Circadian rhythms in humans are biological rhythms that regulate various physiological processes within a 24-hour time frame. Critical illness can disrupt the circadian rhythm, as can environmental and clinical factors, including altered light exposure, organ replacement therapies, disrupted sleep-wake cycles, noise, continuous enteral feeding, immobility, and therapeutic interventions. Nonpharmacological interventions, controlling the ICU environment, and pharmacological treatments are among the treatment strategies for circadian disruption. Nutrition establishes biological rhythms in metabolically active peripheral tissues and organs through appropriate synchronization with endocrine signals. Therefore, adhering to a feeding schedule based on the biological clock, a concept known as "chrononutrition," appears to be vitally important for regulating peripheral clocks. Chrononutritional approaches, such as intermittent enteral feeding that includes overnight fasting and consideration of macronutrient composition in enteral solutions, could potentially restore circadian health by resetting peripheral clocks. However, due to the lack of evidence, further studies on the effect of chrononutrition on clinical outcomes in critical illness are needed. The purpose of this review was to discuss the role of chrononutrition in regulating biological rhythms in critical illness, and its impact on clinical outcomes.

Circadian rhythms are critical to coordinating body processes to external environmental cues, such as light and feeding, to ensure efficiency and maintain optimal health. These rhythms are controlled by 'clock' transcription factors, such as Clock, Bmal1, Per1/2, Cry1/2, and Rev-erbs, which are present in almost every tissue. In modern society, disruptions to normal circadian rhythms are increasingly prevalent due to extended lighting, shift work, and long-distance travel. These disruptions misalign external cues to body processes and contribute to diseases such as obesity and non-alcoholic fatty liver disease. They also exacerbate pre-existing health issues, such as depression and inflammatory bowel disease. The normal inflammatory response to acute infection displays remarkable circadian rhythmicity in humans with increased inflammatory activity during the normal night or rest period. Severe bloodborne infections, exemplified in sepsis and the progression to septic shock, can not only disrupt the circadian rhythmicity of inflammatory processes but can be exacerbated by circadian misalignment. Examples of circadian disruptions during sepsis and septic shock include alteration or loss of hormonal rhythms controlling blood pressure and inflammation, white blood cell counts, and cytokine secretions. These changes to circadian rhythms hinder sepsis and septic shock recovery and also increase mortality. Chronotherapy and chronopharmacotherapy are promising approaches to resynchronise circadian rhythms or leverage circadian rhythms to optimise medication efficacy, respectively, and hold much potential in the treatment of sepsis and septic shock. Despite knowledge of how circadian rhythms change in these grave conditions, very little research has been undertaken on the use of these therapies in support of sepsis management. This review details the circadian disruptions associated with sepsis and septic shock, the influence they have on morbidity and mortality, and the potential clinical benefits of circadian-modulating therapies.

Critical illness is a complex condition that can have a devastating impact on health and quality of life. Nutritional support is a crucial component of critical care that aims to maintain or restore nutritional status and muscle function. A one-size-fits-all approach to the components of nutritional support has not proven beneficial. Recent randomized controlled trials challenge the conventional strategy and support the safety and potential benefits of below-usual calorie and protein intakes at the early, acute phase of critical illness. Further research is needed to define optimal nutritional support throughout the intensive care unit stay. Individualized nutritional strategies relying on risk assessment tools or biomarkers deserve further investigation in rigorously designed, large, multicenter, randomized, controlled trials. Importantly, although nutritional support is crucial, it might not be sufficient to enhance the recovery of critically ill patients. Thus, achieving the greatest efficacy may require individualized nutritional support combined with early, prolonged physical rehabilitation within a multimodal, holistic care program throughout the patient's recovery journey.

Over half of patients who spend >48 hours in the intensive care unit (ICU) are fed via a nasogastric (NG) tube. Current guidance recommends continuous delivery of feed throughout the day and night. Emerging evidence from healthy human studies shows that NG feeding in an intermittent pattern (rather than continuous) promotes phasic hormonal, digestive and metabolic responses that are important for effective nutrition. It is not yet known whether this will translate to the critically ill population. Here, we present the protocol for a proof-of-concept study comparing diurnal intermittent vs continuous feeding on hormonal and metabolic outcomes for patients in the ICU.

The study is a single-centre, prospective, randomised, open-label trial comparing intermittent enteral nutrition with the current standard practice of continuous enteral feeding. It aims to recruit participants (n=30) needing enteral nutrition via an NG tube for >24 hours who will be randomised to a diurnal intermittent or a continuous feeding regimen with equivalent nutritional value. The primary outcome is peak plasma insulin/c-peptide within 3 hours of delivering the morning intermittent feed on the second study day, compared with that seen in the continuous feed delivery group at the same time point. Secondary outcomes include feasibility, tolerability, efficacy and metabolic/hormonal profiles.

We obtained ethical approval from the Wales Research Ethics Committee 3 prior to data collection (reference 23/WA/0297). We will publish the results of this study in an open-access peer-reviewed journal.

NCT06115044.

The circadian timing system coordinates daily cycles in physiological functions, including glucose metabolism and insulin sensitivity. Here, the aim was to characterise the 24-h variation in glucose levels in critically ill patients during continuous enteral nutrition after controlling for potential sources of bias.

Time-stamped clinical data from adult patients who stayed in the Intensive Care Unit (ICU) for at least 4 days and received enteral nutrition were extracted from the Medical Information Mart for Intensive Care (MIMIC)-IV database. Linear mixed-effects and XGBoost modelling were used to determine the effect of time of day on blood glucose values.

