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Critical illness and flat batteries

Singer, M; (2017) Critical illness and flat batteries. Critical Care , 21 (Suppl 3) , Article 309. 10.1186/s13054-017-1913-9. Green open access

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Abstract

An exaggerated, dysregulated host response to insults such as infection (i.e. sepsis), trauma and ischaemia-reperfusion injury can result in multiple organ dysfunction and death. While the focus of research in this area has largely centred on inflammation and immunity, a crucial missing link is the precise identification of mechanisms at the organ level that cause this physiological-biochemical failure. Any hypothesis must reconcile this functional organ failure with minimal signs of cell death, availability of oxygen, and (often) minimal early local inflammatory cell infiltrate. These failed organs also retain the capacity to usually recover, even those that are poorly regenerative. A metabolic-bioenergetic shutdown, akin to hibernation or aestivation, is the most plausible explanation currently advanced. This shutdown appears driven by a perfect storm of compromised mitochondrial oxidative phosphorylation related to inhibition by excessive inflammatory mediators, direct oxidant stress, a tissue oxygen deficit in the unresuscitated phase, altered hormonal drive, and downregulation of genes encoding mitochondrial proteins. In addition, the efficiency of oxidative phosphorylation may be affected by a substrate shift towards fat metabolism and increased uncoupling. A lack of sufficient ATP provision to fuel normal metabolic processes will drive downregulation of metabolism, and thus cellular functionality. In turn, a decrease in metabolism will provide negative feedback to the mitochondrion, inducing a bioenergetic shutdown. Arguably, these processes may offer protection against a prolonged inflammatory hit by sparing the cell from initiation of death pathways, thereby explaining the lack of significant morphological change. A narrow line may exist between adaptation and maladaptation. This places a considerable challenge on any therapeutic modulation to provide benefit rather than harm.

Type: Article
Title: Critical illness and flat batteries
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1186/s13054-017-1913-9
Publisher version: http://doi.org/10.1186/s13054-017-1913-9
Language: English
Additional information: © The Author(s). 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Experimental and Translational Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10041494
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