Análisis de los intermediarios del ciclo de krebs durante las primeras 6 horas de endotoxemia inducida por lipopolisacárido en un modelo de sepsis porcina.

ilustraciones

Autores:
Caicedo Ruiz, Juan Daniel
Tipo de recurso:
Fecha de publicación:
2023
Institución:
Universidad Nacional de Colombia
Repositorio:
Universidad Nacional de Colombia
Idioma:
spa
OAI Identifier:
oai:repositorio.unal.edu.co:unal/84766
Acceso en línea:
https://repositorio.unal.edu.co/handle/unal/84766
https://repositorio.unal.edu.co/
Palabra clave:
610 - Medicina y salud::612 - Fisiología humana
Respiración de la célula
Ácidos tricarboxilicos
Respiração Celular
Tricarboxylic Acids
Ciclo de krebs
Ciclo de los ácidos tricarboxílicos
Sepsis
Choque séptico
Reprogramación metabolica
Cromatografía líquida
Krebs cycle
Tricarboxylic acid cycle
Sepsis
Septic shock
Metabolic reprogramming
Liquid chromatography
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openAccess
License
Atribución-NoComercial-SinDerivadas 4.0 Internacional
id UNACIONAL2_344e87699f740b99f25f51731d1112bb
oai_identifier_str oai:repositorio.unal.edu.co:unal/84766
network_acronym_str UNACIONAL2
network_name_str Universidad Nacional de Colombia
repository_id_str
dc.title.spa.fl_str_mv Análisis de los intermediarios del ciclo de krebs durante las primeras 6 horas de endotoxemia inducida por lipopolisacárido en un modelo de sepsis porcina.
dc.title.translated.eng.fl_str_mv Krebs cycle intermediates during the first 6 hours of lipopolysaccharide-induced endotoxemia in a swine sepsis model
title Análisis de los intermediarios del ciclo de krebs durante las primeras 6 horas de endotoxemia inducida por lipopolisacárido en un modelo de sepsis porcina.
spellingShingle Análisis de los intermediarios del ciclo de krebs durante las primeras 6 horas de endotoxemia inducida por lipopolisacárido en un modelo de sepsis porcina.
610 - Medicina y salud::612 - Fisiología humana
Respiración de la célula
Ácidos tricarboxilicos
Respiração Celular
Tricarboxylic Acids
Ciclo de krebs
Ciclo de los ácidos tricarboxílicos
Sepsis
Choque séptico
Reprogramación metabolica
Cromatografía líquida
Krebs cycle
Tricarboxylic acid cycle
Sepsis
Septic shock
Metabolic reprogramming
Liquid chromatography
title_short Análisis de los intermediarios del ciclo de krebs durante las primeras 6 horas de endotoxemia inducida por lipopolisacárido en un modelo de sepsis porcina.
title_full Análisis de los intermediarios del ciclo de krebs durante las primeras 6 horas de endotoxemia inducida por lipopolisacárido en un modelo de sepsis porcina.
title_fullStr Análisis de los intermediarios del ciclo de krebs durante las primeras 6 horas de endotoxemia inducida por lipopolisacárido en un modelo de sepsis porcina.
title_full_unstemmed Análisis de los intermediarios del ciclo de krebs durante las primeras 6 horas de endotoxemia inducida por lipopolisacárido en un modelo de sepsis porcina.
title_sort Análisis de los intermediarios del ciclo de krebs durante las primeras 6 horas de endotoxemia inducida por lipopolisacárido en un modelo de sepsis porcina.
dc.creator.fl_str_mv Caicedo Ruiz, Juan Daniel
dc.contributor.advisor.none.fl_str_mv Diaztagle Fernández, Juan José
dc.contributor.author.none.fl_str_mv Caicedo Ruiz, Juan Daniel
dc.contributor.orcid.spa.fl_str_mv 0000-0001-6488-806X
dc.subject.ddc.spa.fl_str_mv 610 - Medicina y salud::612 - Fisiología humana
topic 610 - Medicina y salud::612 - Fisiología humana
Respiración de la célula
Ácidos tricarboxilicos
Respiração Celular
Tricarboxylic Acids
Ciclo de krebs
Ciclo de los ácidos tricarboxílicos
Sepsis
Choque séptico
Reprogramación metabolica
Cromatografía líquida
Krebs cycle
Tricarboxylic acid cycle
Sepsis
Septic shock
Metabolic reprogramming
Liquid chromatography
dc.subject.decs.spa.fl_str_mv Respiración de la célula
Ácidos tricarboxilicos
dc.subject.decs.eng.fl_str_mv Respiração Celular
Tricarboxylic Acids
dc.subject.proposal.spa.fl_str_mv Ciclo de krebs
Ciclo de los ácidos tricarboxílicos
Sepsis
Choque séptico
Reprogramación metabolica
Cromatografía líquida
dc.subject.proposal.eng.fl_str_mv Krebs cycle
Tricarboxylic acid cycle
Sepsis
Septic shock
Metabolic reprogramming
Liquid chromatography
description ilustraciones
publishDate 2023
dc.date.accessioned.none.fl_str_mv 2023-10-05T16:00:38Z
dc.date.available.none.fl_str_mv 2023-10-05T16:00:38Z
dc.date.issued.none.fl_str_mv 2023-10-02
dc.type.spa.fl_str_mv Trabajo de grado - Maestría
dc.type.driver.spa.fl_str_mv info:eu-repo/semantics/masterThesis
dc.type.version.spa.fl_str_mv info:eu-repo/semantics/acceptedVersion
dc.type.content.spa.fl_str_mv Text
dc.type.redcol.spa.fl_str_mv http://purl.org/redcol/resource_type/TM
status_str acceptedVersion
dc.identifier.uri.none.fl_str_mv https://repositorio.unal.edu.co/handle/unal/84766
dc.identifier.instname.spa.fl_str_mv Universidad Nacional de Colombia
dc.identifier.reponame.spa.fl_str_mv Repositorio Institucional Universidad Nacional de Colombia
dc.identifier.repourl.spa.fl_str_mv https://repositorio.unal.edu.co/
url https://repositorio.unal.edu.co/handle/unal/84766
https://repositorio.unal.edu.co/
identifier_str_mv Universidad Nacional de Colombia
Repositorio Institucional Universidad Nacional de Colombia
dc.language.iso.spa.fl_str_mv spa
language spa
dc.relation.references.spa.fl_str_mv 1. Seymour CW, Kennedy JN, Wang S, Chang CH, Elliott CF, Xu Z, et al. Derivation, validation, and potential treatment implications of novel clinical phenotypes for sepsis. JAMA. 2019; 321(20): 2003-2017.
2. Rhee C, Dantes R, Epstein L, et al. Incidence and trends of sepsis in US hospitals using clinical vs claims data, 2009-2014.JAMA. 2017;318(13):1241- 1249.
3. Rhodes, A., Evans, L.E., Alhazzani, W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med 2017; 43: (3) 304-377
4. Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001; 286: 1869-78.
5. Vincent JL, Francois B, Zabolotskikh I, Daga MK, Lascarrou JB, Kirovet MY, et al. Effect of a recombinant human soluble thrombomodulin on mortality in patients with sepsis-associated coagulopathy: the SCARLET randomized clinical trial. JAMA 2019; 321: 1993-2002.
6. Vincent JL. Improved survival in critically ill patients: are large RCTs more useful than personalized medicine? No. Intensive Care Med 2016; 42: 1778-80.
7. Kent DM, Hayward RA. Limitations of applying summary results of clinical trials to individual patients: the need for risk stratification. JAMA. 2007;298(10):1209-1212.
8. Itenov TS, Murray DD, Jensen JUS. Sepsis: personalized medicine utilizing “omic” technologies-a paradigm shift? Healthcare (Basel) 2018; 6:1-9.
9. Langley RJ, Tsalik EL, Velkinburgh JCV, Glickman SW, Rice BJ, Wang C, et al. An integrated clinico-metabolomic model improves prediction of death in sepsis. Sci Transl Med. 2013; 5: 195ra95.
10. Clayton TA, Lindon JC, Cloarec O, Antti H, Charuel C, Hanton G. et al. Pharmaco-metabonomomic phenotyping and personalized drug treatment. Nature 2006; 440: 1073-7.
11. Van Wyngene L., Vandewalle J., Libert C. (2018). Reprogramming of basic metabolic pathways in microbial sepsis: therapeutic targets at last? EMBO Mol. Med. 10:e8712.
12. Gomez H, Kellum JA, Ronco C. Metabolic reprogramming and tolerance during sepsis-induced AKI. Nat Rev Nephrol 2017; 13: 143-15119.
13. Pool R, Gomez H, Kellum JA. Mechanisms of Organ Dysfunction in Sepsis. Crit Care Clin 2018; 34: 63-80.
14. Sun J, Zhang J, Tian J, Virzì GM, Digvijay K, Cueto L, et al. Mitochondria in Sepsis-Induced AKI. JASN 2019; 30 (7): 1151-1161.
15. Hotchkiss RS, Karl IE. Reevaluation of the role of cellular hypoxia and bioenergetic failure in sepsis. JAMA 1992; 267:1503–1510.
16. Spronk P, Zandstra D, Ince C. Bench-to-bedside review: Sepsis is a disease of the microcirculation Crit Care 2004; 8 (6): 462–68.
17. Nelson DP, Samsel RW, Wood LDH, et al: Pathological supply dependence of systemic and intestinal 02 uptake during endotoxemia. J Appl Physiol. 1988; 64:2410-2419.
18. Ospina-Tascón GA, García Marin AF, Echeverri GJ, Bermudez WF, Madriñan-Navia H, Valencia JD, et al. Effects of dobutamine on intestinal microvascular blood flow heterogeneity and O2 extraction during septic shock. Journal of Applied Physiology. (1985) 2017; 122 (6): 1406-1417.
19. Fink MP. Cytopathic Hypoxia Mitochondrial Dysfunction as Mechanism Contributing to Organ Dysfunction in Sepsis. Crit Care Clin 2001; 17: 219-237
20. Warburg O. The metabolism of carcinoma cells. Cancer Res 1925; 9: 148-163.
21. Srivastava A, Mannam P. Warburg revisited: lessons for innate immunity and sepsis. Front Physiol 2015; 6: 70.
22. Cheng S, Scicluna B, Arts R. Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis. Nat. Immunol. 2016; 17:406-413.
23. Cambiaghi A, Pinto BB, Brunelli L, Falcetta F, Aletti F, Bendjelid K, et al. Characterization of a metabolomic profile associated with responsiveness to therapy in the acute phase of septic shock. Sci Rep. 2017; 7 (1): 9748.
24. Whelan SP, Carchman EH, Kautza B, et al. Polymicrobial sepsis is associated with decreased hepatic oxidative phosphorylation and an altered metabolic profile. J Surg Res 2014; 186:297–303.
25. Waltz P, Carchman E, Gomez H, and Zuckerbraun B. Sepsis results in an altered renal metabolic and osmolyte profile. J Surg Res. 2016; 202: 8-12.
26. Weinberg JM, Venkatachalam MA, Roeser NF, Nissim I. Mitochondrial dysfunction during hypoxia/reoxygenation and its correction by anaerobic metabolism of citric acid cycle intermediates. Proc Natl Acad Sci USA 2000; 97: 2826–2831.
27. Chinopoulos C. Which way does the citric acid cycle turn during hypoxia? - The critical role of alpha-ketoglutarate dehydrogenase complex. J. Neurosci. Res. 2013; 91: 1030–1043.
28. Randall HM Jr, Cohen JJ. Anaerobic CO2 production by dog kidney in vitro. Am J Physiol 1966; 211: 493-505.
29. Baldwin JE, Krebs H. the evolution of metabolic cycles. Nature 1981; 291: 381-382.
30. Owen OE, Kalhan SC, Hanson RW. The key role of anaplerosis and cataplerosis for citric acid cycle function. J Biol Chem 2002; 277:30409-30412.
