DeliKet (Substudy of KetoNiFast Study ID 22-1398_1)

Overview

Postoperative delirium is a common problem of the critically ill patient and associated with an increased mortality. Intermittent fasting and ketogenesis have been shown to be beneficial for maintaining a circadian rhythm and initiating anti-inflammatory repair mechanisms which could potentially be neuroprotective. However, so far there is little data if cyclic enteral feeding with ketogenic nighttime fasting might be beneficial for reducing the rate of postoperative delirium. The study hypothesis is that equicaloric cyclic enteral feeding (12 hrs) during daytime with ketogenic fasting and exogenous ketone supplementation at nighttime compared to continuous standard enteral nutrition (24 hours) decreases the incidence of postoperative delirium in critically ill patients.

Postoperative delirium remains a common postoperative problem in critically ill patients with a prevalence of up to 20% and even up to 50% in the elderly population. But postoperative delirium has a negative impact on mortality as several studies were able to show in the past. Therefore, aiming for a reduction of postoperative delirium has an important impact on patients' outcome. One helpful tool for avoiding postoperative delirium is maintaining a circadian pattern. Enteral feeding may play an important role here. Healthy humans have a circadian feeding pattern with nighttime fasting. There is increasing evidence that a circadian rhythm of feeding (cyclic feeding) could be beneficial for critical ill patients. Cyclic feeding and fasting are assumed to have positive effects on the gut microbiome resulting in optimization of host responses to gastrointestinal pathogens. Another positive effect of cyclic feeding potentially results from activation of a "fasting response", inducing repair pathways such as ketogenesis, mitochondrial biogenesis, anti-inflammatory pathways, antioxidant defenses and autophagy processes. The activation of these repair pathways could diminish cellular stress and promote cellular recovery in critical ill patients. This could have a positive effect on postoperative delirium. A randomized controlled trial by van Dyck et al. could show that fasting-mimicking intervals of 12 hours are sufficient to generate a metabolic fasting response without risking a caloric deficit. This fasting response can be enhanced by additional supplementation of exogenous ketones. The study objective is that equicaloric cyclic enteral feeding (for 12 hours) during daytime with ketogenic fasting (for 12 hours) at nighttime (aiming for a ß-hydroxybutyrate blood concentrations ≥ 0.5mM by exogenous ketone supplementation) compared to continuous (for 24 hours) standard enteral nutrition as per patients' nutritional requirements decreases the incidence of postoperative delirium of critically ill patients.