{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T14:47:25Z","timestamp":1769266045391,"version":"3.49.0"},"reference-count":65,"publisher":"Elsevier BV","issue":"2","license":[{"start":{"date-parts":[[2010,4,1]],"date-time":"2010-04-01T00:00:00Z","timestamp":1270080000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Critical Care Clinics"],"published-print":{"date-parts":[[2010,4]]},"DOI":"10.1016\/j.ccc.2009.12.001","type":"journal-article","created":{"date-parts":[[2010,4,12]],"date-time":"2010-04-12T03:24:46Z","timestamp":1271042686000},"page":"409-421","source":"Crossref","is-referenced-by-count":48,"title":["Detection of Hypoxia at the Cellular Level"],"prefix":"10.1016","volume":"26","author":[{"given":"Laurie A.","family":"Loiacono","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David S.","family":"Shapiro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"78","reference":[{"key":"10.1016\/j.ccc.2009.12.001_bib1","first-page":"833","article-title":"Defining hypoxia: a systems view of VO2, glycolysis, energetics, and intracellular PO2","volume":"68","author":"Connett","year":"1990","journal-title":"J Appl Phys"},{"key":"10.1016\/j.ccc.2009.12.001_bib2","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1136\/adc.81.4.343","article-title":"Dysoxia and lactate","volume":"81","author":"Duke","year":"1999","journal-title":"Arch Dis Child"},{"key":"10.1016\/j.ccc.2009.12.001_bib3","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1097\/00003246-199907000-00002","article-title":"Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction","volume":"27","author":"Hotchkiss","year":"1999","journal-title":"Crit Care Med"},{"key":"10.1016\/j.ccc.2009.12.001_bib4","series-title":"Nunn's applied respiratory physiology","first-page":"247","article-title":"Oxygen","author":"Nunn","year":"1993"},{"key":"10.1016\/j.ccc.2009.12.001_bib5","series-title":"Textbook of medical physiology","first-page":"543","article-title":"Transport of oxygen and carbon dioxide in the blood and body fluids","author":"Guyton","year":"1976"},{"key":"10.1016\/j.ccc.2009.12.001_bib6","first-page":"69","article-title":"Intracellular PO2 in heart and skeletal muscle","volume":"14","author":"Whalen","year":"1971","journal-title":"Physiologist"},{"key":"10.1016\/j.ccc.2009.12.001_bib7","first-page":"351","article-title":"Homeostasis of oxygen supply in liver and kidney","volume":"vol. 37A","author":"Kessler","year":"1973"},{"key":"10.1016\/j.ccc.2009.12.001_bib8","first-page":"277","article-title":"Basic principles of tissue oxygenation determination from mitochondrial signals","volume":"vol. 37A","author":"Chance","year":"1973"},{"key":"10.1016\/j.ccc.2009.12.001_bib9","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1378\/chest.129.2.225","article-title":"Translating research to clinical practice: a 1-year experience with implementing early goal-directed therapy for septic shock in the emergency department","volume":"129","author":"Treciak","year":"2006","journal-title":"Chest"},{"key":"10.1016\/j.ccc.2009.12.001_bib10","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1097\/01.CCM.0000050074.82486.B2","article-title":"Impaired mitochondrial function induced by serum from septic shock patients is attenuated by inhibition of nitric oxide synthase and poly (ADP-ribose) synthase","volume":"31","author":"Boulos","year":"2003","journal-title":"Crit Care Med"},{"issue":"9","key":"10.1016\/j.ccc.2009.12.001_bib11","doi-asserted-by":"crossref","first-page":"2016","DOI":"10.1097\/01.CCM.0000281637.08984.6E","article-title":"The influence of early hemodynamic optimization on biomarker patterns of severe sepsis and septic shock","volume":"35","author":"Rivers","year":"2007","journal-title":"Crit Care Med"},{"key":"10.1016\/j.ccc.2009.12.001_bib12","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1111\/j.1399-6576.1997.tb05514.x","article-title":"Cytopathic hypoxia in sepsis","volume":"110","author":"Fink","year":"1997","journal-title":"Acta Anaesthesiol Scand Suppl"},{"issue":"5","key":"10.1016\/j.ccc.2009.12.001_bib13","first-page":"337","article-title":"Cytopathic hypoxia. A concept to explain organ dysfunction in