In total, 207,647 glucose measurements collected during enteral nutrition were available from 6,929 ICU patients (3,948 males and 2,981 females). Using linear mixed-effects modelling, time of day had a significant effect on blood glucose levels (p < 0.001), with a peak of 9.6 [9.5-9.6; estimated marginal means, 95% CI] mmol/L at 10:00 in the morning and a trough of 8.6 [8.5-8.6] mmol/L at 02:00 at night. A similar impact of time of day on glucose levels was found with the XGBoost regression model.

These results revealed marked 24-h variation in glucose levels in ICU patients even during continuous enteral nutrition. This 24-h pattern persists after adjustment for potential sources of bias, suggesting it may be the result of endogenous biological rhythmicity.

This work was supported by a VENI grant from the Netherlands Organisation for Health Research and Development (ZonMw), an institutional project grant, and by the Dutch Research Council (NWO).

The finding that animals with circadian gene mutations exhibit diet-induced obesity and metabolic syndrome with hypoinsulinemia revealed a distinct role for the clock in the brain and peripheral tissues. Obesogenic diets disrupt rhythmic sleep/wake patterns, feeding behavior, and transcriptional networks, showing that metabolic signals reciprocally control the clock. Providing access to high-fat diet only during the sleep phase (light period) in mice accelerates weight gain, whereas isocaloric time-restricted feeding during the active period enhances energy expenditure due to circadian induction of adipose thermogenesis. This perspective focuses on advances and unanswered questions in understanding the interorgan circadian control of healthful metabolism.

Acute gastrointestinal injury (AGI) is very common in critically ill patients, and its severity is positively correlated with mortality. Critically ill patients with digestive and absorption dysfunction caused by AGI face higher nutritional risks, making nutritional support particularly important. Early enteral nutrition (EN) support is extremely important because it can promote the recovery of intestinal function, protect the intestinal mucosal barrier, reduce microbiota translocation, reduce postoperative complications, shorten hospital stay, and improve clinical prognosis. In recent years, many nutritional guidelines have been proposed for critically ill patients; however, there are few recommendations for the implementation of EN in patients with AGI, and their quality of evidence is low. The use of EN feeding strategies in critically ill patients with AGI remains controversial. The aim of this review was to elaborate on how EN feeding strategies should transition from limited to progressive to open feeding and explain the time window for this transition.

The pediatric intensive care unit (PICU) is bright, loud, and disruptive to children. Strategies to improve the sleep of adults in the ICU have improved delirium and mortality rates. Children need more sleep than adults for active growth, healing, and development when well; this is likely true when they are critically ill. This review was performed to describe what we know in this area to date with the intent to identify future directions for research in this field. Since the 1990s, 16 articles on 14 observational trials have been published investigating the sleep on a total of 312 critically ill children and the melatonin levels of an additional 144. Sleep measurements occurred in 9 studies through bedside observation (n = 2), actigraphy (n = 2), electroencephalogram (n = 1) and polysomnography (n = 4), of which polysomnography is the most reliable. Children in the PICU sleep more during the day, have fragmented sleep and disturbed sleep architecture. Melatonin levels may be elevated and peak later in critically ill children. Early data suggest there are at-risk subgroups for sleep and circadian disruption in the PICU including those with sepsis, burns, traumatic brain injury and after cardiothoracic surgery. The available literature describing the sleep of critically ill children is limited to small single-center observational studies with varying measurements of sleep and inconsistent findings. Future studies should use validated measurements and standardized definitions to begin to harmonize this area of medicine to build toward pragmatic interventional trials that may shift the paradigm of care in the pediatric intensive care unit.

In recent years, in-depth research on chronobiology has been conducted, and the circadian rhythm has become a new target for the treatment of diseases. Circadian rhythms are closely related to the normal physiological functions of organisms. Increasing evidence indicates that circadian rhythm disorders are the pathological basis of diseases such as sleep disorders, depression, cardiovascular diseases, and cancer. As an economical, safe, and effective treatment method, electroacupuncture has been widely used in clinical practice. In this paper, we summarize the current literature on electroacupuncture's regulation of circadian rhythm disorders and circadian clock genes. In addition, we briefly explore the optimization of electroacupuncture intervention programmes and the feasibility of implementing electroacupuncture intervention programmes at selected times in clinical practice. We conclude that electroacupuncture may have good application prospects in circadian rhythm regulation, but this conclusion needs to be confirmed by clinical trials.

To summarize recent research on critical care nutrition focusing on the optimal composition, timing, and monitoring of enteral feeding strategies for (post)-ICU patients. We provide new insights on energy and protein recommendations, feeding intolerance, and describe nutritional practices for coronavirus disease 2019 ICU patients.

The use of indirect calorimetry to establish individual energy requirements for ICU patients is considered the gold standard. The limited research on optimal feeding targets in the early phase of critical illness suggests avoiding overfeeding. Protein provision based upon the absolute lean body mass is rational. Therefore, body composition measurements should be considered. Body impedance analysis and muscle ultrasound seem reliable, affordable, and accessible methods to assess body composition at the bedside. There is inadequate evidence to change our practice of continuous enteral feeding into intermittent feeding. Finally, severe acute respiratory syndrome coronavirus 2 patients are prone to underfeeding due to hypermetabolism and should be closely monitored.

Nutritional therapy should be adapted to the patient's characteristics, diagnosis, and state of metabolism during ICU stay and convalescence. A personalized nutrition plan may prevent harmful over- or underfeeding and attenuate muscle loss. Despite novel insights, more research is warranted into tailored nutrition strategies during critical illness and convalescence.