Discussion
critically ill, dysbiosis, critically ill patientThese
CRITICALLY ILL, COLLAPSE, CRITICAL ILLNESS, KLEBSIELLA, MULTI-ORGAN FAILURE
We performed a detailed metabolic analysis of amino acid, lipid and small molecule profiling in response to intermittent enteral feeding compared to continuous enteral feeding in critically ill patients, in the context of a multi-centre randomised controlled trial. We examined these three specific metabolite panels, composed of twenty four amino acid metabolites, nineteen lipid based metabolites and 44 small molecule metabolites over a four hour window within a day and longitudinally up to 10 days, in addition to between arms. No differences were seen between groups at each of the individual time points. Using a mixed effect moderated empirical Bayesian approach, we confirmed this finding, allowing us to collapse the study arms and examine changes over time of specific metabolites. Decreases in relative concentrations of small metabolites related to fatty acid, ketone acid and carbohydrate metabolism were observed over the first 10 days of critical illness.Metabolic profiling of these critically ill patients was surprisingly stable over time, with alterations only being seen at 10 days as opposed to variations at earlier timepoints. This may reflect the population chosen, as all patients had multi-organ failure, and reach an abnormal equilibrium of cellular metabolism early, and resolve slowly. This is in keeping with our previous observations in skeletal muscle and the limited clinical metabolomics data in critically ill patientsDecreases in circulating glutamine have been well described in the critical care literature, although supplementation is associated with an increase in mortality, perhaps through ammonia generation2,3-Butandiol is produced from sugar-fermenting microbes (e.g. Klebsiella sp, Entrobacter Sp, Serratia Sp, Bacillus Sp), and the decrease in metabolite levels are likely to reflect dysbiosis of critical illness, of which our understanding is still nascentTeasing apart the relationship between these processes across time and determining the true biological significance of the findings remains challenging, and will remain so until experimental and interventional studies can perturb these processes in the critically ill. Our data are the first to demonstrate these changes longitudinally as opposed to across cohorts, strengthening the case for focusing intervention development on these pathways. Metabolite profiling has been used in the past to determine effects of interventions such as Vitamin DWe were unable to demonstrate a difference in metabolite patterns between trial arms at individual timepoints. These data suggest that intermittent feeding is unable to sufficiently alter metabolism in critically ill patients, and therefore is unlikely to be better than continuous feeding in affecting end-organ metabolism. This does not, however, rule out the existence of other benefits of intermittent feeding regimens, such as increased nutrition delivery by overcoming difficulties in the process of nutritional delivery to the critically ill patientThese data represent one of the the largest matrices of metabolomics data in critical illness, as a result of the repeated sampling within days and across 7–10 days which, to our knowledge, has not been performed previously. The multi-centre nature of the trial suggests that these data have significant external validity. Most of the results presented are independent of feeding regimen across length of ICU admission