sepsis","volume":"66","author":"Fink","year":"2000","journal-title":"Minerva Anestesiol"},{"issue":"4","key":"10.1016\/j.ccc.2009.12.001_bib14","first-page":"290","article-title":"Cytopathic hypoxia in sepsis: a true problem?","volume":"67","author":"Fink","year":"2001","journal-title":"Minerva Anestesiol"},{"issue":"1","key":"10.1016\/j.ccc.2009.12.001_bib15","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/S0749-0704(03)00071-X","article-title":"Cytopathic hypoxia. Is oxygen use impaired in sepsis as a result of an acquired intrinsic derangement in cellular respiration?","volume":"18","author":"Fink","year":"2002","journal-title":"Crit Care Clin"},{"key":"10.1016\/j.ccc.2009.12.001_bib16","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1097\/01.ccx.0000130150.33814.71","article-title":"Research: advances in cell biology relevant to critical illness","volume":"10","author":"Fink","year":"2004","journal-title":"Curr Opin Crit Care"},{"issue":"9","key":"10.1016\/j.ccc.2009.12.001_bib17","doi-asserted-by":"crossref","first-page":"2224","DOI":"10.1097\/01.CCM.0000281464.75703.AD","article-title":"Administration of exogenous cytochrome c as a novel approach for the treatment of cytopathic hypoxia","volume":"35","author":"Fink","year":"2007","journal-title":"Crit Care Med"},{"key":"10.1016\/j.ccc.2009.12.001_bib18","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1086\/315214","article-title":"Pro- versus anti-inflammatory cytokine profile in patients with severe sepsis: a marker for prognosis and future therapeutic options","volume":"181","author":"Gogos","year":"2000","journal-title":"J Infect Dis"},{"key":"10.1016\/j.ccc.2009.12.001_bib19","doi-asserted-by":"crossref","first-page":"1967","DOI":"10.4049\/jimmunol.177.3.1967","article-title":"Circulating cytokine\/inhibitor profiles reshape the understanding of the SIRS\/CARS continuum in sepsis and predict mortality","volume":"177","author":"Osuchowski","year":"2006","journal-title":"J Immunol"},{"key":"10.1016\/j.ccc.2009.12.001_bib20","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1056\/NEJMoa010307","article-title":"Early goal-directed therapy in the treatment of severe sepsis and septic shock","volume":"345","author":"Rivers","year":"2001","journal-title":"N Engl J Med"},{"issue":"1","key":"10.1016\/j.ccc.2009.12.001_bib21","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/S0749-0704(05)70161-5","article-title":"Cytopathic hypoxia. Mitochondrial dysfunction as mechanism contributing to organ dysfunction in sepsis","volume":"17","author":"Fink","year":"2001","journal-title":"Crit Care Clin"},{"key":"10.1016\/j.ccc.2009.12.001_bib22","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1097\/00024382-199608000-00002","article-title":"Sepsis-induced alterations in pyruvate dehydrogenase complex activity in rat skeletal muscle: effects on plasma lactate","volume":"8","author":"Vary","year":"1996","journal-title":"Shock"},{"key":"10.1016\/j.ccc.2009.12.001_bib23","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1023\/A:1006993910781","article-title":"Sepsis alters pyruvate dehydrogenase kinase activity in skeletal muscle","volume":"198","author":"Vary","year":"1999","journal-title":"Mol Cell Biochem"},{"key":"10.1016\/j.ccc.2009.12.001_bib24","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1042\/bj3150295","article-title":"Rapid reduction of nitric oxide by mitochondria, and reversible inhibition of mitochondrial respiration by nitric oxide","volume":"315","author":"Borutaite","year":"1996","journal-title":"Biochem J"},{"key":"10.1016\/j.ccc.2009.12.001_bib25","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1006\/abbi.1996.0178","article-title":"Differential inhibitory action of nitric oxide and peroxynitrite on mitochondrial electron transport","volume":"328","author":"Cassina","year":"1996","journal-title":"Arch Biochem Biophys"},{"key":"10.1016\/j.ccc.2009.12.001_bib26","doi-asserted-by":"crossref","first-page":"2120","DOI":"10.1097\/01.CCM.0000278914.85340.FE","article-title":"Mitochondrial resuscitation with exogenous cytochrome c in the septic heart","volume":"35","author":"Piel","year":"2007","journal-title":"Crit Care