31. Tannahill, G.M et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature. 2013; 496:238-242
32. Koivunen P, Hirsilä M, Remes AM, et al. Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF. J Biol Chem 2007; 282: 4524-4532.
33. Mills, E. L. et al. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell. 2016; 167: 457-470.
34. Chouchani ET, Pell VR, Gaude E, Aksentijevíc D, Sundier SY, Robb EL et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 2014; 525: 431-436.
35. Mickiewicz B, Duggan GE, Winston BW, Doig C, Kubes P, Vogel HJ. Metabolic profiling of serum samples by 1H nuclear magnetic resonance spectroscopy as a potential diagnostic approach for septic shock. Crit Care Med. 2014; 42: 1140–1149.
36. Fedotcheva NI, Litvinova EG, Osipov AA, Olenin AY, Moroz VV, et al. Influence of Microbial Metabolites of Phenolic Nature on the Activity of Mitochondrial Enzymes. Biofzika 2015; 60 (6): 1118-1124.
37. Mackenzie IM. The haemodynamics of human septic shock. Anaesthesia 2001; 56: 130-144.
38. Hotchkiss R, et al. Sepsis & Septic Shock. Nature Review 2016; 45 (2): 1-21.
39. Ince C, Mik E. Microcirculatory and mitochondrial hypoxia in sepsis, shock, and resuscitation. J Appl Physiol 2016; 120: 226-35.
40. Delabranche X, Helms J, Meziani F. Immunohaemostasis: a new view on haemostasis during sepsis. Ann. Intensive Care 2017; 7: 117
41. Koutroulis I, Batabyal R, McNamara B, Ledda M, Hoptay C, Freishtat R. Sepsis immunometabolism: from defining sepsis to understanding how energy production affects immune response. Critical Care Explorations 2019; 1 (11):e0061.
42. Andrades M, Spasic M, Spasic S, Spasojević I. Bench to bedside review: Sepsis - from the redox point of view. Crit Care 2011; 15(5): 230.
43. Singer M. The role of mitochondrial dysfunction in sepsis-induced multi-organ failure. Virulence 2014; 5: 66–72.
44. Weil M, Afifi A. Experimental and clinical studies on lactate and pyruvate as indicators of the severity of acute circulatory failure (Shock). Circulation 1970; 41: 989-1001.
45. Chertoff J, Chisum M, Garcia B, et al. Lactate kinetics in sepsis and septic shock: a review of the literature and rationale for further research. J Intensive Care. 2015; 3: 39-42.
46. Lee I, Huttemann M. Energy crisis: the role of oxidative phosphorylation in acute inflammation and sepsis. Biochim Biophys Acta. 2014; 1842: 1579-1586.
47. D’Alessandro A, Moore HB, Moore EE, Wither M, Nemkov T, Gonzalez E, Slaughter A, Fragoso M, Hansen KC, Silliman CC, et al. Early hemorrhage triggers metabolic responses that build up during prolonged shock. Am J Physiol – Regul Integr Comp Physiol. 2015; 308 (12): R1034–44.
48. Servià L, Jové M, Sol J, Pamplona R, Badia M, Montserrat N, et al. A prospective pilot study using metabolomics discloses specific fatty acid, catecholamine and tryptophan metabolic pathways as possible predictors for a negative outcome after severe trauma. J Scand J Trauma Resusc Emerg Med. 2019; 27 (1): 56.
49. Liu Z, Triba MN, Amathieu R, Lin X, Bouchemal N, Hantz E, et al. Nuclear magnetic resonance-based serum metabolomic analysis reveals different disease evolution profiles between septic shock survivors and non-survivors. Crit. Care. 2019; 23: 169.
50. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Bernard GR, Annane D, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 2016; 315: 801-810.
51. Silva S, Teboul JL. Defining the adequate arterial pressure target during septic shock: not a “micro” issue but the microcirculation can help. Crit care. 2011; 15:1004.
52. Saugel B, Trepte CJ, Heckel H, Wagner JY, Reuter DA. Hemodynamic management of septic shock: is it time for “individualized goal-directed hemodynamic therapy” and for specifically targeting the microcirculation? Shock 2015. 43 (6): 522-529.
53. Monnet X, Saugel B. Could resuscitation be based on microcirculation data? We are not sure. Intensive Care Med. 2018; 44: 950-953.
54. Ince, C. Hemodynamic coherence and the rationale for monitoring the microcirculation. Crit Care 2015; 19: S8
55. Hernandez, G., Teboul J.L. Is the macrocirculation really dissociated from the microcirculation in septic shock? Intensive Care Med 2016; 42:1621-24.
56. Dubin A, Pozo MO, Casabella CA, Palizas F jr; Murias G, Moseinco MC, et al. Increasing arterial blood pressure with norepinephrine does not improve microcirculatory blood flow: a prospective study. Crit Care 2009; 13 (3): R92
57. De Backer D, Foulon P. Minimizing catecholamines and optimizing perfusion. Critical Care 2019; 23 (1): 149.
58. Hotchkiss RS, Rust RS, Dence CS, et al. Evaluation of the role of cellular hypoxia in sepsis by the hypoxic marker [18F] fluoromisonidazole. Am J Physiol Regul Integr Comp Physiol 1991; 261: R965–72
59. Groeneveld AB, van Lambalgen AA, van den Bos GC, et al. Maldistribution of heterogeneous coronary blood flow during canine endotoxin shock. Cardiovasc Res 1991; 25: 80–8
60. Chew MS, Johansson A, Anderson C, Ersson A, et al. Decreases in myocardial glucose and increases in pyruvate but not ischaemia are observed during porcine endotoxaemia. Acta Anaesthesiol Scand 2008; 52: 959–68
61. Abraham E, Singer M. Mechanisms of sepsis-induced organ dysfunction. Crit Care Med 2007; 35: 2408–16.
62. Fink MP. Cytopathic hypoxia and sepsis: is mitochondrial dysfunction pathophysiologically important or just an epiphenomenon. Pediatr Crit Care Med 2015; 16: 89-91.
63. Shoemaker W, Appel P, kram HB, Bishop MH, Abraham E. temporal hemodynamic and oxygen transport patterns in medical patients. Septic Shock. Chest 1993; 1529-36.
64. Elbers PW, Ince C. Bench-to-bedside review: Mechanisms of critical illness – classifying microcirculatory flow abnormalities in distributive shock. Critical Care 2006; 10: 221.
65. Kakihana Y, Ito K, Nakahara M, Yamaguchi K, Yasuda T. Sepsis-induced myiocardial dysfunction: pathophysiology and management. Journal of Intensive Care 2016; 4:22,
66. Marx G, Vangerow B, Burczyk C, Gratz KF, Maassen N, Cobas Meyer M, et al. Evaluation of noninvasive determinants for capillary leakage syndrome in septic shock patients. Intensive Care Med 2000; 26:1252–1258.
67. Magder S, Vanelli G. Circuit factors in the high cardiac output of sepsis. J Crit Care 1996; 11: 155–166.
68. Jianhui L, Rosenblatt-Velin N, Loukili N, Pacher P, Feihl F, Waeber B, et al. Endotoxin impairs cardiac hemodynamics by affecting loading conditions but not by reducing cardiac inotropism. Am J Physiol Heart Circ Physiol 2010; 299: H492–H501. .
69. Groeneveld AB, Nauta JJ, Thijs LG.Peripheral vascular resistance in septic shock: its relation to outcome. Intensive Care Med 1988; 14:141-147.
70. Chan CM, Klinger JR. The Right Ventricle in Sepsis. Clin Chest Med 2008; 29: 661 – 676.
71. Court O, Kumar A, Parrillo JE, et al. Clinical review: Myocardial depression in sepsis and septic shock. Crit Care 2002; 6:500-508.
72. Silva Ramos FJ, Azevedo LC: Hemodynamic and perfusion end points for volemic resuscitation in sepsis. Shock. 2010; 34: 34-39.
73. Marx G, Pedder S, Smith L, Swaraj S, Grime S, Stockdale H, et al. Resuscitation from septic shock with capillary leakage: Hydroxyethyl starch (130 kd), but not Ringer's solution maintains plasma volume and systemic oxygenation. Shock 2004; 21: 336–41.
74. Perner A, Cecconi M, Cronhjort M, Darmon M, Jakob S, Pettila V. Expert statement for the management of hypovolemia in sepsis. Intensive Care Med 2018; 44: 791-798.
75. Parrillo JE, Parker MM, Natanson C, et al. Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med 1990; 113: 227-242.
76. Guarracino F, Bertini P, Pinsky MR. Cardiovascular determinants of resuscitation from sepsis and septic shock. Critical Care 2019; 23: 118.
77. De Backer D. Detailing the cardiovascular profile in shock patients. Critical Care 2017; 21 (3): 311.
78. Garcia-Alvarez M, Paul Marik, Rinaldo Bellomo. Sepsis-associated hyperlactatemia. Critical Care 2014; 18: 503-513.
79. Suetrong B, Walley KR. Lactic Acidosis in Sepsis: It’s Not All Anaerobic Implications for Diagnosis and Management. CHEST 2016; 149:252-261
80. Vincent JL, Quintairos A, Couto L, et al. The value of blood lactate kinetics in critically ill patients: a systematic review. Critical Care 2016; 20: 257-270.
81. Dunser M, Takala J, Brunauer A, Bakker J. Rethinking resuscitation: leaving blood pressure cosmetics behind and moving forward to permissive hypotension and a tissue perfusion-based approach. Critical Care 2013; 17 (5): 326
82. Aird WC. Endothelium as an organ system. Crit Care Med 2004; 32: S271-S279.
83. Segal S. Regulation of blood flow in the microcirculation. Microcirculation 2005; 12: 33-45.
84. Davis MJ. Perspective: physiological role(s) of the vascular myogenic response. MicrocirCulation 2012; 19: 99-114.
85. Moore J, Dyson A, Singer M, et al. Microcirculatory dysfunction and resuscitation: why, when, and how. British Journal of Anaesthesia 2015: 366–75
86. Chen K, Popel AS. Theoretical analysis of biochemical pathways of nitric oxide release from vascular endothelial cells. Free Radic Biol Med 2006; 41: 668-80.
87. Trzeciak S, Cinel I, Phillip Dellinger R, et al. Resuscitating the microcirculation in sepsis: the central role of nitric oxide, emerging concepts for novel therapies, and challenges for clinical trials. Acad Emerg Med 2008; 15: 399-413.
88. De Backer D, Ospina-Tascon G, Salgado D, et al. Monitoring the microcirculation in the critically ill patient: current methods and future approaches. Intensive Care Med 2010; 36: 1813 – 1825.
89. Chelazzi C, Villa G, Mancinelli P, De Gaudio AR, Adembri C. Glycocalyx and sepsis-induced alterations in vascular permeability. Crit Care 2015; 19: 26.
90. Price SA, Spain DA, Wilson MA, Harris PD, Garrison RN. Subacute sepsis impairs vascular smooth muscle contractile machinery and alters vasoconstrictor and dilator mechanisms. J Surg Res 1999; 83: 75–80.
91. Marechal X, Favory R, Joulin O, et al. Endothelial glycocalyx damage during endotoxemia coincides with microcirculatory dysfunction and vascular oxidative stress. Shock 2008; 29: 572-576.
92. Eichelbrönner O, Sielenkämper A, Cepinskas G, Sibbald WJ, ChinYee IH. Endotoxin promotes adhesion of human erythrocytes to human vascular endothelial cells under conditions of flow. Crit Care Med 2000; 28: 1865–70.
93. Ince C, Sinaasappel M. Microcirculatory oxygenation and shunting in sepsis and shock. Crit Care Med 27: 1369 –1377, 1999.
