Comprehensive metabolic amino acid flux analysis in critically ill patients

Abstract

Amino acid (AA) metabolism is severely disturbed in critically ill ICU patients. To be able to make a more scientifically based decision on the type of protein or AA nutrition to deliver in ICU patients, comprehensive AA phenotyping with measurements of plasma concentrations and whole body production (WBP) is needed. Therefore, we studied ICU patients and matched control subjects using a novel pulse isotope method to obtain in-depth metabolic analysis. In 51 critically ill ICU patients (SOFA~6.6) and 49 healthy controls, we measured REE and body composition/phase-angle using BIA. In the postabsorptive state, we collected arterial (ized) blood for CRP and AA. Then, we administered an 8 mL solution containing 18 stable AA tracers as a pulse and calculated WBP. Enrichments: LC-MS/MS and statistics: t-test, ANCOVA. Compared to healthy, critically ill ICU patients had lower phase-angle (p < 0.00001), and higher CRP (p < 0.0001). Most AA concentrations were lower in ICU patients (p < 0.0001), except tau-methylhistidine and phenylalanine. WBP of most AA were significantly (p < 0.0001) higher with increases in glutamate (160%), glutamine (46%), and essential AA. Remarkably, net protein breakdown was lower. There were only weak relationships between AA concentrations and WBP. Critically ill ICU patients (SOFA 8-16) had lower values for phase angle (p = 0.0005) and small reductions of most plasma AA concentrations, but higher tau-methylhistidine (p = 0.0223) and hydroxyproline (p = 0.0028). Remarkably, the WBP of glutamate and glutamine were lower (p < 0.05), as was their clearance, but WBP of tau-methylhistidine (p = 0.0215) and hydroxyproline (p = 0.0028) were higher. Our study in critically ill ICU patients shows that comprehensive metabolic phenotyping was able to reveal severe disturbances in specific AA pathways, in a disease severity dependent way. This information may guide improving nutritional compositions to improve the health of the critically ill patient. CLINICAL TRIAL REGISTRY: Data are from the baseline measurements of study NCT02770092 (URL: https://ichgcp.net/clinical-trials-registry/NCT02770092) and NCT03628365 (URL: https://ichgcp.net/clinical-trials-registry/NCT03628365).

Keywords: Amino acids; Critically ill; Human; ICU; Sepsis; Stable isotopes.

Conflict of interest statement

Conflicts of interest The authors have no conflict of interest to declare.

Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Figures

Figure 1

Glutamate plasma concentration (left panel) and whole body production (right panel) in healthy subjects and critically ill patients with a moderate or high SOFA score. Individual data points and geometric mean with 95% CI are shown. Statistics are between healthy subjects and critically ill patients (plasma concentration: p=0.00004, whole body production: p

Figure 2

Glutamine plasma concentration (left panel) and whole body production (right panel) in healthy subjects and critically ill patients with a moderate or high SOFA score. Individual data points and geometric mean with 95% CI are shown. Statistics are between healthy subjects and critically ill patients (plasma concentration: p

Figure 3

Citrulline plasma concentration (left panel), whole-body production (middle panel), and arginine de novo production (right panel) in healthy subjects and critically ill patients with a moderate or high SOFA score. Individual data points and geometric mean with 95% CI are shown. Statistics are between healthy subjects and critically ill patients (plasma concentration: p

Figure 4

Arginine plasma concentration (left panel) and whole-body production (right panel) in healthy subjects and critically ill patients with a moderate or high SOFA score. Individual data points and geometric mean with 95% CI are shown. Statistics are between healthy subjects and critically ill patients (plasma concentration: p=0.00001, whole body production: p=0.0083) and between critically ill patients with a moderate or high SOFA score (plasma concentration: p=0.065, whole body production: p=0.46).

Figure 5

Summary of the whole body production and conversions of the healthy subjects and the critically ill patients in % difference from healthy subjects. Data are geometric mean with 95% CI (see Table 4).

Figure 6

The correlation between the plasma amino acids concentration, depicted as [amino acid], and the whole body production (WBP) of the measured amino acids. The color bar on the right shows a gradual color change from dark blue (correlation=1) to white (correlation=0) to dark red (correlation= −1). A correlation coefficient larger than 0.27 indicates a p-value less than 0.05 (37).