Med"},{"key":"10.1016\/j.ccc.2009.12.001_bib27","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1113\/jphysiol.2003.058701","article-title":"Lactate metabolism \u2013 a new paradigm for the third millennium","volume":"558","author":"Gladden","year":"2004","journal-title":"J\u00a0Physiol"},{"issue":"4","key":"10.1016\/j.ccc.2009.12.001_bib28","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1097\/00005768-200004000-00011","article-title":"Intra- and extra-cellular lactate shuttles","volume":"32","author":"Brooks","year":"2000","journal-title":"Med Sci Sports Exerc"},{"key":"10.1016\/j.ccc.2009.12.001_bib29","series-title":"Clinical and biochemical aspects of lactic acidosis","author":"Cohen","year":"1976"},{"key":"10.1016\/j.ccc.2009.12.001_bib30","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1097\/00003246-200001000-00019","article-title":"Evolution of lactate\/pyruvate and arterial ketone body ratios in the early course of catecholamine-treated septic shock","volume":"28","author":"Levy","year":"2000","journal-title":"Crit Care Med"},{"key":"10.1016\/j.ccc.2009.12.001_bib31","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1164\/arrd.1986.134.5.873","article-title":"The effect of liquid loading, blood transfusion, and catecholamine infusion on oxygen delivery and consumption in patients with sepsis","volume":"134","author":"Gilbert","year":"1986","journal-title":"Am Rev Respir Dis"},{"key":"10.1016\/j.ccc.2009.12.001_bib32","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1097\/00000658-199607000-00015","article-title":"Lactic acidosis during sepsis is related to increased pyruvate production, not deficits in tissue oxygen availability","volume":"224","author":"Gore","year":"1996","journal-title":"Ann Surg"},{"key":"10.1016\/j.ccc.2009.12.001_bib33","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1097\/01.ccx.0000235208.77450.15","article-title":"Lactate and shock state: the metabolic review","volume":"12","author":"Levy","year":"2006","journal-title":"Curr Opin Crit Care"},{"key":"10.1016\/j.ccc.2009.12.001_bib34","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1097\/00003246-199404000-00021","article-title":"Skeletal muscle partial pressure of oxygen in patients with sepsis","volume":"22","author":"Boeksteggers","year":"1994","journal-title":"Crit Care Med"},{"key":"10.1016\/j.ccc.2009.12.001_bib35","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1001\/jama.1992.03480110079038","article-title":"Reevaluation of the role of cellular hypoxia and bioenergetic failure in sepsis","volume":"267","author":"Hotchkiss","year":"1992","journal-title":"JAMA"},{"key":"10.1016\/j.ccc.2009.12.001_bib36","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1056\/NEJM198308183090702","article-title":"Treatment of lactic acidosis with dichloroacetate","volume":"309","author":"Stacpoole","year":"1983","journal-title":"N Engl J Med"},{"key":"10.1016\/j.ccc.2009.12.001_bib37","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1097\/00003246-200102000-00005","article-title":"The hepatosplanchnic area is not a common source of lactate in patients with severe sepsis","volume":"29","author":"De Baker","year":"2001","journal-title":"Crit Care Med"},{"key":"10.1016\/j.ccc.2009.12.001_bib38","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1186\/cc1519","article-title":"Bench-to-bedside review: lactate and the lung","volume":"6","author":"Iscra","year":"2002","journal-title":"Crit Care"},{"key":"10.1016\/j.ccc.2009.12.001_bib39","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/0006-291X(91)90958-A","article-title":"Altered glucose transporter mRNA abundance in the rat model of endotoxemic shock","volume":"176","author":"Zeller","year":"1991","journal-title":"Biochem Biophys Res Commun"},{"key":"10.1016\/j.ccc.2009.12.001_bib40","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/s001340000790","article-title":"The endothelial response to oxygen deprivation: biology and clinical implications","volume":"27","author":"Karimova","year":"2001","journal-title":"Intensive Care Med"},{"key":"10.1016\/j.ccc.2009.12.001_bib41","series-title":"Functional histology: a text and colour