Clinical implications of skeletal muscle rhythms for critically ill patients

Maintaining typical circadian rhythmicity of skeletal muscle is especially important for critically ill individuals. Despite a worldwide increase in survival rates of critically ill patients, long-term outcomes for those who do survive remain poor. A significant proportion experience chronic impairment in metabolism, sleep, physical function and cognitive and psychological health^{(Reference Rousseau, Prescott and Brett38)}. These adverse outcomes can be attributed to a myriad of factors, such as muscle disuse and inflammation stemming from injury or illness, among others^{(Reference Woolfson, Saour and Ricketts11–Reference Luttikhold, van Norren and Rijna13)}. While these factors could theoretically vary based on the specific conditions and circumstances of each patient, one common element that could markedly impact all critically ill patients is circadian disruption due to the stark contrast between typical daily life and the 24-h schedule of a working ICU environment^{(Reference Kouw, Heilbronn and van Zanten10,Reference Regmi and Heilbronn39–Reference Bear, Hart and Puthucheary41)} . Consequently, understanding and addressing circadian disruption could be a key aspect of improving outcomes in critically ill patients. One such practically feasible strategy for targeting circadian disruption is through the appropriate provision (e.g. amount and timing) of nutrition to critically ill patients.

Enteral feeding patterns in critically ill patients

Annually, critical care units in the UK admit approximately 200,000 patients⁽⁴²⁾ and it’s estimated that between 30 and 50% of these patients are already malnourished at the time of their admission^{(Reference Lew, Yandell and Fraser43)}. Approximately half of admitted critically ill patients will be fed enterally, providing vital support for various conditions (e.g. palliative, post-surgical and intensive care)^{(Reference Wang, McIlroy and Plank44)}, because they are unable to feed themselves for a prolonged period^{(Reference Binnekade, Tepaske and Bruynzeel45)}. However, ∼33% of enterally fed patients develop insulin resistance and a larger portion experience substantial muscle atrophy^{(Reference Dirks, Wall and van de Valk12,Reference Dirks, Hansen and Van Assche46,Reference Gonzalez, Dirks and Holwerda47)} . Both of these could be explained, in part, by inappropriate delivery of enteral nutrition – which may exacerbate circadian disruption, further impairing metabolism at the tissue level of skeletal muscle. There is evidently a need to consider the implications of enteral feeding patterns in critically ill patients to maintain daily rhythmicity and prevent further deterioration of metabolism.

The default and most prevalent pattern worldwide is to deliver nutrients continuously, yet this decision is based on convenience, not evidence. Recent systematic reviews consistently call for research into whether an intermittent feeding pattern may be superior^{(Reference Ichimaru48–Reference Patel, Rosenthal and Heyland50)}. A number of studies have explored the effects of intermittent feeding in the Intensive Care Unit (ICU). These studies have not been successful in showing improvements in morbidity or mortality^{(Reference Bear, Hart and Puthucheary41,Reference Van Dyck and Casaer51,Reference McNelly, Bear and Connolly52)} . However, it is worth noting that intermittent feeding protocols often still include nighttime feeding or lack a sufficiently long fasting period, factors that could potentially undermine the potential benefits of this approach^{(Reference McNelly, Bear and Connolly52–Reference Steevens, Lipscomb and Poole58)}.