94. Hernandez G, Bruhn A, Ince C. Microcirculation in sepsis: new perspectives. Curr Vasc Pharmacol 2013; 11: 161–69.
95. Trzeciak S, McCoy JV, Phillip Dellinger R. Early increases in microcirculatory perfusion during protocol-directed resuscitation are associated with reduced multi-organ failure at 24 h in patients with sepsis. Intensive Care Med 2008; 34: 2210-2217.
96. Nelson A, Berkestedt I, Schmidtchen A, Ljunggren L, Bodelsson M. Increased levels of glycosaminoglycans during septic shock: relation to mortality and the antibacterial actions of plasma. Shock 2008; 30: 623–27.
97. Bateman RM, Sharpe MD, Jagger JE, et al. Sepsis impairs microvascular autoregulation and delays capillary response within hypoxic capillaries. Crit Care 2015. 19: 389.
98. Borutaite V, Matthias A, Harris H, et al. Reversible inhibition of cellular respiration by nitric oxide in vascular inflammation. Am J Physiol Heart Circ Physiol 2001; 281: H2256 –H2260.
99. Bateman RM, Sharpe MD, Ellis CG. Microvascular dysfunction in sepsis— hemodynamics, oxygen transport, and nitric oxide. Crit Care 2003; 7: 359 –73.
100. Marik PE. The demise of early goal directed therapy for severe sepsis and septic shock. Acta Anaesthesiol Scand 2015; 59: 561-567.
101. Singer M, De Santis V, Vitale D, et al. Multiorgan failure is an adaptive, endocrine-mediated, metabolic response to overwhelming systemic inflammation. Lancet 2004; 364: 545-8.
102. Hotchkiss RS, Swanson PE, Freeman BD, et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 1999; 27:1230-1251.
103. VanderMeer TJ, Wang H, Fink MP. Endotoxemia causes ileal mucosal acidosis in the absence of mucosal hypoxia in a normodynamic porcine model of septic shock. Crit Care Med 1995; 23: 1217-1226.
104. Sair M, Etherington PJ, Winlove CP, et al. Tissue oxygenation and perfusion in patients with systemic sepsis. Crit Care Med 2001; 29: 1343 -1349.
105. Singer M. Mitochondrial function in sepsis: acute phase versus multiple organ failure. Crit Care Med 2007; 35: 441-448
106. Schumacker PT, Chandel N, Agusti AG. Oxygen conformance of cellular respiration in hepatocytes. Am J Physiol Lung Cell Mol Physiol 1993; 265: 395- 400.
107. Brealey D, Karyampudi S, Jacques TS, et al. Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure. American Journal of Physiology—Regulatory Integrative and Comparative Physiology 2004; 286: 491-497.
108. Levy RJ. Mitochondrial dysfunction, bioenergetic impairment, and metabolic down-regulation in sepsis. Shock. 2007; 28: 24–28.
109. Carré, J.E. & Singer, M. Cellular energetic metabolism in sepsis: the need for a systems approach. Biochim Biophys Acta 2008; 1777:763–771.
110. Fink MP. Bench-to-bedside review: Cytopathic hypoxia. Crit Care 2002; 6: 491–99.
111. Bar-Or D, Carrick MM, Mains CW, Rael LT, Slone D, Brody EN. Sepsis, oxidative stress, and hypoxia: are there clues to better treatment? Redox Rep 2015; 20: 193-197.
112. Levy B, Desebbe O, Montemont C, et al. Increased aerobic glycolysis through beta2 stimulation is a common mechanism involved in lactate formation during shock states. Shock 2008; 30: 417-21.
113. Robergs R, Ghiasvand F, Parker D. Biochemistry of exercise-induced metabolic acidosis. Am J Physiol Regul Integr Comp Physiol 2004; 287: 502-516.
114. Crouser ED, Julian MW, Blaho DV, Pfeiffer DR. Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity. Crit Care Med. 2002; 30: 276–284.
115. Eyenga P, Roussel D, Morel J, et al. Early septic shock induces loss of oxidative phosphorylation yield plasticity in liver mitochondria. J Physiol Biochem 2014; 70: 285-296
116. Taylor DE, Ghio AJ, Piantadosi CA. Reactive oxygen species produced by liver mitochondria of rats in sepsis. Arch Biochem Biophys. 1995; 316: 70-76.
117. Galley H. F. Oxidative stress and mitochondrial dysfunction in sepsis. British Journal of Anaesthesia. 2011; 107: 57–64.
118. Levy RJ, Deutschman CS. Deficient mitochondrial biogenesis in critical illness: cause, effect, or epiphenomenon? Crit Care. 2007; 11: 158-159
119. Chaudry IH, Wichterman KA, Baue AE. Effect of sepsis on tissue adenine nucleotide levels. Surgery. 1979; 85: 205-211.
120. Hotchkiss RS, Morikawa S, Inubushi T, et al. Gluconeogenesis and phosphoenergetics in rat liver during endotoxemia. J Surg Res. 1998; 74: 179-186.
121. Brealey D, Brand M, Hargreaves I, et al. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 2002. 360: 219-23.
122. Frayn KN, et al. Metabolic regulation. A human perspective. 3rd edn. 2010. Oxford: Willey Blackwell, 2010.
123. Alberts B, et al. Molecular Biology of the Cell. 6th edn. 2015. New York. Taylor & Francis Group: Garland Science, 2015.
124. Rolfe DF, Brown GC. Cellular energy utilization and molecular origin of standard metabolic rate in mammals. Physiol Rev 1997; 77: 731-758.
125. Lehninger AL, Nelson DL, Cox MM. Lehninger principles of biochemistry 6th edn 2010. New York. Worth Publishers, 2010.
126. Nalos M, Robergs R. Underestanding hyperlactatemia in human sepsis: Are we there yet?. Am J Respir Crtic Care Med 2019; 200: 1069-70.
127. Corrêa TD, Jakob SM, Takala J. Mitochondrial function in sepsis. Crit Care Horizons. 2015; 1: 31-41.
128. Solaini G, Baracca A, Lenaz G, et al. Hypoxia and mitochondrial oxidative metabolism. Biochim. Biophys. Acta 2010; 1797: 1171–1177.
130. Duke T. Dysoxia and lactate. Archives of Disease in Childhood 1999; 81: 343-350.
131. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 1992; 12: 5447-5454.
132. Hochachka PW, Somero GN. Biochemical Adaptations. Mechanisms and Process 1st edn 1983. Princeton NJ, Princeton Univ Press 1983.
133. Hochachka PW. Oxygen, homeostasis, and metabolic regulation. Adv Exp Med Biol 2000; 475: 311-335.
134. Zhang JZ., Behrooz A., Ismail-Beigi F. Regulation of glucose transport by hypoxia. American Journal of Kidney Diseases 1999; 34 (1): 189-202.
135. Greijer A, van der Groep P, Kemming D, Shvarts A, Semenza G, Meijer G, et al. Up-regulation of gene expression by hypoxia is mediated predominantly by hypoxia-inducible factor 1 (HIF-1). The Journal of Pathology 2005; 206(3): 291–304.
136. Lum JJ, Bui T, Gruber M, et al. The transcription factor HIF-1alpha plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis. Genes Dev 2007; 21: 1037-1049.
137. Kim JW, Tchernyshyov I, Semenza GL, et al. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 2006; 3: 177-185.
138. Viollet B, Athea Y, Mounier R, et al. AMPK: lessons from transgenic and knockout animals. Front Biosci Review 2009; 14: 19-44.
139. Chandel NS, E. Maltepe E, Goldwasser E, et al. Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci USA 1998; 95: 11715-11720.
140. Warburg O. On the origin of cancer cells. Science 1956; 123: 309-314.
141. Bar-Or D, Carrick M, Tanner A, et al. Overcoming the Warburg Effect: Is it the key to survival in sepsis? J Crit Care 2018; 43:197-201.
142. Ganeshan K, Ajay Chawla A. Metabolic Regulation of Immune Responses. Annual Review of Immunology. 2014; 32:1, 609-634.
143. Staples JF. Metabolic suppression in mammalian hibernation: the role of mitochondria. J Exp Biol 2014; 217:2032-2036.
144. Senyilmaz D, Teleman AA. Chicken or the egg: Warburg effect and mitochondrial dysfunction. F1000Prime Rep 2015; 7: 41-47
145. Carré JE, Orban J-C, Re L, Felsmann K, Iffert W, Bauer M, et al. Survival in critical illness is associated with early activation of mitochondrial biogenesis. Am J Respir Crit Care Med. 2010; 182: 745-51.
146. Kim V, Tchernyshyov I, Semenza GL, et al. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 2006; 3: 177-185.
147. Handzlik MK, Constantin-Teodosiu D, Greenhaff PL, et al. Increasing cardiac pyruvate dehydrogenase flux during chronic hypoxia improves acute hypoxic tolerance. J Physiol 2018; 596 (15): 3357-3369.
148. Nuzzo E, Berg KM, Andersen LW. Pyruvate Dehydrogenase Activity Is Decreased in the Peripheral Blood Mononuclear Cells of Patients with Sepsis - A Prospective Observational Trial. Ann Am Thorac Soc 2015; 12 (11):1662-6.
149. Cooper CE, Giulivi C. Nitric oxide regulation of mitochondrial oxygen consumption II: molecular mechanism and tissue physiology. Am. J. Physiol. Cell Physiol 2007. 292: 1993–2003.
150. Galkin A, Abramov AY, Frakich N, et al. Lack of oxygen deactivates mitochondrial Complex I: implications for ischemic injury? J Biol Chem 2009. 284: 36055–36061.
151. Forget AP, Mangalaboyi J, Mordon S, et al. Escherichia coli endotoxin reduces cytochrome aa3 redox status in pig skeletal muscle. Crit Care Med 2000; 28: 3491-3497.
152. Barth E, Radermacher P, Thiemermann C, et al. Role of inducible nitric oxide synthase in the reduced responsiveness of the myocardium to catecholamines in a hyperdynamic, murine model of septic shock. Crit Care Med 2006; 34: 307-313.
153. Poyton RO, Ball KA, Castello PR. Mitochondrial generation of free radicals and hypoxic signaling. Trends Endocrinol. Metab 2009; 7: 332-340.
154. Haisch M, Fukagawa NK, Matthews DE. Oxidation of glutamine by the splanchnic bed in humans. Am J Physiol Endocrinol Metab 2000; 278: 593-602.
155. Owen OE, Smalley KJ, D’Alessio DA, et al. Protein, fat, and carbohydrate requirements during starvation: anaplerosis and cataplerosis. The American Journal of Clinical Nutrition 1998; 68: 12-34.
156. Meléndez-Hevia E, Waddell TG. Cascante M.The puzzle of the Krebs citric acid cycle: Assembling the pieces of chemically feasible reactions, and opportunism in the design of metabolic pathways during evolution. J Mol Evol 1996; 43: 293-303.
157. Martin W, Muller M. The hydrogen hypothesis for the first eukaryote. Nature 1998; 392: 37-41
158. Randall HM Jr, Cohen JJ. Anaerobic CO2 production by dog kidney in vitro. Am J Physiol 1966; 211: 493-505
159. D’Alessandro A, Slaughter AL, Peltz ED, et al. Trauma/hemorrhagic shock instigates aberrant metabolic flux through glycolytic pathways, as revealed by preliminary 13C-glucose labeling metabolomics. J Transl Med 2015; 13: 253-265.
160. Randle PJ, England PJ, Denton RM.Control of the tricarboxylate cycle and its interactions with glycolysis during acetate utilization in rat heart. Biochem J 1970; 117: 677-695.
161. Guynn RW, Gelberg HJ & Veech RL. Equilibrium constants of the malate dehydrogenase, citrate synthase, citrate lyase, and acetyl coenzyme A hydrolysis reactions under physiological conditions. J. Biol. Chem. 1973; 248: 6957–6965.