atlas","author":"Wheater","year":"1979"},{"key":"10.1016\/j.ccc.2009.12.001_bib42","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1046\/j.1471-4159.1997.69010423.x","article-title":"Brain lactate is an obligatory aerobic energy substrate for functional recovery after hypoxia: further in vitro validation","volume":"69","author":"Schurr","year":"1997","journal-title":"J Neurochem"},{"key":"10.1016\/j.ccc.2009.12.001_bib43","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1097\/00024382-200014020-00023","article-title":"Lactate improves cardiac efficiency after hemorrhagic shock","volume":"14","author":"Kline","year":"2000","journal-title":"Shock"},{"key":"10.1016\/j.ccc.2009.12.001_bib44","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1164\/ajrccm.157.4.9705037","article-title":"Mild hyperlactatemia in stable septic patients is due to impaired lactate clearance rather than overproduction","volume":"157","author":"Levraut","year":"1998","journal-title":"Am J Respir Crit Care Med"},{"key":"10.1016\/j.ccc.2009.12.001_bib45","doi-asserted-by":"crossref","first-page":"2235","DOI":"10.1097\/01.CCM.0000181525.99295.8F","article-title":"Lactate and glucose metabolism in severe sepsis and septic shock","volume":"33","author":"Revelly","year":"2005","journal-title":"Crit Care Med"},{"key":"10.1016\/j.ccc.2009.12.001_bib46","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1177\/0091270003254637","article-title":"Efficacy of dichloroacetate as a lactate-lowering drug","volume":"43","author":"Stacpoole","year":"2003","journal-title":"J Clin Pharmacol"},{"key":"10.1016\/j.ccc.2009.12.001_bib47","doi-asserted-by":"crossref","first-page":"L301","DOI":"10.1152\/ajplung.00153.2006","article-title":"Integrating acute lung injury and regulation of alveolar fluid clearance","volume":"291","author":"Guidot","year":"2006","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"issue":"1","key":"10.1016\/j.ccc.2009.12.001_bib48","doi-asserted-by":"crossref","first-page":"H304","DOI":"10.1152\/ajpheart.00077.2008","article-title":"Role of cGMP-dependent protein kinase in regulation of pulmonary vascular smooth muscle cell adhesion and migration: effect of hypoxia","volume":"297","author":"Negash","year":"2009","journal-title":"Am J Physiol Heart Circ Physiol"},{"issue":"5","key":"10.1016\/j.ccc.2009.12.001_bib49","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1097\/00000542-200211000-00028","article-title":"Reactive oxygen species scavengers attenuate endotoxin-induced impairment of hypoxic pulmonary vasoconstriction in mice","volume":"97","author":"Baboolal","year":"2002","journal-title":"Anesthesiology"},{"key":"10.1016\/j.ccc.2009.12.001_bib50","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1161\/HYPERTENSIONAHA.109.130138","article-title":"Regulation of proliferation and membrane potential by chloride currents in rat pulmonary artery smooth muscle cells","volume":"54","author":"Liang","year":"2009","journal-title":"Hypertension"},{"key":"10.1016\/j.ccc.2009.12.001_bib51","first-page":"533","article-title":"Release of mitochondrial enzyme carbamoyl phosphate synthase under septic conditions","volume":"23","author":"Struck","year":"2005","journal-title":"Shock"},{"issue":"9","key":"10.1016\/j.ccc.2009.12.001_bib52","doi-asserted-by":"crossref","first-page":"2439","DOI":"10.1097\/01.CCM.0000230240.02216.21","article-title":"Carbamoyl phosphate synthase-1: a marker of mitochondrial damage and depletion in the liver during sepsis","volume":"34","author":"Crouser","year":"2006","journal-title":"Crit Care Med"},{"issue":"1","key":"10.1016\/j.ccc.2009.12.001_bib53","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1308\/003588407X155536","article-title":"Acute renal failure and the critically ill surgical patient","volume":"89","author":"Sykes","year":"2007","journal-title":"Ann R Coll Surg Engl"},{"key":"10.1016\/j.ccc.2009.12.001_bib54","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1111\/j.1440-1681.2006.04472.x","article-title":"Renal parenchymal oxygenation and hypoxia adaptation in acute kidney injury","volume":"33","author":"Rosenberger","year":"2006","journal-title":"Clin Exp Pharmacol Physiol"},{"key":"10.1016\/j.ccc.2009.12.001_bib55","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1111\/j.1365-2044.2005.04278.x","article-title":"The