Abstract

BackgroundNumerous pathologies result in multiple-organ failure, which is thought to be a direct consequence of compromised cellular bioenergetic status. Neither the nature of this phenotype nor its relevance to survival are well understood, limiting the efficacy of modern life-support. MethodsTo explore the hypothesis that survival from critical illness relates to changes in cellular bioenergetics, we combined assessment of mitochondrial respiration with metabolomic, lipidomic and redox profiling in skeletal muscle and blood, at multiple timepoints, in 21 critically ill patients and 12 reference patients. ResultsWe demonstrate an end-organ cellular phenotype in critical illness, characterized by preserved total energetic capacity, greater coupling efficiency and selectively lower capacity for complex I and fatty acid oxidation (FAO)-supported respiration in skeletal muscle, compared to health. In survivors, complex I capacity at 48 h was 27% lower than in non-survivors (p = 0.01), but tended to increase by day 7, with no such recovery observed in non-survivors. By day 7, survivors’ FAO enzyme activity was double that of non-survivors (p = 0.048), in whom plasma triacylglycerol accumulated. Increases in both cellular oxidative stress and reductive drive were evident in early critical illness compared to health. Initially, non-survivors demonstrated greater plasma total antioxidant capacity but ultimately higher lipid peroxidation compared to survivors. These alterations were mirrored by greater levels of circulating total free thiol and nitrosated species, consistent with greater reductive stress and vascular inflammation, in non-survivors compared to survivors. In contrast, no clear differences in systemic inflammatory markers were observed between the two groups. ConclusionCritical illness is associated with rapid, specific and coordinated alterations in the cellular respiratory machinery, intermediary metabolism and redox response, with different trajectories in survivors and non-survivors. Unravelling the cellular and molecular foundation of human resilience may enable the development of more effective life-support strategies.

Highlights

  • Critical illness is poorly defined but generally refers to a condition in which acute organ dysfunction, involving two or more organs, has occurred to the degree that supportive intervention is required on an intensive care unit (ICU) [1]

  • Integrated bioenergetic, metabolic and redox phenotyping in patients with critical illness

  • A vastus lateralis muscle biopsy was performed within 48 h following admission to the ICU and repeated, when possible, at day 5–7 (n = 12)

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Summary

Introduction

Critical illness is poorly defined but generally refers to a condition in which acute organ dysfunction, involving two or more organs, has occurred to the degree that supportive intervention is required on an intensive care unit (ICU) [1]. No definite explanation for multiple-organ failure has been found, but it generally involves tissue injury (from trauma, infection, or other inflammatory cause), triggering a systemic humoral and inflammatory response, with subsequent alterations to macro- and microcirculatory blood flow and tissue oxygen demand [2]. It is associated with high short-term mortality (approximately 35–65%) even with provision of artificial organ support [3,4]. By day 7, survivors’ FAO enzyme activity was double that of non-survivors (p = 0.048), in whom plasma triacylglycerol accumulated Increases in both cellular oxidative stress and reductive drive were evident in early critical illness compared to health. Unravelling the cellular and molecular foundation of human resilience may enable the development of more effective life-support strategies

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