The Feasibility of Studying Metabolites in PICU Multi-Organ Dysfunction Syndrome Patients over an 8-Day Course Using an Untargeted Approach.

Mara Leimanis-Laurens,Claire Krohn,Andrew Kampfschulte,Todd A. Lydic,Jeremy W. Prokop,Dominic Sanfilippo,Danny Gil,Surender Rajasekaran,Elizabeth Prentice

doi:10.3390/children8020151

Mara Leimanis-Laurens, Claire Krohn + Show 7 more

Open Access

https://doi.org/10.3390/children8020151

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Abstract

Metabolites are generated from critical biological functions and metabolism. This pediatric study reviewed plasma metabolites in patients suffering from multi-organ dysfunction syndrome (MODS) in the pediatric intensive care unit (PICU) using an untargeted metabolomics approach. Patients meeting the criteria for MODS were screened for eligibility and consented (n = 24), and blood samples were collected at baseline, 72 h, and 8 days; control patients (n = 4) presented for routine sedation in an outpatient setting. A subset of MODS patients (n = 8) required additional support with veno-atrial extracorporeal membrane oxygenation (VA-ECMO) therapy. Metabolites from thawed blood plasma were determined from ion pairing reversed-phase liquid chromatography–mass spectrometry (LC-MS) analysis. Chromatographic peak alignment, identification, relative quantitation, and statistical and bioinformatics evaluation were performed using MAVEN and MetaboAnalyst 4.0. Metabolite analysis revealed 115 peaks per sample. From the partial least squares-discriminant analysis (PLS-DA) with variance of importance (VIP) scores above ≥2.0, 7 dynamic metabolites emerged over the three time points: tauro-chenodeoxycholic acid (TCDCA), hexose, p-hydroxybenzoate, hydroxyphenylacetic acid (HPLA), 2_3-dihydroxybenzoic acid, 2-keto-isovalerate, and deoxyribose phosphate. After Bonferroni adjustment for repeated measures, hexose and p-hydroxybenzoate were significant at one time point or more. Kendall’s tau-b test was used for internal validation of creatinine. Metabolites may be benign or significant in describing a patient’s pathophysiology and require operator interpretation.

Highlights

The ability to identify, quantify, and analyze the metabolic profile of a pediatric patient allows us to investigate the interaction between both physiological and pathologic states
There is a gap in our understanding of the complex interaction between pediatric critical illness, multi-organ dysfunction syndrome (MODS) [13], and their respective blood metabolites
These 24 patients were further classified as needing veno-arterial extracorporeal membrane oxygenation (VA-ECMO) as a therapeutic modality (n = 8) according to Extracorporeal Life Support Organization (ELSO) criteria [16]

Summary

Introduction

The ability to identify, quantify, and analyze the metabolic profile of a pediatric patient allows us to investigate the interaction between both physiological and pathologic states. We have previously described the current cohort of patients for patient whole blood transcriptomics [10,11] and plasma lipidome [12] This has revealed a complex biology in a heterogenous patient population with a non-uniform patient response to treatments over an 8-day course (stabilization and recovery phases) of illness during pediatric intensive care unit (PICU) admission. Complementary to these previously reported analytic modalities from whole blood [10,11,12], the aim of this current report was threefold: (1) to determine the feasibility of undertaking blood plasma metabolite work in the PICU setting, (2) characterize total blood plasma metabolites (polar, charged) using an untargeted approach, and (3) to determine change in metabolites over an 8-day PICU course. There is a gap in our understanding of the complex interaction between pediatric critical illness, multi-organ dysfunction syndrome (MODS) [13] (affecting 20% of PICU admissions [14], resulting in 10 times the mortality rate [15]), and their respective blood metabolites

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