Divergent trajectories of cellular bioenergetics, intermediary metabolism and systemic redox status in survivors and non-survivors of critical illness
Helen T. McKenna,
Katie A. O'Brien,
Bernadette O. Fernandez,
Magdalena Minnion,
Adam Tod,
Ben D. McNally,
James A. West,
Julian L. Griffin,
Michael P. Grocott,
Michael G. Mythen,
Martin Feelisch,
Andrew J. Murray,
Daniel S. Martin
Affiliations
Helen T. McKenna
Division of Surgery and Interventional Science, University College London, Royal Free Hospital, London, NW3 2QG, UK; Intensive Care Unit, Royal Free Hospital, London, NW3 2QG, UK; Peninsula Medical School, University of Plymouth, John Bull Building, Derriford, Plymouth, PL6 8BU, UK
Katie A. O'Brien
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, UK
Bernadette O. Fernandez
Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK
Magdalena Minnion
Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK
Adam Tod
Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK
Ben D. McNally
Department of Biochemistry and the Cambridge Systems Biology Centre, University of Cambridge, CB2 1GA, UK
James A. West
Cambridge Institute of Therapeutic Immunology and Infectious Disease, Department of Medicine, Jeffrey Cheah Biomedical Centre, University of Cambridge, CB2 0RE, UK
Julian L. Griffin
Department of Biochemistry and the Cambridge Systems Biology Centre, University of Cambridge, CB2 1GA, UK; Section of Biomolecular Medicine, Department of Digestion, Metabolism and Reproduction, Imperial College London, SW7 2AZ, UK
Michael P. Grocott
Anaesthesia Perioperative and Critical Care Research Group, Southampton National Institute of Health Research Biomedical Research Centre, University Hospital Southampton, SO16 6YD, UK
Michael G. Mythen
University College London Hospitals and Great Ormond Street, National Institute of Health Research Biomedical Research Centres, London, WC1N 1EH, UK
Martin Feelisch
Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK; Anaesthesia Perioperative and Critical Care Research Group, Southampton National Institute of Health Research Biomedical Research Centre, University Hospital Southampton, SO16 6YD, UK
Andrew J. Murray
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, UK; Corresponding author. Department of Physiology, Development and Neuroscience, University of Cambridge, CB2 3EG, UK.
Daniel S. Martin
Division of Surgery and Interventional Science, University College London, Royal Free Hospital, London, NW3 2QG, UK; Intensive Care Unit, Royal Free Hospital, London, NW3 2QG, UK; Peninsula Medical School, University of Plymouth, John Bull Building, Derriford, Plymouth, PL6 8BU, UK
Background: Numerous 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. Methods: To 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. Results: We 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. Conclusion: Critical 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.
