Metabolomic Profile Associated With Hyperglycemia And Chronic Diseases And Metabolic Homeostasis Derangement In Critical Illness: Post-hoc metabolomic cohort study of the VITdAL-ICU Trial

Abstract

ABSTRACT Critical illnesses contribute to the maximum morbidity and mortality of hospitalized patients. Critical illness often results in the loss of metabolic homeostasis, characterized by the severe disruption of various metabolic processes, including energy production and utilization. Despite significant advancements in care for critically ill patients (1,2), approximately 500000 patients (one in five) die in the ICU each year in the USA (3). Metabolomics can provide a comprehensive technique for understanding an organism's phenotype as metabolites indicate cellular and gene activity. Regardless of the patient's diabetes status, hyperglycemia has been associated with poor clinical outcomes in critically ill patients. Acute hyperglycemia impairs innate immunity, despite proinflammatory changes (4). Early metabolomic studies in critical illness showed illness severity and predicted outcomes. However, no existent study has defined the metabolic response to hyperglycemia in the critically ill. We hypothesize that hyperglycemia is associated with metabolism differences related to innate immunity in critically ill patients. Critically ill patients often have chronic medical conditions affecting the severity of the acute illness, treatment, and outcomes. Plasma metabolomics studies in critical illness show a consistent alteration of metabolism linked to acute illness severity and outcome prediction. But the importance of energy utilization pathways among critically ill patients with comorbidities is unknown. Therefore, we hypothesized that a higher chronic disease burden, as assessed by the updated Charlson Comorbidity Index (uCCI), is associated with differential energy utilization pathways in critically ill adult patients. This work depicted two critical-care VITdAL-ICU metabolomics studies. Two ICU studies found different plasma metabolomics responses to hyperglycemia and chronic comorbidities (ICUs). Results: Based on longitudinal metabolomics data and mixed-effect linear regression analysis, we found 84 metabolites had significantly positive (q-value .05) associations with serum glucose, dominated by increases in diacylglycerol (DAG) species, branched-chain amino acids (BCAAs), and glycerophospholipid species (phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol) and including plasma glucose, alanine, and lactate. These metabolic profile alterations indicate that energy utilization is altered in critically ill hyperglycemic patients, explicitly indicating a metabolic shift involving mitochondria and the endoplasmic reticulum. We found 430 metabolites strongly associated with uCCI or uCCI>4. In repeated measure metabolomics data, several metabolites increased with increasing uCCI, including BCAA, short-chain acylcarnitines, purine nucleotides (1-methyladenosine (m1A), N2, N2-dimethyl guanosine (m22G), and pentose phosphate pathway activation. In contrast, others decreased, such as Sphingomyelin. Alteration of these metabolic pathways associated with comorbidities indicates chronic diseases are related to differential utilization of energy pathways among critically ill patients.