Prediction of sepsis mortality using metabolite biomarkers in the blood: a meta-analysis of death-related pathways and prospective validation

Abstract

Background: Sepsis is a leading cause of death in intensive care units (ICUs), but outcomes of individual patients are difficult to predict. The recently developed clinical metabolomics has been recognized as a promising tool in the clinical practice of critical illness. The objective of this study was to identify the unique metabolic biomarkers and their pathways in the blood of sepsis nonsurvivors and to assess the prognostic value of these pathways. Methods: We searched PubMed, EMBASE, Cochrane, Web of Science, CNKI, Wangfang Data, and CQVIP from inception until July 2019. Eligible studies included the metabolomic analysis of blood samples from sepsis patients with the outcome. The metabolic pathway was assigned to each metabolite biomarker. The meta-analysis was performed using the pooled fold changes, area under the receiver operating characteristic curve (AUROC), and vote-counting of metabolic pathways. We also conducted a prospective cohort metabolomic study to validate the findings of our meta-analysis. Results: The meta-analysis included 21 cohorts reported in 16 studies with 2509 metabolite comparisons in the blood of 1287 individuals. We found highly limited overlap of the reported metabolite biomarkers across studies. However, these metabolites were enriched in several death-related metabolic pathways (DRMPs) including amino acids, mitochondrial metabolism, eicosanoids, and lysophospholipids. Prediction of sepsis death using DRMPs yielded a pooled AUROC of 0.81 (95% CI 0.76-0.87), which was similar to the combined metabolite biomarkers with a merged AUROC of 0.82 (95% CI 0.78-0.86) (P > 0.05). A prospective metabolomic analysis of 188 sepsis patients (134 survivors and 54 nonsurvivors) using the metabolites from DRMPs produced an AUROC of 0.88 (95% CI 0.78-0.97). The sensitivity and specificity for the prediction of sepsis death were 80.4% (95% CI 66.9-89.4%) and 78.8% (95% CI 62.3-89.3%), respectively. Conclusions: DRMP analysis minimizes the discrepancies of results obtained from different metabolomic methods and is more practical than blood metabolite biomarkers for sepsis mortality prediction. Trial registration: The meta-analysis was registered on OSF Registries, and the prospective cohort study was registered on the Chinese Clinical Trial Registry (ChiCTR1800015321).

The lipid biology of sepsis

“…The roles of eicosanoids and SPMs have been investigated in sepsis and inflammatory processes (17)(18)(19)(20)(21). Mice subjected to the cecal ligation puncture (CLP) model of sepsis accumulate thromboxane B2 (TXB2, derived from biologically-active thromboxane A2) and 12-HETE, major platelet-derived eicosanoids that promote thrombus formation by inducing platelet activation, platelet aggregation, and vasoconstriction (22).…”

The infection-tolerant mammalian reservoir of Lyme disease and other zoonoses broadly counters the inflammatory effects of endotoxin

“…The latter two vitamers were reported to have anti-inflammatory effects in an LPS model by reducing expression of IL-1b and suppressing NF-kB activation in macrophages and, moreover, protected mice from lethal endotoxic shock [55]. Among patients with sepsis, higher concentrations in vitamin B6 metabolite biomarkers in the blood were associated with greater likelihood of survival in two clinical research studies [56,57].…”

Potential Lipid Signatures for Diagnosis and Prognosis of Sepsis and Systemic Inflammatory Response Syndrome

“…The quaternary ammonium compound carnitine and its acyl esters (acylcarnitines) are essential for the oxidative catabolism of fatty acids and thence for maintaining energy homeostasis in the human body. Downregulation of fatty acid oxidation is evidenced by an increased presence of acylcarnitines in plasma [ 36 ]. Their accumulation in the plasma is marked in sepsis non-survivors, indicating a possible mitochondrial dysfunction in energy production.…”