–pituitary–adrenal (HPA) homeostasis comprises a feedback system within which circulating levels of glucocorticoid hormones maintain the brain and body in an optimal steady state. However, studies involving new techniques for investigating the real-time dynamics of both glucocorticoid hormones and glucocorticoid receptor function paint a different picture — namely, of continuous dynamic equilibration throughout this neuroendocrine system. This dynamic state is dictated by feedforward and feedback regulatory loops and by stochastic interactions at the level of DNA binding. We propose that this continuous oscillatory activity is crucial for optimal responsiveness of glucocorticoid-sensitive neural processes.

The development of real-time fMRI has enabled us to watch our own brain in action 'live'. Christopher deCharms provides an overview of current and potential applications of this technique, including its use as a brain–machine interface and in learned control over brain activation. For centuries people have aspired to understand and control the functions of the mind and brain. It has now become possible to image the functioning of the human brain in real time using functional MRI (fMRI), and thereby to access both sides of the mind–brain interface — subjective experience (that is, one's mind) and objective observations (that is, external, quantitative measurements of one's brain activity) — simultaneously. Developments in neuroimaging are now being translated into many new potential practical applications, including the reading of brain states, brain–computer interfaces, communicating with locked-in patients, lie detection, and learning control over brain activation to modulate cognition or even treat disease.

Twenty-two children with autism spectrum disorders who had not responded to supported behaviour management strategies for severe dysomnias entered a double blind, randomised, controlled crossover trial involving 3 months of placebo versus 3 months of melatonin to a maximum dose of 10 mg. 17 children completed the study. There were no significant differences between sleep variables at baseline. Melatonin significantly improved sleep latency (by an average of 47 min) and total sleep (by an average of 52 min) compared to placebo, but not number of night wakenings. The side effect profile was low and not significantly different between the two arms.

Suvorexant (Belsomra ® ), a first-in-class, orally active dual orexin-1 receptor and orexin-2 receptor antagonist, has been developed by Merck for the treatment of insomnia. Variations in the levels of the neuropeptides orexin A and orexin B have been linked to circadian rhythms and wakefulness. Orexin-producing neurons in the lateral hypothalamus regulate wakefulness by signalling through orexin receptors. Blockade of orexin receptors is known to promote sleep. Suvorexant was approved in the US in August 2014 for the treatment of adults with sleep onset and/or sleep maintenance insomnia. The drug is also preregistration in Japan, with approval submissions planned for other countries worldwide for this indication. This article summarizes the milestones in the development of suvorexant leading to this first approval for insomnia.

Ketamine is widely used as a procedural sedation agent in pediatrics, where its safety and efficacy are supported by numerous studies. Emergency physicians use ketamine infrequently in adults, as it is believed to have a more significant side effect profile in this population. However, adult data on ketamine use in the emergency medicine literature are sparse. Our objective was to determine ketamine's adverse effect profile in adults when used for procedural sedation. We performed a literature review based on adverse effect research methodology recommendations. PubMed, EMBASE, TOXNET, and a variety of specialized databases were queried without regard to publication date or language. Experts were contacted to locate additional data. Inclusion criteria included adult study; ketamine used to facilitate the performance of painful procedures; dose of at least 1 mg/kg intravenous or at least 2 mg/kg intramuscular; original data and adverse events reported; spontaneously breathing patient, and no continuous cotherapies. Studies that met inclusion criteria were abstracted onto structured forms and their results qualitatively summarized. Of the 5512 unique citations that were evaluated, 87 met criteria for inclusion. Most studies were performed in the 1970s and published in the anesthesia literature. Contexts, end points, and methodological quality varied widely across studies. Ketamine reliably produces conditions that facilitate the performance of painful procedures. Pharyngeal reflexes are generally preserved and cardiovascular tone stimulated, including a rise in blood pressure and myocardial oxygen demand. Laryngospasm and airway obstruction are reported, and though ketamine is a respiratory stimulant, a brief period of apnea around the time of injection is common. Reports of significant cardiorespiratory adverse events are rare, despite ketamine's frequent use in austere, poorly monitored settings. Dysphoric emergence phenomena occur in 10% to 20% of cases; sedating medications are effective in preventing and managing these reactions. When ketamine is used for procedural sedation in adults, emergence phenomena occur in 10% to 20% of patients. Although providers must be prepared to recognize and manage airway obstruction, cardiorespiratory adverse events are rare and typically do not affect outcomes.

Purpose To access the effect of propofol administration on sleep quality in critically ill patients ventilated on assisted modes. Methods This was a randomized crossover physiological study conducted in an adult ICU at a tertiary hospital. Two nights’ polysomnography was performed in mechanically ventilated critically ill patients with and without propofol infusion, while respiratory variables were continuously recorded. Arterial blood gasses were measured in the beginning and at the end of the study. The rate of propofol infusion was adjusted to maintain a sedation level of 3 on the Ramsay scale. Sleep architecture was analyzed manually using predetermined criteria. Patient–ventilator asynchrony was evaluated breath by breath using the flow–time and airway pressure–time waveforms. Results Twelve patients were studied. Respiratory variables, patient–ventilator asynchrony, and arterial blood gasses did not differ between experimental conditions. With or without propofol all patients demonstrated abnormal sleep architecture, expressed by lack of sequential progression through sleep stages and their abnormal distribution. Sleep efficiency, sleep fragmentation, and sleep stage distribution (1, 2, and slow wave) did not differ with or without propofol. Compared to without propofol, both the number of patients exhibiting REM sleep ( p  = 0.02) and the percentage of REM sleep ( p  = 0.04) decreased significantly with propofol. Conclusions In critically ill patients ventilated on assisted modes, propofol administration to achieve the recommended level of sedation suppresses the REM sleep stage and further worsens the poor sleep quality of these patients.