162. Cooney GJ, Taegtmeyer H, Newsholme EA. Tricarboxylic acid cycle flux and enzyme activities in the isolated working rat heart. Biochem J 1981; 200: 701-703.
163. Hochachka PW, Dressendorfer RH. Succinate accumulation in man during exercise. Eur J Appl Physiol Occup Physiol 1976. 35: 235-242.
164. Sanborn T, Gavin W, Berkowitz S, et al. Augmented conversion of aspartate and glutamate to succinate during anoxia in rabbit heart. Am J Physiol 1979; 237: H535-H541.
165. Shi Q, Gibson GE. Upregulation of the mitochondrial malate dehydrogenase by oxidative stress is mediated by miR-743a. J Neurochem 2011; 118: 440-448.
166. Des Rosiers C, Fernandez CA, David F, Brunengraber H. Reversibility of the mitochondrial isocitrate dehydrogenase reaction in the perfused rat liver. Evidence from isotopomer analysis of citric acid cycle intermediates. J Biol Chem 1994; 269: 27179-27182.
167. Comte B, Vincent G, Bouchard B, Benderdour M, Des Rosiers C. Reverse flux through cardiac NADP1-isocitrate dehydrogenase under normoxia and ischemia. Am J Physiol Heart Circ Physiol 2002; 283: H1505-H1514.
168. Mullen AR, Wheaton WW, Jin ES, et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 2012; 481: 385-388.
169. Phillips D, Aponte AM, French SA, Chess DJ, Balaban RS. Succinyl-CoA synthetase is a phosphate target for the activation of mitochondrial metabolism. Biochemistry 2009; 48: 7140-7149.
170. Siegel JH, Cerra FB, Coleman B, et al. Physiologic and metabolic correlations in human sepsis. Surgery 1979; 85:163.
171. Cerra FB, Siegel JH, Coleman B, et al. Septic autocannibalism a failure of exogenous nutritional support. Ann Surg 1980; 192: 570-579.
172. Infantino V, Convertini P, Cucci L, et al. The mitochondrial citrate carrier: a new player in inflammation. Biochem. J. 2011; 438: 433–436.
173. Infantino V, Iacobazzi V, Menga A, et al. A key role of the mitochondrial citrate carrier (SLC25A1) in TNFα- and IFNγ-triggered inflammation. Biochimica et biophysica acta 2014; 1839:1217-1225.
174. Cimen H, Han MJ, Yang Y, et al. Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria. Biochemistry 2010; 49: 304-311.
175. Mills E, O'Neill LA. Succinate: a metabolic signal in inflammation. Trends Cell Biol 2014; 24:313-320.
176. Rubic T, Lametschwandtner G, Hinteregger S, et al. Triggering the succinate receptor GPR91 on dendritic cells enhances immunity. Nat Immunol 2008; 9: 1261-1269.
177. Zhang Z1, Tan M, Xie Z, et al. Identification of lysine succinylation as a new post-translational modification. Nat Chem Biol. 2011; 7: 58-63.
178. Selak MA, Armour SM, MacKenzie ED, et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF- prolylhydroxylase. Cancer Cell 2005;7: 77-85.
179. Reisz JA, Wither MJ, Moore EE, Slaughter AL, Moore HB, Ghasabyan A, et al. All animals are equal but some animals are more equal than others: plasma lactate and succinate in hemorrhagic shock-A comparison in rodents, swine, nonhuman primates, and injured patients. J Trauma Acute Care Surg. 2018;84(3):537–41.
180. Hatib F, Jansen JRC, Pinsky MR. Peripheral vascular decoupling in porcine endotoxic shock. J Appl Physiol. 2011; 111:853–60.
181. Parkin WG, Leaning MS. Therapeutic control of the circulation. J Clin Comput Monit. 2008; 22:391.
182. Forni LG, McKinnon W, Lord GA, et al. Circulating anions usually associated with the Krebs cycle in patients with metabolic acidosis. Crit Care. 2005; 9: R591-R595.
183. McKinnon W, Lord GA, Forni LG, et al: A rapid LC-MS method for determination of plasma anion profiles of acidotic patients. J Chromatogr 2006, B833: 179-185.
184. Shurubor YI, Cooper AJ, Isakova EP, Deryabina YI, Beal MF, Krasnikov BF. Simultaneous determination of tricarboxylic acid cycle metabolites by high-performance liquid chromatography with ultraviolet detection. Analytical Biochemistry. 2017; 503: 8-10.
185. Mycielska ME, Patel A, Rizaner A, Mazurek MP, Keun H, Patel A, et al. Citrate transport and metabolism in mammalian cells: prostate epithelial cells and prostate cancer. Bioessays 2009; 31 (1): 10–20.
186. Dabek M, Kruszewska D, Filip R, Hotowy A, Pierzynowski L, Wojtasz-Pajak A, et al. Alpha-Ketoglutarate (AKG) absorption from pig intestine and plasma pharmacokinetics. J. Anim. Physiol. Anim. Nutr. 2005; 89: 419–426.
187. Hofmann GF, Meier-Augenstein W, Stöckler S, Surtees R, Rating D, Nyhan WL. Physiology and pathophysiology of organic acids in cerebrospinal fuid. Journal of Inherited Metabolic Disease 1993; 16 (4): 648–669.
188. Mongan, PD, Fontana, JL, Chen, R, Bünger, R. Intravenous pyruvate prolongs survival during hemorrhagic shock in swine. Am J Physiol Heart Circ Physiol 1999; 277: H2253–63.
189. Hofmaier F., Dinger K., Braun R., Sterner-Kock A. Range of blood lactate values in farm pigs prior to experimental surgery. Lab. Anim. 2013; 47: 130–132.
190. Jakob SM, Suistomaa M, Takala J. Lactate, Lactate/Pyruvate Ratio, Low Tissue Perfusion and Outcome. En: Vincent JL editor, Yearbook of Intensive Care and Emergency Medicine 2001. Berlin, Heidelberg: Springer; 2001:268-277.
191. Hess M, Hastillo A, Greenfield L. Spectrum of cardiovascular function during gram negative sepsis. Progress in cardiovascular diseases. 1980;23(4):279-289
192. Pinsky M Rico P. Cardiac Contractility Is Not Depressed in Early Canine Endotoxic Shock. Am. J. Respir. 1999; 161:4
193. Fink MP, Heard SO. Laboratory models of sepsis and septic shock. J. Surg. Res. 1990; 49: 186–196.
194. Schmidhammer R, Wassermann E, Germann P, Redl H, Ullrich R. Infusion of increasing doses of endotoxin induces progressive acute lung injury but prevents early pulmonary hypertension in pigs. Shock 2006;25(4):389-94.
195. Houser B, Vogt J, Wachter U, Brückner UB, Fink MP. Ethyl pyruvate improves systemic and hepatosplanchnic hemodynamics and prevents lipid peroxidation in a porcine model of resuscitated hyperdynamic endotoxemia. Crit Care Med 2005;33(9):2034-42.
196. Cunha-Goncalves, Perez-de-sa V. Inotropic support during experimental endotoxemic shock: part I. The effects of levosimendan on splanchnic perfusion. Anesth Analg 2009;109(5):1568-75.
197. Udhoji VN, Weil MH. Hemodynamic and metabolic studies on shock associated with bacteremia. Ann Intern Med. 1985; 62: 966-978.
198. van Genderen, J De Jonge, Visser SS, Voorbeijtel J. Microvascular Perfusion as a Target for Fluid Resuscitation in Experimental Circulatory Shock. Crit Care Med 2014;42(2):e96-e105.
199. Byrne L, Obonyo NG, Diab S, Dunster K, Passmore M. An ovine model of hyperdynamic endotoxemia and vital organ metabolism. Shock 2018;49(1):99-107.
200. Cunha-Goncalves Perez-de-sa V. Inotropic support during experimental endotoxemic shock: part II. A comparison of levosimendan with dobutamine Anesth Analg 2009 Nov;109(5):1576-83.
201. Natanson C, Danner RL, Fink MP, MacVittie TJ, Walker RI, Conklin JJ, Parrillo JE. Cardiovascular performance with E. coli challenges in a canine model of human sepsis. Am J Physiol. 1988; 254: H558-H569.
202. Shoemaker WC. Cardiorespiratory patterns in complicated uncomplicated septic shock. Ann Surg. 1971; 174: 119-125.
203. Natanson C, Fink MP, Ballantyne HK, MacVittie TJ, Conklin JJ, Parrillo JE. Gram-negative bacteremia produces both severe systolic and diastolic cardiac dysfunction in a canine model that simulates human septic shock. J Clin Invest. 1986;78(1):259-270.
204. Chittock DR, Ronco JJ, Rusell JA. Monitoring of oxygen transport and oxygen consumption. En: Tobin JM editor, Principles and practice of intensive care monitoring. New York: McGraw-Hill; 1998. 317-344.
205. Chemla D, Coirault C, Hebert JL, Lecarpentier Yves. Mechanics of relaxation of the human heart. Physiology 2000; 15: 2: 78-83.
206. Schumacker PT, Cain SM. The concept of a critical oxygen delivery. Intensive Care Med 1987; 13: 223–9.
207. Friedman G, De Backer D, Shahla M, Vincent JL. Oxygen supply dependency can characterize septic shock Intensive Care Medicine 1998; 24 (2): 118–123.
208. Walley KR. Heterogeneity of oxygen delivery impairs oxygen extraction by peripheral tissues: theory. J Appl Physiol 1996; 81: 885–894.
209. Grist G. Oxygen pressure field theory: a detailed description of vital gas exchange, at the capillary level for perfusionist. Progress in Pediatric Cardiology; 24 (2): 89-99
210. Donati A, Damiani E, Domizi R, Romano R, Adrario E, Pelaia P, et al. Alteration of the sublingual microvascular glycocalyx in critically ill patients. Microvasc Res. 2013; 90: 86-89.
211. Siegemund M, van Bommel J, Schwarte LA, Studer W, Girard T, Marsch S, Radermacher P, Ince C. Inducible nitric oxide synthase inhibition improves intestinal microcirculatory oxygenation and CO2 balance during endotoxemia in pigs. Intensive Care Med 2005; 31: 985–992,
212. Stratton HH, Feustel PJ, Newell JC: Regression of calculated variables in the presence of shared measurement error. J Appl Physiol. 1987; 62: 2083-2093.
213. Ronco JJ, Phang PT, Walley KR, et al: Oxygen consumption is independent of changes in oxygen delivery in severe adult respiratory distress syndrome. Am Rev Respir Dis. 1991; 143:1267-1273.
214. Vincent JL, Roman A, De Backer D, Kahn RJ. Oxygen uptake/supply dependency: effects of short-term dobutamine infusion. Am Rev Respir Dis. 1990; 142: 2–8.
215. Liu MS, GF Kang. Liver glycogen metabolism in endotoxin shock. I. Endotoxin administration decreases glycogen synthase activities in dog livers. Biochem. Med. Metab. Biol 1987; 37: 61–72.
216. van der Crabben SN, Blümer RM, Stegenga ME, Ackermans MT, Endert E, Tanck MW, et al. Early endotoxemia increases peripheral and hepatic insulin sensitivity in healthy humans. J Clin Endocrinol Metab. 2009 Feb; 94 (2): 463-8.
217. Hagar JA, Edin ML, Lih FB, Thurlow LR, Koller BH, Cairns BA, et al. Lipopolysaccharide potentiates insulin-driven hypoglycemic shock. The Journal of Immunology. 2017; 199 (10): 3634-3643.
