Discussion
muscle mass, diarrhoea, arterial blood acidaemia, critically ill, ketosis, Ketosis, Diarrhoea, a decrease, gastrointestinal absorption, critically ill patientsOctanoic Acid, multi-organ failure
HYPOGLYCAEMIA, CRITICALLY ILL, ADVERSE EVENTS, RECRUITMENT, KETOSIS, KETOSIS, SECONDARY, FRAGILITY, MUSCLE WASTING, SEPARATION, MULTI-ORGAN FAILURE
We have demonstrated that inducing sustained ketosis using a ketogenic enteral feeding regimen is safe, well tolerated, and feasible in critically ill patients with multi-organ failure. Although some secondary endpoints could not be collected due to COVID-19 restrictions, recruitment and retention rates were high. Variability in glycaemic control improved, and differences between arms in terms of hypoglycaemia, insulin dosing and glucose variability all point towards a favourable metabolic profile and ketone bodies being used as a substrate preferentially over glucose. In keeping with tissue ketone body metabolism, ketosis was not associated with development of arterial blood acidaemia. Exploratory untargeted metabolomic analyses showed a clear separation of arms at the end of the intervention. Metabolite abundance data suggest that a favourable metabolic profile developed in response to the intervention, within pathways involved in protein homeostasis and urea cycle flux. This hypothesis requires prospective testing in a larger trial.Prior to this trial, concerns had been raised regarding the safety and feasibility of inducing ketosis in physiologically unstable patients. Ketosis is traditionally associated with pathological states in clinical medicineSupport for the study may be in part due to the safety profile observed, with little differences seen in adverse events or tolerability, except for the incidence of diarrhoea. We had not pre-specified the definition of diarrhoea, and several such definitions exist. Diarrhoea is common in critically ill patientsOctanoic Acid and Decanoic Acid were delivered as part of the intervention, and the increased presence of these in the circulation supports data from recent stable isotope studies that gastrointestinal absorption is not a limiting factorOf note, measurement of muscle mass was neither an essential nor recommended outcome measure in the Core Outcome Set for metabolic and nutritional interventions in critically ill patients and would therefore be unlikely to form part of our subsequent efficacy trialExploratory metabophenotyping demonstrated good metabolic separation between arms following the 10-day intervention. Given the multiple tissue metabolites contributing to plasma metabolite profiles, this separation lends weight to the hypothesis that ketone bodies are being used for substrate metabolism in diverse physiological pathways. Pathways unrelated to metabolism of nutritional lipids were differentially regulated implying tissue metabolism was additionally altered. Alterations in Cahill cycle flux result in a differential metabolite abundance in the alanine pathway, suggesting a decrease in muscle protein breakdown for alanine productionThis study has considerable strengths. First, the very comprehensive prospective data collection gives a high level of confidence in the safety data for future trials, and suggests that such trials are unlikely to require such extensive data collection (thus reducing the data collection burden). Second, the extensive biochemical and metabolomic analysis gives insight into metabolic processes brought into play by the delivery of ketogenic enteral feeding. Untargeted metabolomic profiling was used in an exploratory fashion, to generate potential panels for future targeted work, coupled with targeted ketone and medium chain fatty acid analyses. The advantage of this approach was seen in the identification of panels separate from those that we would have used a priori e.g. energetic intermediate pathways such as TCA Cycle metabolites and NAD Metabolites. In our future trials, additional targeted panels will include those pertaining to urea cycle flux, glucoronate metabolism, carbohydrate and lipid disposal and ketone metabolites. Limitations include the need to focus on safety and feasibility which determined the sample size. Imbalances in the study cohort between arms are likely driven by this (e.g., APACHE score inequality versus SOFA equality). Regardless, all patients recruited were in multi-organ failure, and at risk of both altered substrate utilisation, muscle wasting, and subsequent physical functional impairment. All signals reported relating to efficacy should be viewed as hypothesis generating only as this trial was not powered to detect these endpoints. A further limitation relates to the missing data for some of the physical outcomes – an indication of the strain put on healthcare systems by the COVID-19 pandemic. From a feasibility perspective, future trials would require dedicated time and funding for this, as these data expose the fragility of using routinely collected physical outcome data. A lack of data on functional impacts might be considered a weakness. However, this study was primarily intended to provide feasibility and safety data, while also garnering mechanistic/physiological data upon which to base design of a trial adequately powered to detect impact on meaningful functional outcomes.In conclusion, ketogenic enteral feeding in critically ill patients with multi-organ failure is safe and feasible. Patients who received ketogenic enteral feeding developed a different metabolic profile from controls. The efficacy of this altered metabolic profile in improving patient outcomes requires testing in prospective trials.