The metabolic effects of intermittent versus continuous feeding in critically ill patients

Abstract

Intermittent (or bolus) feeding regimens in critically ill patients have been of increasing interest to clinicians and scientists. Changes in amino acid, fat and carbohydrate metabolites over time might yet deliver other benefits (e.g. modulation of the circadian rhythm and sleep, and impacts on ghrelin secretion, insulin resistance and autophagy). We set out to characterise these changes in metabolite concentration. The Intermittent versus Continuous Feeding in Critically Ill paitents study (NCT02358512) was an eight-centre single-blinded randomised controlled trial. Patients were randomised to received a continuous (control arm) or intermittent (6x/day, intervention arm) enteral feeding regimen. Blood samples were taken on trial days 1, 7 and 10 immediately before and 30 min after intermittent feeds, and at equivalent timepoints in the control arm. A pre-planned targeted metabolomic analysis was performend using Nuclear Resonance Spectroscopy. Five hundred and ninety four samples were analysed from 75 patients. A total of 24 amino acid-, 19 lipid based-, and 44 small molecule metabolite features. Across the main two axes of variation (40-60% and 6-8% of variance), no broad patterns distinguished between intermittent or continuous feeding arms, across intra-day sampling times or over the 10 days from initial ICU admission. Logfold decreases in abundance were seen in metabolites related to amino acids (Glutamine - 0.682; Alanine - 0.594), ketone body metabolism (Acetone - 0.64; 3-Hydroxybutyric Acid - 0.632; Acetonacetic Acid - 0.586), fatty acid (carnitine - 0.509) and carbohydrate metabolism ( Maltose - 0.510; Citric Acid - 0.485). 2-3 Butanediol, a by-product of sugar-fermenting microbial metabolism also decreased (- 0.489). No correlation was seen with change in quadriceps muscle mass for any of the 20 metabolites varying with time (all p > 0.05). Increasing severity of organ failure was related to increasing ketone body metabolism (3 Hydroxybutyric Acid-1 and - 3; p = 0.056 and p = 0.014), carnitine deficiency (p = 0.002) and alanine abundancy (p - 0.005). A 6-times a day intermittent feeding regimen did not alter metabolite patterns across time compared to continuous feeding in critically ill patients, either within a 24 h period or across 10 days of intervention. Future research on intermittent feeding regimens should focus on clinical process benefits, or extended gut rest and fasting.

Figure 1

(A–C) Principal Component Analyses of; (A) Amino Acid Metabolites, (B) Lipid Metabolites and (C) Small Molecule Metabolites to assess for patterns of variability that might underpin physiological changes due to time of day (top graph in panel), time since admission (middle graph in panel) and feeding regimen (bottom graph in each panel).

Figure 2

(A–C) Volcano Plots depicting numbers of metabolites whose abundance altered over time, independent of feeding regimen across length of ICU admission for; (A) Amino Acid Metabolites, (B) Small Molecule Metabolites and (C) Lipid Metabolites. Vertical and horizontal cutoffs represent -log10 False Discovery Rate corrected p value and log fold change respectively, with differences from day 10 to day 1 presented in the left hand panel, differences from day 10 to day 7 in the middle panel and differences from day 7 to day 1 in the right hand panel. Four possible outcomes are presented; NS = Non-significant, FC =  > than log fold change cut off (0.5) ; p-val = FDR corrected significant change and p-val and FC = FDR corrected significant change and > log fold change cut off.