218. Breadley D, Singer M. Hyperglicemia in critical illness: A review J Diabetes Sci Technol 2009; 3 (6):1250-1260.
219. Kvidera SK, Horst EA, Mayorga EJ, Sanz-Fernandez MV, Abuajamieh M, Baumgard LH. Estimating glucose requirements of an activated immune system in growing pigs. J Anim Sci. 2017; 11: 5020-5029.
220. Raetzsch CF, Brooks NL, Alderman JM, Moore KS, Hosick PA, Klebanov S, et al. Lipopolysaccharide inhibition of glucose production through the Toll-like receptor-4, myeloid differentiation factor 88, and nuclear factor kappa b pathway Hepatology 2009; 50: 592–600.
221. Tanaka H, Nishikawa Y, Fukushima T, Taniguchi A, Fujita Y, Tsuda K, et al. Lipopolysaccharide inhibits hepatic gluconeogenesis in rats: The role of immune cells. Journal of diabetes investigation 2017; 9 (3): 494–504.
222. Lv S, Qiu X, Li J, Li W, Zhang C, Zhang ZN et al. Suppression of CRTC2-mediated hepatic gluconeogenesis by TRAF6 contributes to hypoglicemia in septic shock. Cell Discov 2016; 2: 16046.
223. Clendenen N, Nunns GR, Moore EE, Reisz JA, Gonzalez E, Peltz E, et al. Hemorrhagic shock and tissue injury drive distinct plasma metabolome derangements in swine. J Trauma Acute Care Surg. 2017; 83(4): 635–642.
224. Varvarousis D, Xanthos T, Ferino G, Noto A, Iacovidou N, Mura M, Scano P, Chalkias A, Papalois A, De-Giorgio F, Baldi A, Mura P, Staikou C, Stocchero M, Finco G, d'Aloja E, Locci E. Metabolomics profiling reveals different patterns in an animal model of asphyxial and dysrhythmic cardiac arrest. Sci Rep 2017; 7:16575.
225. Solberg R, Enot D, Deigner HP, Koal T, Scholl-Bürgi S, Saugstad OD,Matthias K. Metabolomic analyses of plasma reveals new insights into asphyxia and resuscitation in pigs. PLoS One. 2010; 5: e9606.
226. Chinopoulos C. Succinate in ischemia: Where does it come from? Int J Biochem Cell Biol. 2019; 115:105580.
227. Lukyanova LD, Kirova YI, Germanova, EL. The Role of Succinate in Regulation of Immediate HIF-1α Expression in Hypoxia. Bulletin of Experimental Biology and Medicine, 2018; 164(3): 298–303.
228. Zhang J, Wang YT, MillerJH, DayMM, Munger JC, Brookes PS. Accumulation of succinate in cardiac ischemia primarily occurs via canonical krebs cycle activity. Cell Rep. 2018; 23: 2617 - 2628.
229. Hunter FE. Anaerobic phosphorylation due to a coupled oxidation-reduction between alpha-ketoglutaric acid and oxalacetic acid. J. Biol. Chem. 1949; 177: 361–372.
230. Kiss G, Konrad C, Pour-Ghaz I, Mansour JJ, Nemeth B, Starkov AA, et al. Mitochondrial diaphorases as NAD(+) donors to segments of the citric acid cycle that support substrate-level phosphorylation yielding ATP during respiratory inhibition. FASEB J. 2014; 28: 1682–1697.
231. Tugtekin IF, Radermacher P, Theisen M, Matejovic M, Stehr A, Ploner K, et al. Increased ileal-mucosal-arterial PCO2 gap is associated with impaired villus microcirculation in endotoxic pigs. Intensive Care Med. 2001; 27:757-766.
232. Langenberg C, Wan L, Egi M, May CN, Bellomo R. Renal blood flow in experimental septic acute renal failure. Kidney Int 2006; 69: 1996–2002.
233. Cossu AP, Suelzu S, Piu P, Orecchioni M, Bazzu G, Padua G. Do on- and off-pump coronary bypass surgery differently affect perioperative peripheral tissue metabolism? Minerva Anestesiol 2012;78(1):26-33.
234. Sahuquillo J, Merino M-A, Sánchez-Guerrero A, Arikan F, Vidal-Jorge M, Martínez-Valverde T. Lactate and the Lactate-to-Pyruvate Molar Ratio Cannot Be Used as Independent Biomarkers for Monitoring Brain Energetic Metabolism: A Microdialysis Study in Patients with Traumatic Brain Injuries. PLoS ONE 9(7): e102540.
235. von Platen A, D`Souza M. Evaluation of Intrahepatic Lactate / Pyruvate Ratio As a Marker for Ischemic Complications. Transplant Direct. 2019; 5(12): e505
236. Kilgour E, Vernon RG. Catecholamine activation of pyruvate dehydrogenase in white adipose tissue of the rat in vivo. Biochem J 1987;241:415–9.
237. Kuyper AC, Mattill HA. Some aspects of citric acid metabolism. J. Biol. Chem. 103: 51-60.
238. Costello LC, Franklin RB. Plasma citrate homeostasis, how it is regulated, and its physiological and clinical implications. An important, but neglected, relationship in medicine. HSOA J. Hum. Endocrinol. 2016; 1: 5.
239. Mycielska ME, Milenkovic VM, Wetzel CH, Rümmele P, Geissler E.K. Extracellular Citrate in Health and Disease. Curr. Mol. Med. 2015; 15: 884–891.
240. Jha AK, Huang SC, Sergushichev A, Lampropoulou V, Ivanova Y, Loginicheva E, Chmielewski K. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization.Immunity. 2015; 42: 419-430.
241. Williams NC, O’Neill LA. A role for the Krebs cycle intermediate citrate in metabolic reprogramming in innate immunity and inflammation. Front. Immunol. 2018: 9: 141.
242. Fensterheim BA, Young JD, Luan L, Kleinbard RR, Stothers CL, Patil NK, et al. The TLR4 Agonist Monophosphoryl Lipid A Drives Broad Resistance to Infection via Dynamic Reprogramming of Macrophage Metabolism. J Immunol 2018;200(11):3777-3789.
243. Lampropoulou V, Sergushichev A, Bambouskova M, Nair S, Vincent EE, Loginicheva E, et al. Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab. 2016; 24: 158–166.
244. Mcbride MA, Owen AM, Stothers CL, Hernandez A, Luan L, Burelbach KR, et al. The Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma. Front Immunol 2020;11:1–21.
245. Vary TC, Siegel JH, Nakatani T, Sato T, Aoyama H: Effect of sepsis on the activity of the pyruvate dehydrogenase complex in skeletal muscle and liver. Am J Physiol. 1986; 250: E634-E640.
246. Beloborodova NV, Pautova AK, Sergeev, Fedotcheva NI. Serum Levels of Mitochondrial and Microbial Metabolites Reflect Mitochondrial Dysfunction in Different Stages of Sepsis. Metabolites. 2019; 9 (10):196.
247. Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010; 303: 739-46.
248. Puskarich MA, Trzeciak S, Shapiro NI, Arnold RC, Heffner AC, Kline JA, et al. Prognostic value and agreement of achieving lactate clearance or central venous oxygen saturation goals during early sepsis resuscitation. Acad Emerg Med. 2012; 19: 252-258.
249. Hernandez G, Ospina-Tascón GA, Damiani LP, et al. Effect of a resuscitation strategy targeting peripheral perfusion status vs serum lactate levels on 28-day mortality among patients with septic shock: the ANDROMEDA-SHOCK randomized clinical trial. JAMA. 2019; 321: 654-64.
250. Hernandez G, Bellomo R, Bakker J. The ten pitfalls of lactate clearance in sepsis. Intensive Care Med. 2019; 45 (1): 82-85.
251. Huckabee WE. Relationships of pyruvate and lactate during anaerobic metabolism. 1. Effects of infusion of pyruvate or glucose and of hyperventilation. J Clin Invest. 1958; 37:244-254
252. Broder G, Weil MH. Excess Lactate: An Index of Reversibility of Shock in Human Patients. Science. 1964; 143:1457–1459.
253. Howell MD, Donnino M, Clardy P, Talmor D, Shapiro NI. Occult hypoperfusion and mortality in patients with suspected infection. Intensive Care Med. 2007 Nov; 33(11): 1892–1899.
254. Gattinoni L, Vasques F, Camporota L, Meessen J, Romitti F, Pasticci I, et al. Understanding lactatemia in human sepsis: potential impact for early management. Am J Respir Crit Care Med. 2019; 200: 582–589.
255. Takala J, Uusaro A, Parviainen I, Ruokonen E. Lactate metabolism and regional lactate exchange after cardiac surgery. New Horiz 1996; 4: 483-492.
256. Mizock BA. The hepatosplanchnic area and hyperlactatemia: A tale of two lactates. Crit Care Med. 2001; 29 (2): 447–449.
257. Bellomo R. Bench-to-bedside review: Lactate and the kidney. Crit Care. 2002; 6(4): 322-326.
258. Revelly JP, Tappy L, Martinez A, Bollmann M, Cayeux MC, Berger MM, et al. Lactate and glucose metabolism in severe sepsis and cardiogenic shock. Crit Care Med. 2005; 33: 2235-40.
259. Myburgh JA, Higgins A, Jovanovska A, Lipman J, Ramakrishnan N, Santamaria J CAT Study Investigators. A comparison of epinephrine and norepinephrine in critically ill patients. Intensive Care Med. 2008;34:2226–2234.
260. Levy B, Sadoune LO, Gelot AM, Bollaert PE, Nabet P, Larcan A: Evolution of lactate/pyruvate and arterial ketone body ratios in the early course of catecholamine-treated septic shock. Crit Care Med. 2000; 28: 114-119.
261. Rimachi R, De Carvahlo FB, Orellano-Jimenez C, Cotton F, Vincent JL, De Backer D. Lactate/Pyruvate Ratio as a Marker of Tissue Hypoxia in Circulatory and Septic Shock. Anaesthesia and Intensive Care. 2012; 40 (3): 427-432.
262. Huckabee W. Abnormal resting blood lactate. Am. J. Med 1961;30: 833-839
263. Brandt S, Regueira T, Bracht H, Porta F, Djafarzadeh S, Takala J, et al. Effect of fluid resuscitation on mortality and organ function in experimental sepsis models Crit Care. 2009; 13(6): R186.
264. Khodakova A, Beloborodova N. Mitochondrial metabolites in the blood patients with sepsis. Crit Care 2007; 11 (4): P5.
265. Fedotcheva NI, Kazakov RE, Kondrashova MN, Beloborodova NV. Toxic effects of microbial phenolic acids on the functions of mitochondria. Toxycol. Lett. 2008; 180: 182-188.
266. Cordes T, Wallace M, Michelucci A, Divakaruni AS, Sapcariu SC, Sousa C, et al. Immunoresponsive gene 1 and itaconate inhibit succinate dehydrogenase to modulate intracellular succinate levels. J. Biol. Chem. 2016; 291: 14274-14284.
267. Meiser J, Kraemer L, Jaeger C,Madry H, Link A, Lepper PM, Hiller K, Schneider JG. Itaconic acid indicates cellular but not systemic immune system activation. Oncotarget. 2018; 9: 32098-32107.
268. Liu MS, Zhang JN. Glycolytic and tricarboxylic acid cycle intermediates in dog livers during endotoxic shock. Biochemical medicine 1985; 34 (3): 335-343.
269. Plummer MP, Deane AM. Dysglycemia and Glucose Control During Sepsis. Clinics in Chest Medicine 2016; 37(2): 309-319.
270. Ferreira FBD, dos Santos C, Bruxel MA, Nunes EA, Spiller F, Rafacho A. Glucose homeostasis in two degrees of sepsis lethality induced by caecum ligation and puncture in mice. Int J Exp Pathol 2017; 98: 98-40.
271. Yang S, Cioffi WG, Bland KI, Chaudry IH, Wang P. Differential alterations in systemic and regional oxygen delivery and consumption during the early and late stages of sepsis. J Trauma 1999; 47: 706-12.