Continuous feeding presents practical problems, with unscheduled interruptions for clinical procedures such that nutritional targets are unmet. Moreover, a permanently postprandial (fed) state extending throughout most, or all of the sleeping phase is unlikely to be optimal for physiological function or circadian alignment. By contrast, regular bolus feedings specific to the daylight/waking phase are more aligned both with our natural eating patterns and with entrained biological rhythms in clinically relevant processes such as metabolic regulation/flexibility, protein turnover and autophagy^{(Reference Bear, Hart and Puthucheary41,Reference Van Dyck and Casaer51,Reference de Cabo and Mattson59,Reference Thorburn60)} . For instance, intermittent protein ingestion more effectively stimulates muscle protein synthesis than a continuous amino acid supply, which is an important outcome in critically ill patients to minimise the risk of muscle wastage^{(Reference Atherton, Etheridge and Watt61–Reference Zaromskyte, Prokopidis and Ioannidis63)}. Normal meal intake results in the pulsatile release of insulin and ghrelin^{(Reference Cummings, Purnell and Frayo64)}, which is preserved with intermittent enteral feeding but lost with continuous feeding. Given that insulin is a potent modulator of clock gene and/or protein expression in multiple tissues, this pulsatile release may be necessary for maintaining rhythmicity in skeletal muscle^{(Reference Asher, Gatfield and Stratmann65,Reference Crosby, Hamnett and Putker66,Reference Mukherji, Kobiita and Chambon67,Reference Sun, Dang and Zhang68,Reference Tuvia, Pivovarova-Ramich and Murahovschi69)} . Interestingly, under controlled conditions the diurnal rhythm of skeletal muscle genes related to glucose, lipid and protein metabolism are temporally related to the diurnal profile of insulin, highlighting the potential for feeding patterns to modulate and entrain skeletal muscle rhythmicity^{(Reference Smith, Templeman and Davis25)}. Notably, shortening of the eating window through time-restricted feeding has been shown to increase the amplitude of oscillating muscle transcripts^{(Reference Lundell, Parr and Devlin70)}. However, neither the acute response (i.e. 24-h) nor adaptation time of skeletal muscle to novel feeding patterns has been established^{(Reference Bear, Hart and Puthucheary41,Reference Johnston, Ordovás and Scheer71)} .

Nonetheless, intermittent provision of enteral nutrition attenuates the progressive rise in plasma leptin and insulinemia seen with continuous feeding during bed res^{t(Reference Gonzalez, Dirks and Holwerda47)} potentially enhancing splanchnic blood flow, and improve gastrointestinal tolerance of enteral nutrition while influencing skeletal muscle autophagy^{(Reference Chowdhury, Murray and Hoad72)}. While intermittent enteral nutrition may increase the risk of diarrhoea, it can reduce the incidence of constipation, without affecting other gastrointestinal outcomes^{(Reference Heffernan, Talekar and Henain73)}. From a practical perspective, intermittent feeding offers several advantages. It imposes less limitation on patient mobility and necessitates fewer pauses for procedures or tests. It may also help achieve enteral calorie targets faster than continuous feeding in line with international guidelines emphasising the importance of providing early adequate enteral nutrition for critically ill patients^{(Reference McNelly, Bear and Connolly52–Reference MacLeod, Lefton and Houghton54,Reference Arabi, Casaer and Chapman74–Reference Singer, Blaser and Berger76)} .

In theory, intermittent feedings could sustain organ stress resistance and promote overall resilience, thus improving patient response to treatment and recovery from illness^{(Reference Van Dyck and Casaer51,Reference de Cabo and Mattson59,Reference Thorburn60)} . It is thus remarkable that the links between nutrient timing, chronobiological strain and human health outcomes remain to be established^{(Reference Lewis, Oster and Korf77)} and skeletal muscle metabolic responses have never been examined. However, in practice, improvements in morbidity and mortality are not yet observed.

Recommendations for future research

The existing body of research clearly indicates the existence of diurnal rhythms in skeletal muscle and the detrimental metabolic outcomes that can arise from disruption of these rhythms. However, a significant knowledge gap remains regarding how different feeding patterns influence these 24-hour profiles. In particular, it is now important to establish whether these rhythms occur independently from, of or are driven by, feeding pattern (i.e., whether they are driven by endogenous or exogenous clocks, respectively). Furthermore, disruption of circadian clocks as a result of enteral feeding pattern may also lead to insulin resistance, yet no studies to date have examined skeletal muscle clocks in response to divergent feeding patterns. Given the critical role of skeletal muscle in postprandial metabolic regulation^{(Reference DeFronzo, Jacot and Jequier20,Reference DeFronzo and Tripathy35)} , it is important to establish the temporal responses of this tissue to enteral nutrition delivery pattern.

In addition to furthering mechanistic understanding of divergent feeding patterns, it is important to recognise the need for translational studies to determine whether intermittent feeding with overnight fasting can produce improvements in physiological, hormonal and metabolic responses in critically ill patients. Specifically, we need complementary studies that map tissue-level physiology onto whole-body and clinical outcomes. Given that existing studies of intermittent enteral nutrition still provide nutrition through the night studies aiming to establish the clinical feasibility, tolerability and efficacy of intermittent diurnal feeding in critically ill adults would be particularly useful. Additional work should also seek to establish the effects of intermittent enteral nutrition on long-term outcomes (e.g. metabolism, sleep, physical function and cognitive and psychological health).