Metabolic signatures of sepsis in critical care: an individualised approach to diagnosis and management
File(s)
Author(s)
McLymont, Natalie
Type
Thesis
Abstract
Sepsis is a clinical syndrome of great importance associated with a high rate of multiple organ failure and death and currently no accurate means of predicting those at particular risk of such outcomes. Energy metabolism involves many interdependent processes performed by the liver and kidneys and adequate function is essential to survival; conversely detrimental changes are associated with adverse outcomes. Thus, changes in energy metabolism in sepsis have the potential to be utilised in the early diagnosis of sepsis-related liver and kidney injury and general risk stratification.
This thesis describes the metabolic response of a cohort of critically ill patients (n=50) with severe sepsis, specifically sepsis-related organ dysfunction and survival using metabolic profiling techniques based on 1H-Nuclear Magnetic Resonance (NMR) spectroscopy and Ultra-Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS) and multivariate statistical analyses. This consisted of three parts: (1) demonstration of the feasibility of 1H-NMR analyses of urine as a method of global metabolic profiling in a cohort of critically ill patients including the development of a 1H-NMR spectroscopy drug standards database to aid drug metabolite identification. (2) Characterisation of metabolic changes associated with sepsis-related liver injury (SRLI) using 1H-NMR of urine and serum samples from the sepsis cohort. (3) Characterisation of lipid changes associated with SRLI using lipid profiling based on UPLC-MS analyses of plasma from the sepsis cohort.
The feasibility of metabolic profiling based on 1H-NMR analyses of urine was demonstrated in the critically ill cohort. Together, 1H-NMR analyses of serum and lipid profiling of plasma demonstrated changes in lysine and methionine and 18 plasma lipids associated with liver dysfunction in severe sepsis that were in keeping with our current understanding, and provided further insights into the pathophysiology of SRLI. These findings could also be used in the early diagnosis of SRLI and improve its prognosis and warrants further investigation.
This thesis describes the metabolic response of a cohort of critically ill patients (n=50) with severe sepsis, specifically sepsis-related organ dysfunction and survival using metabolic profiling techniques based on 1H-Nuclear Magnetic Resonance (NMR) spectroscopy and Ultra-Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS) and multivariate statistical analyses. This consisted of three parts: (1) demonstration of the feasibility of 1H-NMR analyses of urine as a method of global metabolic profiling in a cohort of critically ill patients including the development of a 1H-NMR spectroscopy drug standards database to aid drug metabolite identification. (2) Characterisation of metabolic changes associated with sepsis-related liver injury (SRLI) using 1H-NMR of urine and serum samples from the sepsis cohort. (3) Characterisation of lipid changes associated with SRLI using lipid profiling based on UPLC-MS analyses of plasma from the sepsis cohort.
The feasibility of metabolic profiling based on 1H-NMR analyses of urine was demonstrated in the critically ill cohort. Together, 1H-NMR analyses of serum and lipid profiling of plasma demonstrated changes in lysine and methionine and 18 plasma lipids associated with liver dysfunction in severe sepsis that were in keeping with our current understanding, and provided further insights into the pathophysiology of SRLI. These findings could also be used in the early diagnosis of SRLI and improve its prognosis and warrants further investigation.
Version
Open Access
Date Issued
2016-10
Date Awarded
2017-10
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Gordon, Anthony
Brett, Stephen
Li, Jia
Sponsor
Imperial College London
National Institute for Health Research (Great Britain)
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)