272. Morita Y, Chin-Yee I, Yu P, Sibbald WJ, Martin CM. Critical Oxygen Delivery in Conscious Septic Rats under Stagnant or Anemic Hypoxia. American Journal of Respiratory and Critical Care Medicine 2003; 167(6): 868–872.
273. Tao W, Deyo DJ, Traber DL, Johnston WE, Sherwood ER. Hemodynamic and Cardiac Contractile Function During Sepsis Caused by Cecal Ligation and Puncture in Mice. Shock 2004; 21(1): 31–37.
274. Hotchkiss RS, Song SK, Neil JJ, Chen RD, Manchester JK, Karl IE, et al. Sepsis does not impair tricarboxylic acid cycle in the heart. Am J Physiol Cell Physiol 1991; 260 (1):C50–C57.
275. Lado-Abeal J, Martinez-Sánchez N, Cocho JA, Martín-Pastor M, Castro-Piedras I, Couce-Pico ML, et al. Lipopolysaccharide (LPS)-induced septic shock causes profound changes in myocardial energy metabolites in pigs. Metabolomics 2018; 14 (10): 131.
276. Liu Z, Yin P, Amathieu R, Savarin P, Xu G. Application of LC-MS-based metabolomics method in differentiating septic survivors from non-survivors. Analytical and Bioanalytical Chemistry 2016; 408 (27): 7641-7649.
277. Cerra FB. The hypermetabolism organ failure complex. World J. Surg. 1987; 11: 173-181.
278. Muleme HM, Walpole AC, Staples JF. Mitochondrial metabolism in hibernation: metabolic suppression, temperature effects, and substrate preferences. Physiol Biochem Zool 2006; 79: 474-483.
279. Fedotcheva NI, Litvinova EG, Kamzolova SV, Morguno IG, Amerkhanov ZG. Mitochondrial metabolites in tissues as indicators of metabolic alterations during hibernation. Cryo Lett 2010; 31: 392-400.
280. Zhao Z, Oort A, Tao Z, O’Brien WG, Lee CC. Metabolite profiling of 5′-AMP induced hypometabolism. Metabolomics. 2014; 10: 63-76.
281. Lei Z, Huhman DV, Sumner L.W. Mass spectrometry strategies in metabolomics. J. Biol. Chem. 2011; 286: 25435–25442.
282. Al Kadhi O, Melchini A, Mithen R, Saha S. Development of a LC-MS-MS method for the simultaneous detection of tricarboxylic acid cycle intermediates in a range of biological matrices.Journal of Analytical Methods in Chemistry. 2017, 5391832.
283. Beloborodova NV, Sarshor YN, Bedova AY, Chernevskaya EA, Pautova AK. Involvement of aromatic metabolites in the pathogenesis of septic shock. Shock 2018, 50, 273–279.
284. Ospina-Tascón GA, Umaña M, Bermudez W, Bautista-Rincon DF, Hernandez G, Bruhn A. et al. Combination of arterial lactate levels and venous-arterial CO2 to arterial-venous O 2 content difference ratio as markers of resuscitation in patients with septic shock. Intensive Care Med 2015; 41: 796-805
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dc.publisher.branch.spa.fl_str_mv Universidad Nacional de Colombia - Sede Bogotá
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spelling Atribución-NoComercial-SinDerivadas 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Diaztagle Fernández, Juan José6a5c3f8d549d0a68744a83a0196723e2Caicedo Ruiz, Juan Daniel8e00e258277ad9a2d92eab830a2e77fc0000-0001-6488-806X2023-10-05T16:00:38Z2023-10-05T16:00:38Z2023-10-02https://repositorio.unal.edu.co/handle/unal/84766Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/ilustracionesRESUMEN. Introducción: El ciclo de Krebs o ciclo de los ácidos tricarboxilicos (CAT) se considera tradicionalmente como una vía cíclica que opera acoplada a la fosforilación oxidativa. En condiciones de hipoxia se asume que el CAT se encuentra detenido. Sin embargo, la persistencia del funcionamiento del CAT en estados de choque ha sido documentada, así como la “fragmentación” de sus reacciones enzimáticas en modelos animales de hipoxia conllevando a la persistencia de sus reacciones catabólicas. El objetivo de este trabajo es identificar la cinética de los intermediarios del CAT en el plasma durante el choque por endotoxemia en un modelo porcino. Métodos: Estudio experimental, a 9 porcinos se les suministró LPS de E. Coli hasta el desarrollo de choque (PAM<50 mmHg), 3 porcinos se utilizaron como controles. Se obtuvieron muestras de sangre venosa en 3 tiempos: T0: inmediatamente antes del suministro de endotoxina o placebo, T1: 3-horas posterior a su suministro, T2: 6-horas posterior a su suministro. La cuantificación de los intermediarios del CAT, lactato y piruvato en plasma se realizó mediante cromatografía liquida. Como medida de la progresión a la anaerobiosis se utilizó la relación entre lactato y piruvato (L/P). Las diferencias de las medianas de las concentraciones entre T0-T1, T0-T2 y T1-T2 para cada grupo se analizaron con el test de Wilkoxon, igualmente, se analizó la diferencia entre grupo control y grupo endotoxina para cada tiempo. Finalmente, se realizó una regresión lineal univariada entre las concentraciones de los intermediarios del CAT y los valores de lactato. Resultados: En el grupo control el citrato fue el metabolito del CAT predominante en plasma en T2 (180 μmol/L). En contraste, en condiciones de endotoxemia el succinato fue el metabolito mas abundante a nivel plasmatico (783 μmol/L). En el grupo de endotoxemia los únicos metabolitos del CAT que presentaron variaciones significativas fueron: Succinato (T0:370.00 - T1:586.67 - T2:783.33 μmol/L; p<0.05) y citrato (T0:190 - T2: 540 μmol/L; p<0.05). Los demás intermediarios no presentaron variaciones significativas durante la experimentación. La regresión lineal entre los niveles de lactato y succinato obtuvo un coeficiente de determinación de 0.347 (p=0.003). Conclusiones: La elevación reportada en los niveles de succinato y citrato durante el transcurso de nuestro biomodelo de endotoxemia sugiere un incremento de la actividad catabólica a nivel celular. Así mismo, los niveles elevados de succinato se correlacionan de manera parcial con la hiperlactatemia que se observa durante la endotoxemia. (Texto tomado de la fuente)SUMMARY. Introduction: The Krebs cycle or tricarboxylic acid cycle (TAC) is traditionally considered as a cyclic pathway that operates coupled to oxidative phosphorylation. Under conditions of hypoxia it is assumed that the TAC is arrested. However, the persistence of TAC function in shock states has been documented, as well as the "fragmentation" of its enzymatic reactions in animal models of hypoxia leading to the persistence of its catabolic reactions. The aim of this work is to identify the kinetics of TAC intermediates in plasma during endotoxemia shock in a swine model. Methods: Experimental study, 9 swine were given LPS of E. coli until the development of shock (MAP<50 mmHg), 3 swine were used as controls. Venous blood samples were obtained at 3 times: T0: immediately before endotoxin or placebo administration, T1: 3-hours after administration, T2: 6-hours after administration. The quantification of TAC intermediates, lactate and pyruvate in plasma was performed by liquid chromatography. The lactate to pyruvate ratio (L/P) was used as a measure of progression to anaerobiosis. The differences in median concentrations between T0-T1, T0-T2 and T1-T2 for each group were analyzed with the Wilkoxon test, as well as the difference between the control group and the endotoxin group for each time. Finally, a univariate linear regression was performed between the concentrations of TAC intermediates and lactate values. Results: In the control group citrate was the predominant TAC metabolite in plasma at T2 (180 μmol/L). In contrast, under endotoxemia conditions succinate was the most abundant metabolite at plasma level (783 μmol/L). In the endotoxemia group the only TAC metabolites that presented significant variations were: succinate (T0:370.00 - T1:586.67 - T2:783.33 μmol/L; p<0.05) and citrate (T0:190 - T2: 540 μmol/L; p<0.05). The other intermediates did not present significant variations during the experimentation. Linear regression between lactate and succinate levels obtained a coefficient of determination of 0.347 (p=0.003). Conclusions: The reported elevation in succinate and citrate levels during the course of our endotoxemia biomodel suggests increased catabolic activity at the cellular level. Likewise, elevated succinate levels correlate partially with the hyperlactatemia observed during endotoxemia.Maestría112 páginasapplication/pdfspa610 - Medicina y salud::612 - Fisiología humanaRespiración de la célulaÁcidos tricarboxilicosRespiração CelularTricarboxylic AcidsCiclo de krebsCiclo de los ácidos tricarboxílicosSepsisChoque sépticoReprogramación metabolicaCromatografía líquidaKrebs cycleTricarboxylic acid cycleSepsisSeptic shockMetabolic reprogrammingLiquid chromatographyAnálisis de los intermediarios del ciclo de krebs durante las primeras 6 horas de endotoxemia inducida por lipopolisacárido en un modelo de sepsis porcina.Krebs cycle intermediates during the first 6 hours of lipopolysaccharide-induced endotoxemia in a swine sepsis modelTrabajo de grado - Maestríainfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/acceptedVersionTexthttp://purl.org/redcol/resource_type/TMBogotá - Medicina - Maestría en FisiologíaFacultad de MedicinaBogotá, ColombiaUniversidad Nacional de Colombia - Sede Bogotá1. Seymour CW, Kennedy JN, Wang S, Chang CH, Elliott CF, Xu Z, et al. Derivation, validation, and potential treatment implications of novel clinical phenotypes for sepsis. JAMA. 2019; 321(20): 2003-2017.2. Rhee C, Dantes R, Epstein L, et al. Incidence and trends of sepsis in US hospitals using clinical vs claims data, 2009-2014.JAMA. 2017;318(13):1241- 1249.3. Rhodes, A., Evans, L.E., Alhazzani, W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med 2017; 43: (3) 304-3774. Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001; 286: 1869-78.5. Vincent JL, Francois B, Zabolotskikh I, Daga MK, Lascarrou JB, Kirovet MY, et al. Effect of a recombinant human soluble thrombomodulin on mortality in patients with sepsis-associated coagulopathy: the SCARLET randomized clinical trial. JAMA 2019; 321: 1993-2002.6. Vincent JL. Improved survival in critically ill patients: are large RCTs more useful than personalized medicine? No. Intensive Care Med 2016; 42: 1778-80.7. Kent DM, Hayward RA. Limitations of applying summary results of clinical trials to individual patients: the need for risk stratification. JAMA. 2007;298(10):1209-1212.8. Itenov TS, Murray DD, Jensen JUS. Sepsis: personalized medicine utilizing “omic” technologies-a paradigm shift? Healthcare (Basel) 2018; 6:1-9.9. Langley RJ, Tsalik EL, Velkinburgh JCV, Glickman SW, Rice BJ, Wang C, et al. An integrated clinico-metabolomic model improves prediction of death in sepsis. Sci Transl Med. 2013; 5: 195ra95.10. Clayton TA, Lindon JC, Cloarec O, Antti H, Charuel C, Hanton G. et al. Pharmaco-metabonomomic phenotyping and personalized drug treatment. Nature 2006; 440: 1073-7.11. Van Wyngene L., Vandewalle J., Libert C. (2018). Reprogramming of basic metabolic pathways in microbial sepsis: therapeutic targets at last? EMBO Mol. Med. 10:e8712.12. Gomez H, Kellum JA, Ronco C. Metabolic reprogramming and tolerance during sepsis-induced AKI. Nat Rev Nephrol 2017; 13: 143-15119.13. Pool R, Gomez H, Kellum JA. Mechanisms of Organ Dysfunction in Sepsis. Crit Care Clin 2018; 34: 63-80.14. Sun J, Zhang J, Tian J, Virzì GM, Digvijay K, Cueto L, et al. Mitochondria in Sepsis-Induced AKI. JASN 2019; 30 (7): 1151-1161.15. Hotchkiss RS, Karl IE. Reevaluation of the role of cellular hypoxia and bioenergetic failure in sepsis. JAMA 1992; 267:1503–1510.16. Spronk P, Zandstra D, Ince C. Bench-to-bedside review: Sepsis is a disease of the microcirculation Crit Care 2004; 8 (6): 462–68.17. Nelson DP, Samsel RW, Wood LDH, et al: Pathological supply dependence of systemic and intestinal 02 uptake during endotoxemia. J Appl Physiol. 