Purpose Hypertriglyceridemia (hyperTG) is common among intensive care unit (ICU) patients, but knowledge about hyperTG risk factors is scarce. The present study aims to identify risk factors favoring its development in patients requiring prolonged ICU treatment. Methods Prospective observational study in the medicosurgical ICU of a university teaching hospital. All consecutive patients staying ≥4 days were enrolled. Potential risk factors were recorded: pathology, energy intake, amount and type of nutritional lipids, intake of propofol, glucose intake, laboratory parameters, and drugs. Triglyceride (TG) levels were assessed three times weekly. Statistics was based on two-way analysis of variance (ANOVA) and linear regression with potential risk factors. Results Out of 1,301 consecutive admissions, 220 patients were eligible, of whom 99 (45 %) presented hyperTG (triglycerides >2 mmol/L). HyperTG patients were younger, heavier, with more brain injury and multiple trauma. Intake of propofol (mg/kg/h) and lipids’ propofol had the highest correlation with plasma TG ( r 2  = 0.28 and 0.26, respectively, both p  < 0.001). Infection and inflammation were associated with development of hyperTG [C-reactive protein (CRP), r 2  = 0.19, p  = 0.004]. No strong association could be found with nutritional lipids or other risk factors. Outcome was similar in normo- and hyperTG patients. Conclusions HyperTG is frequent in the ICU but is not associated with adverse outcome. Propofol and accompanying lipid emulsion are the strongest risk factors. Our results suggest that plasma TG should be monitored at least twice weekly in patients on propofol. The clinical consequences of propofol-related hyperTG should be investigated in further studies.

As most critically ill or injured patients will require some degree of sedation, the goal of this paper was to comprehensively review the literature associated with use of sedative agents in the intensive care unit (ICU). The first and selected latter portions of this article present a narrative overview of the shifting paradigm in ICU sedation practices, indications for uninterrupted or prolonged ICU sedation, and the pharmacology of sedative agents. In the second portion, we conducted a structured, although not entirely systematic, review of the available evidence associated with use of alternative sedative agents in critically ill or injured adults. Data sources for this review were derived by searching OVID MEDLINE and PubMed from their first available date until May 2012 for relevant randomized controlled trials (RCTs), systematic reviews and/or meta-analyses and economic evaluations. Advances in the technology of mechanical ventilation have permitted clinicians to limit the use of sedation among the critically ill through daily sedative interruptions or other means. These practices have been reported to result in improved mortality, a decreased length of ICU and hospital stay and a lower risk of drug-associated delirium. However, in some cases, prolonged or uninterrupted sedation may still be indicated, such as when patients develop intracranial hypertension following traumatic brain injury. The pharmacokinetics of sedative agents have clinical importance and may be altered by critical illness or injury, co-morbid conditions and/or drug-drug interactions. Although use of validated sedation scales to monitor depth of sedation is likely to reduce adverse events, they have no utility for patients receiving neuromuscular receptor blocking agents. Depth of sedation monitoring devices such as the Bispectral Index (BIS©) also have limitations. Among existing RCTs, no sedative agent has been reported to improve the risk of mortality among the critically ill or injured. Moreover, although propofol may be associated with a shorter time to tracheal extubation and recovery from sedation than midazolam, the risk of hypertriglyceridaemia and hypotension is higher with propofol. Despite dexmedetomidine being linked with a lower risk of drug-associated delirium than alternative sedative agents, this drug increases risk of bradycardia and hypotension. Among adults with severe traumatic brain injury, there are insufficient data to suggest that any single sedative agent decreases the risk of subsequent poor neurological outcomes or mortality. The lack of examination of confounders, including the type of healthcare system in which the investigation was conducted, is a major limitation of existing pharmacoeconomic analyses, which likely limits generalizability of their results.

PurposePediatric sedation is commonly required to obtain high-quality images in magnetic resonance imaging (MRI). We performed a systematic review and meta-analysis to assess the effects of dexmedetomidine sedation for MRI in children.MethodsA systematic review was conducted to find all randomized controlled trials concerning dexmedetomidine sedation for MRI in children. We searched databases using the Ovid platform in the Cochrane Controlled Trials Register, MEDLINE, and EMBASE. This study was registered in the PROSPERO database: CRD42020198368.ResultsSeven studies and 753 participants were included. Dexmedetomidine sedation showed a significantly delayed onset time [weighted mean differences (WMD) = 8.13 min, 95% confidence interval (CI) 4.64 to 11.63, I2 = 98%] and recovery time (WMD = 5.22 min, 95% CI 0.35 to 10.09, I2 = 92%) compared to propofol, ketamine, and midazolam sedation. There was no difference in quality of sedation [risk ratio (RR) = 1.25, 95% CI 0.92 to 1.69, I2 = 89%], or incidence of sedation failure (RR = 1.39, 95% CI 0.53 to 3.66, I2 = 83%) between groups. Although a significantly decreased heart rate (WMD = − 17.34 beats/minute, 95% CI − 22.42 to − 12.26, I2 = 96%) was observed, bradycardia that required treatment was not increased (RR = 8.00, 95% CI 1.02 to 62.64, I2 = 0%). Dexmedetomidine sedation had a lower incidence of desaturation events (RR = 0.42, 95% CI 0.20 to 0.86, I2 = 4%). However, there was no difference in incidence of postoperative vomiting (RR = 0.42, 95% CI 0.15 to 1.17, I2 = 17%) between groups.ConclusionsDexmedetomidine sedation provided a similar sedation quality with a reduced incidence of desaturation events. However, the delayed onset and recovery times were drawbacks. The clinical significance of bradycardia is considered to be low. GRADE assessment revealed the quality of the evidence in this meta-analysis ranged from very low to moderate.