diagnosis of acute renal failure in intensive care: mongrel or pedigree?","volume":"60","author":"Tillyard","year":"2005","journal-title":"Anaesthesia"},{"issue":"4323","key":"10.1016\/j.ccc.2009.12.001_bib56","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1126\/science.929199","article-title":"Noninvasive, infrared monitoring of cerebral oxygen sufficiency and circulation parameters","volume":"198","author":"Jobsis","year":"1977","journal-title":"Science"},{"key":"10.1016\/j.ccc.2009.12.001_bib57","doi-asserted-by":"crossref","first-page":"2740","DOI":"10.1152\/jappl.1994.77.6.2740","article-title":"Validation of near-infrared spectroscopy in humans","volume":"776","author":"Mancini","year":"1994","journal-title":"J Appl Physiol"},{"key":"10.1016\/j.ccc.2009.12.001_bib58","unstructured":"Colier WNJM. Near-infrared spectroscopy: toy or tool? An investigation on the\u00a0clinical applicability of near-infrared spectroscopy. Thesis, University of Nijmegen. The Netherlands; 1995. p. 9\u2013106."},{"key":"10.1016\/j.ccc.2009.12.001_bib59","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1097\/00005373-199703000-00023","article-title":"Evidence for early supply independent mitochondrial dysfunction in patients developing multiple organ failure after trauma","volume":"423","author":"Cairns","year":"1997","journal-title":"J Trauma"},{"key":"10.1016\/j.ccc.2009.12.001_bib60","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1097\/00005373-200004000-00009","article-title":"Tissue hemoglobin O2 saturation during resuscitation of traumatic shock monitored using near-infrared spectrometry","volume":"48","author":"McKinley","year":"2000","journal-title":"J Trauma"},{"key":"10.1016\/j.ccc.2009.12.001_bib61","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1097\/00003246-199907000-00031","article-title":"Microcirculatory oxygen and shunting in sepsis and shock","volume":"27","author":"Ince","year":"1999","journal-title":"Crit Care Med"},{"issue":"10","key":"10.1016\/j.ccc.2009.12.001_bib62","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1111\/j.1478-3231.2006.01383.x","article-title":"Correlation of transhepatic near-infrared spectroscopy readings with liver surface readings and perfusion parameters in a piglet endotoxemic shock model","volume":"26","author":"Nahum","year":"2006","journal-title":"Liver Int"},{"issue":"6","key":"10.1016\/j.ccc.2009.12.001_bib63","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1007\/s00134-009-1410-y","article-title":"Thenar oxygen saturation measured by near-infrared spectroscopy as a noninvasive predictor of low central venous oxygenation in septic patients","volume":"35","author":"Mesquida","year":"2009","journal-title":"Intensive Care Med"},{"key":"10.1016\/j.ccc.2009.12.001_bib64","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1007\/s00134-006-0121-x","article-title":"Tissue-oxygenation assessment using near-infrared spectroscopy during severe sepsis: confounding effects of tissue edema on StO2 values","volume":"32","author":"Poeze","year":"2006","journal-title":"Intensive Care Med"},{"key":"10.1016\/j.ccc.2009.12.001_bib65","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1017\/S0265021507003262","article-title":"Critical illness myopathy: sepsis-mediated failure of the peripheral nervous system","volume":"42","author":"Fredrich","year":"2008","journal-title":"Eur J Anaesthesiol Suppl"}],"container-title":["Critical Care Clinics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0749070409001262?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0749070409001262?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2019,5,28]],"date-time":"2019-05-28T01:04:25Z","timestamp":1559005465000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0749070409001262"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,4]]},"references-count":65,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2010,4]]}},"alternative-id":["S0749070409001262"],"URL":"https:\/\/doi.org\/10.1016\/j.ccc.2009.12.001","relation":{},"ISSN":["0749-0704"],"issn-type":[{"value":"0749-0704","type":"print"}],"subject":[],"published":{"date-parts":[[2010,4]]}}}