1988; 64:2410-2419.18. Ospina-Tascón GA, García Marin AF, Echeverri GJ, Bermudez WF, Madriñan-Navia H, Valencia JD, et al. Effects of dobutamine on intestinal microvascular blood flow heterogeneity and O2 extraction during septic shock. Journal of Applied Physiology. (1985) 2017; 122 (6): 1406-1417.19. Fink MP. Cytopathic Hypoxia Mitochondrial Dysfunction as Mechanism Contributing to Organ Dysfunction in Sepsis. Crit Care Clin 2001; 17: 219-23720. Warburg O. The metabolism of carcinoma cells. Cancer Res 1925; 9: 148-163.21. Srivastava A, Mannam P. Warburg revisited: lessons for innate immunity and sepsis. Front Physiol 2015; 6: 70.22. Cheng S, Scicluna B, Arts R. Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis. Nat. Immunol. 2016; 17:406-413.23. Cambiaghi A, Pinto BB, Brunelli L, Falcetta F, Aletti F, Bendjelid K, et al. Characterization of a metabolomic profile associated with responsiveness to therapy in the acute phase of septic shock. Sci Rep. 2017; 7 (1): 9748.24. Whelan SP, Carchman EH, Kautza B, et al. Polymicrobial sepsis is associated with decreased hepatic oxidative phosphorylation and an altered metabolic profile. J Surg Res 2014; 186:297–303.25. Waltz P, Carchman E, Gomez H, and Zuckerbraun B. Sepsis results in an altered renal metabolic and osmolyte profile. J Surg Res. 2016; 202: 8-12.26. Weinberg JM, Venkatachalam MA, Roeser NF, Nissim I. Mitochondrial dysfunction during hypoxia/reoxygenation and its correction by anaerobic metabolism of citric acid cycle intermediates. Proc Natl Acad Sci USA 2000; 97: 2826–2831.27. Chinopoulos C. Which way does the citric acid cycle turn during hypoxia? - The critical role of alpha-ketoglutarate dehydrogenase complex. J. Neurosci. Res. 2013; 91: 1030–1043.28. Randall HM Jr, Cohen JJ. Anaerobic CO2 production by dog kidney in vitro. Am J Physiol 1966; 211: 493-505.29. Baldwin JE, Krebs H. the evolution of metabolic cycles. Nature 1981; 291: 381-382.30. Owen OE, Kalhan SC, Hanson RW. The key role of anaplerosis and cataplerosis for citric acid cycle function. J Biol Chem 2002; 277:30409-30412.31. Tannahill, G.M et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature. 2013; 496:238-24232. Koivunen P, Hirsilä M, Remes AM, et al. Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF. J Biol Chem 2007; 282: 4524-4532.33. Mills, E. L. et al. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell. 2016; 167: 457-470.34. Chouchani ET, Pell VR, Gaude E, Aksentijevíc D, Sundier SY, Robb EL et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 2014; 525: 431-436.35. Mickiewicz B, Duggan GE, Winston BW, Doig C, Kubes P, Vogel HJ. Metabolic profiling of serum samples by 1H nuclear magnetic resonance spectroscopy as a potential diagnostic approach for septic shock. Crit Care Med. 2014; 42: 1140–1149.36. Fedotcheva NI, Litvinova EG, Osipov AA, Olenin AY, Moroz VV, et al. Influence of Microbial Metabolites of Phenolic Nature on the Activity of Mitochondrial Enzymes. Biofzika 2015; 60 (6): 1118-1124.37. Mackenzie IM. The haemodynamics of human septic shock. Anaesthesia 2001; 56: 130-144.38. Hotchkiss R, et al. Sepsis & Septic Shock. Nature Review 2016; 45 (2): 1-21.39. Ince C, Mik E. Microcirculatory and mitochondrial hypoxia in sepsis, shock, and resuscitation. J Appl Physiol 2016; 120: 226-35.40. Delabranche X, Helms J, Meziani F. Immunohaemostasis: a new view on haemostasis during sepsis. Ann. Intensive Care 2017; 7: 11741. Koutroulis I, Batabyal R, McNamara B, Ledda M, Hoptay C, Freishtat R. Sepsis immunometabolism: from defining sepsis to understanding how energy production affects immune response. Critical Care Explorations 2019; 1 (11):e0061.42. Andrades M, Spasic M, Spasic S, Spasojević I. Bench to bedside review: Sepsis - from the redox point of view. Crit Care 2011; 15(5): 230.43. Singer M. The role of mitochondrial dysfunction in sepsis-induced multi-organ failure. Virulence 2014; 5: 66–72.44. Weil M, Afifi A. Experimental and clinical studies on lactate and pyruvate as indicators of the severity of acute circulatory failure (Shock). Circulation 1970; 41: 989-1001.45. Chertoff J, Chisum M, Garcia B, et al. Lactate kinetics in sepsis and septic shock: a review of the literature and rationale for further research. J Intensive Care. 2015; 3: 39-42.46. Lee I, Huttemann M. Energy crisis: the role of oxidative phosphorylation in acute inflammation and sepsis. Biochim Biophys Acta. 2014; 1842: 1579-1586.47. D’Alessandro A, Moore HB, Moore EE, Wither M, Nemkov T, Gonzalez E, Slaughter A, Fragoso M, Hansen KC, Silliman CC, et al. Early hemorrhage triggers metabolic responses that build up during prolonged shock. Am J Physiol – Regul Integr Comp Physiol. 2015; 308 (12): R1034–44.48. Servià L, Jové M, Sol J, Pamplona R, Badia M, Montserrat N, et al. A prospective pilot study using metabolomics discloses specific fatty acid, catecholamine and tryptophan metabolic pathways as possible predictors for a negative outcome after severe trauma. J Scand J Trauma Resusc Emerg Med. 2019; 27 (1): 56.49. Liu Z, Triba MN, Amathieu R, Lin X, Bouchemal N, Hantz E, et al. Nuclear magnetic resonance-based serum metabolomic analysis reveals different disease evolution profiles between septic shock survivors and non-survivors. Crit. Care. 2019; 23: 169.50. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Bernard GR, Annane D, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 2016; 315: 801-810.51. Silva S, Teboul JL. Defining the adequate arterial pressure target during septic shock: not a “micro” issue but the microcirculation can help. Crit care. 2011; 15:1004.52. Saugel B, Trepte CJ, Heckel H, Wagner JY, Reuter DA. Hemodynamic management of septic shock: is it time for “individualized goal-directed hemodynamic therapy” and for specifically targeting the microcirculation? Shock 2015. 43 (6): 522-529.53. Monnet X, Saugel B. Could resuscitation be based on microcirculation data? We are not sure. Intensive Care Med. 2018; 44: 950-953.54. Ince, C. Hemodynamic coherence and the rationale for monitoring the microcirculation. Crit Care 2015; 19: S855. Hernandez, G., Teboul J.L. Is the macrocirculation really dissociated from the microcirculation in septic shock? Intensive Care Med 2016; 42:1621-24.56. Dubin A, Pozo MO, Casabella CA, Palizas F jr; Murias G, Moseinco MC, et al. Increasing arterial blood pressure with norepinephrine does not improve microcirculatory blood flow: a prospective study. Crit Care 2009; 13 (3): R9257. De Backer D, Foulon P. Minimizing catecholamines and optimizing perfusion. Critical Care 2019; 23 (1): 149.58. Hotchkiss RS, Rust RS, Dence CS, et al. Evaluation of the role of cellular hypoxia in sepsis by the hypoxic marker [18F] fluoromisonidazole. Am J Physiol Regul Integr Comp Physiol 1991; 261: R965–7259. Groeneveld AB, van Lambalgen AA, van den Bos GC, et al. Maldistribution of heterogeneous coronary blood flow during canine endotoxin shock. Cardiovasc Res 1991; 25: 80–860. Chew MS, Johansson A, Anderson C, Ersson A, et al. Decreases in myocardial glucose and increases in pyruvate but not ischaemia are observed during porcine endotoxaemia. Acta Anaesthesiol Scand 2008; 52: 959–6861. Abraham E, Singer M. Mechanisms of sepsis-induced organ dysfunction. Crit Care Med 2007; 35: 2408–16.62. Fink MP. Cytopathic hypoxia and sepsis: is mitochondrial dysfunction pathophysiologically important or just an epiphenomenon. Pediatr Crit Care Med 2015; 16: 89-91.63. Shoemaker W, Appel P, kram HB, Bishop MH, Abraham E. temporal hemodynamic and oxygen transport patterns in medical patients. Septic Shock. Chest 1993; 1529-36.64. Elbers PW, Ince C. Bench-to-bedside review: Mechanisms of critical illness – classifying microcirculatory flow abnormalities in distributive shock. Critical Care 2006; 10: 221.65. Kakihana Y, Ito K, Nakahara M, Yamaguchi K, Yasuda T. Sepsis-induced myiocardial dysfunction: pathophysiology and management. Journal of Intensive Care 2016; 4:22,66. Marx G, Vangerow B, Burczyk C, Gratz KF, Maassen N, Cobas Meyer M, et al. Evaluation of noninvasive determinants for capillary leakage syndrome in septic shock patients. Intensive Care Med 2000; 26:1252–1258.67. Magder S, Vanelli G. Circuit factors in the high cardiac output of sepsis. J Crit Care 1996; 11: 155–166.68. Jianhui L, Rosenblatt-Velin N, Loukili N, Pacher P, Feihl F, Waeber B, et al. Endotoxin impairs cardiac hemodynamics by affecting loading conditions but not by reducing cardiac inotropism. Am J Physiol Heart Circ Physiol 2010; 299: H492–H501. .69. Groeneveld AB, Nauta JJ, Thijs LG.Peripheral vascular resistance in septic shock: its relation to outcome. Intensive Care Med 1988; 14:141-147.70. Chan CM, Klinger JR. The Right Ventricle in Sepsis. Clin Chest Med 2008; 29: 661 – 676.71. Court O, Kumar A, Parrillo JE, et al. Clinical review: Myocardial depression in sepsis and septic shock. Crit Care 2002; 6:500-508.72. Silva Ramos FJ, Azevedo LC: Hemodynamic and perfusion end points for volemic resuscitation in sepsis. Shock. 2010; 34: 34-39.73. Marx G, Pedder S, Smith L, Swaraj S, Grime S, Stockdale H, et al. Resuscitation from septic shock with capillary leakage: Hydroxyethyl starch (130 kd), but not Ringer's solution maintains plasma volume and systemic oxygenation. Shock 2004; 21: 336–41.74. Perner A, Cecconi M, Cronhjort M, Darmon M, Jakob S, Pettila V. Expert statement for the management of hypovolemia in sepsis. Intensive Care Med 2018; 44: 791-798.75. Parrillo JE, Parker MM, Natanson C, et al. Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med 1990; 113: 227-242.76. Guarracino F, Bertini P, Pinsky MR. Cardiovascular determinants of resuscitation from sepsis and septic shock. Critical Care 2019; 23: 118.77. De Backer D. Detailing the cardiovascular profile in shock patients. Critical Care 2017; 21 (3): 311.78. Garcia-Alvarez M, Paul Marik, Rinaldo Bellomo. Sepsis-associated hyperlactatemia. Critical Care 2014; 18: 503-513.79. Suetrong B, Walley KR. Lactic Acidosis in Sepsis: It’s Not All Anaerobic Implications for Diagnosis and Management. CHEST 2016; 149:252-26180. Vincent JL, Quintairos A, Couto L, et al. The value of blood lactate kinetics in critically ill patients: a systematic review. Critical Care 2016; 20: 257-270.81. Dunser M, Takala J, Brunauer A, Bakker J. Rethinking resuscitation: leaving blood pressure cosmetics behind and moving forward to permissive hypotension and a tissue perfusion-based approach. Critical Care 2013; 17 (5): 32682. Aird WC. Endothelium as an organ system. Crit Care Med 2004; 32: S271-S279.83. Segal S. Regulation of blood flow in the microcirculation. Microcirculation 2005; 12: 33-45.84. Davis MJ. Perspective: physiological role(s) of the vascular myogenic response. MicrocirCulation 2012; 19: 99-114.85. Moore J, Dyson A, Singer M, et al. Microcirculatory dysfunction and resuscitation: why, when, and how. British Journal of Anaesthesia 2015: 366–7586. Chen K, Popel AS. Theoretical analysis of biochemical pathways of nitric oxide release from vascular endothelial cells. Free Radic Biol Med 2006; 41: 668-80.87. Trzeciak S, Cinel I, Phillip Dellinger R, et al. Resuscitating the microcirculation in sepsis: the central role of nitric oxide, emerging concepts for novel therapies, and challenges for clinical trials. Acad Emerg Med 2008; 15: 399-413.88. De Backer D, Ospina-Tascon G, Salgado D, et al. Monitoring the microcirculation in the critically ill patient: current methods and future approaches. Intensive Care Med 2010; 36: 1813 – 1825.89. Chelazzi C, Villa G, Mancinelli P, De Gaudio AR, Adembri C. Glycocalyx and sepsis-induced alterations in vascular permeability. Crit Care 2015; 19: 26.90. Price SA, Spain DA, Wilson MA, Harris PD, Garrison RN. Subacute sepsis impairs vascular smooth muscle contractile machinery and alters vasoconstrictor and dilator mechanisms. J Surg Res 1999; 83: 75–80.91. Marechal X, Favory R, Joulin O, et al. Endothelial glycocalyx damage during endotoxemia coincides with microcirculatory dysfunction and vascular oxidative stress. Shock 2008; 29: 572-576.92. Eichelbrönner O, Sielenkämper A, Cepinskas G, Sibbald WJ, ChinYee IH. Endotoxin promotes adhesion of human erythrocytes to human vascular endothelial cells under conditions of flow. Crit Care Med 2000; 28: 1865–70.93. Ince C, Sinaasappel M. Microcirculatory oxygenation and shunting in sepsis and shock. Crit Care Med 27: 1369 –1377, 1999.94. Hernandez G, Bruhn A, Ince C. Microcirculation in sepsis: new perspectives. Curr Vasc Pharmacol 2013; 11: 161–69.95. Trzeciak S, McCoy JV, Phillip Dellinger R. Early increases in microcirculatory perfusion during protocol-directed resuscitation are associated with reduced multi-organ failure at 24 h in patients with sepsis. Intensive Care Med 2008; 34: 2210-2217.96. Nelson A, Berkestedt I, Schmidtchen A, Ljunggren L, Bodelsson M. Increased levels of glycosaminoglycans during septic shock: relation to mortality and the antibacterial actions of plasma. Shock 2008; 30: 623–27.97. Bateman RM, Sharpe MD, Jagger JE, et al. Sepsis impairs microvascular autoregulation and delays capillary response within hypoxic capillaries. Crit Care 2015. 19: 389.98. Borutaite V, Matthias A, Harris H, et al. Reversible inhibition of cellular respiration by nitric oxide in vascular inflammation. Am J Physiol Heart Circ Physiol 2001; 281: H2256 –H2260.99. Bateman RM, Sharpe MD, Ellis CG. Microvascular dysfunction in sepsis— hemodynamics, oxygen transport, and nitric oxide. Crit Care 2003; 7: 359 –73.100. Marik PE. The demise of early goal directed therapy for severe sepsis and septic shock. Acta Anaesthesiol Scand 2015; 59: 561-567.101. Singer M, De Santis V, Vitale D, et al. Multiorgan failure is an adaptive, endocrine-mediated, metabolic response to overwhelming systemic inflammation. Lancet 2004; 364: 545-8.102. Hotchkiss RS, Swanson PE, Freeman BD, et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 1999; 27:1230-1251.103. VanderMeer TJ, Wang H, Fink MP. Endotoxemia causes ileal mucosal acidosis in the absence of mucosal hypoxia in a normodynamic porcine model of septic shock. Crit Care Med 1995; 23: 1217-1226.104. Sair M, Etherington PJ, Winlove CP, et al. Tissue oxygenation and perfusion in patients with systemic sepsis. Crit Care Med 2001; 29: 1343 -1349.105. Singer M. Mitochondrial function in sepsis: acute phase versus multiple organ failure. Crit Care Med 2007; 35: 441-448106. Schumacker PT, Chandel N, Agusti AG. Oxygen conformance of cellular respiration in hepatocytes. Am J Physiol Lung Cell Mol Physiol 1993; 265: 395- 400.107. Brealey D, Karyampudi S, Jacques TS, et al. Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure. American Journal of Physiology—Regulatory Integrative and Comparative Physiology 2004; 286: 491-497.108. Levy RJ. Mitochondrial dysfunction, bioenergetic impairment, and metabolic down-regulation in sepsis. Shock. 2007; 28: 24–28.109. Carré, J.E. & Singer, M. Cellular energetic metabolism in sepsis: the need for a systems approach. Biochim Biophys Acta 2008; 1777:763–771.110. Fink MP. Bench-to-bedside review: Cytopathic hypoxia. Crit Care 2002; 6: 491–99.111. Bar-Or D, Carrick MM, Mains CW, Rael LT, Slone D, Brody EN. Sepsis, oxidative stress, and hypoxia: are there clues to better treatment? Redox Rep 2015; 20: 193-197.112. Levy B, Desebbe O, Montemont C, et al. Increased aerobic glycolysis through beta2 stimulation is a common mechanism involved in lactate formation during shock states. Shock 2008; 30: 417-21.113. Robergs R, Ghiasvand F, Parker D. Biochemistry of exercise-induced metabolic acidosis. Am J Physiol Regul Integr Comp Physiol 2004; 287: 502-516.114. Crouser ED, Julian MW, Blaho DV, Pfeiffer DR. Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity. Crit Care Med. 2002; 30: 276–284.115. Eyenga P, Roussel D, Morel J, et al. Early septic shock induces loss of oxidative phosphorylation yield plasticity in liver mitochondria. J Physiol Biochem 2014; 70: 285-296116. Taylor DE, Ghio AJ, Piantadosi CA. Reactive oxygen species produced by liver mitochondria of rats in sepsis. Arch Biochem Biophys. 1995; 316: 70-76.117. Galley H. F. Oxidative stress and mitochondrial dysfunction in sepsis. British Journal of Anaesthesia. 2011; 107: 57–64.118. Levy RJ, Deutschman CS. Deficient mitochondrial biogenesis in critical illness: cause, effect, or epiphenomenon? Crit Care. 2007; 11: 158-159119. Chaudry IH, Wichterman KA, Baue AE. Effect of sepsis on tissue adenine nucleotide levels. Surgery. 1979; 85: 205-211.120. Hotchkiss RS, Morikawa S, Inubushi T, et al. Gluconeogenesis and phosphoenergetics in rat liver during endotoxemia. J Surg Res. 1998; 74: 179-186.121. Brealey D, Brand M, Hargreaves I, et al. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 2002. 360: 219-23.122. Frayn KN, et al. Metabolic regulation. A human perspective. 3rd edn. 2010. Oxford: Willey Blackwell, 2010.123. Alberts B, et al. Molecular Biology of the Cell. 6th edn. 2015. New York. Taylor & Francis Group: Garland Science, 2015.124. Rolfe DF, Brown GC. Cellular energy utilization and molecular origin of standard metabolic rate in mammals. Physiol Rev 1997; 77: 731-758.125. Lehninger AL, Nelson DL, Cox MM. Lehninger principles of biochemistry 6th edn 2010. New York. Worth Publishers, 2010.126. Nalos M, Robergs R. Underestanding hyperlactatemia in human sepsis: Are we there yet?. Am J Respir Crtic Care Med 2019; 200: 1069-70.127. Corrêa TD, Jakob SM, Takala J. Mitochondrial function in sepsis. Crit Care Horizons. 2015; 1: 31-41.128. Solaini G, Baracca A, Lenaz G, et al. Hypoxia and mitochondrial oxidative metabolism. Biochim. Biophys. Acta 2010; 1797: 1171–1177.130. Duke T. Dysoxia and lactate. Archives of Disease in Childhood 1999; 81: 343-350.131. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 1992; 12: 5447-5454.132. Hochachka PW, Somero GN. Biochemical Adaptations. Mechanisms and Process 1st edn 1983. Princeton NJ, Princeton Univ Press 1983.133. Hochachka PW. Oxygen, homeostasis, and metabolic regulation. Adv Exp Med Biol 2000; 475: 311-335.134. Zhang JZ., Behrooz A., Ismail-Beigi F. Regulation of glucose transport by hypoxia. American Journal of Kidney Diseases 1999; 34 (1): 189-202.135. Greijer A, van der Groep P, Kemming D, Shvarts A, Semenza G, Meijer G, et al. Up-regulation of gene expression by hypoxia is mediated predominantly by hypoxia-inducible factor 1 (HIF-1). The Journal of Pathology 2005; 206(3): 291–304.136. Lum JJ, Bui T, Gruber M, et al. The transcription factor HIF-1alpha plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis. Genes Dev 2007; 21: 1037-1049.137. Kim JW, Tchernyshyov I, Semenza GL, et al. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 2006; 3: 177-185.138. Viollet B, Athea Y, Mounier R, et al. AMPK: lessons from transgenic and knockout animals. Front Biosci Review 2009; 14: 19-44.139. Chandel NS, E. Maltepe E, Goldwasser E, et al. Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci USA 1998; 95: 11715-11720.140. Warburg O. On the origin of cancer cells. Science 1956; 123: 309-314.141. Bar-Or D, Carrick M, Tanner A, et al. Overcoming the Warburg Effect: Is it the key to survival in sepsis? J Crit Care 2018; 43:197-201.142. Ganeshan K, Ajay Chawla A. Metabolic Regulation of Immune Responses. Annual Review of Immunology. 2014; 32:1, 609-634.143. Staples JF. Metabolic suppression in mammalian hibernation: the role of mitochondria. J Exp Biol 2014; 217:2032-2036.144. Senyilmaz D, Teleman AA. Chicken or the egg: Warburg effect and mitochondrial dysfunction. F1000Prime Rep 2015; 7: 41-47145. Carré JE, Orban J-C, Re L, Felsmann K, Iffert W, Bauer M, et al. Survival in critical illness is associated with early activation of mitochondrial biogenesis. Am J Respir Crit Care Med. 2010; 182: 745-51.146. Kim V, Tchernyshyov I, Semenza GL, et al. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 2006; 3: 177-185.147. Handzlik MK, Constantin-Teodosiu D, Greenhaff PL, et al. Increasing cardiac pyruvate dehydrogenase flux during chronic hypoxia improves acute hypoxic tolerance. J Physiol 2018; 596 (15): 3357-3369.148. Nuzzo E, Berg KM, Andersen LW. Pyruvate Dehydrogenase Activity Is Decreased in the Peripheral Blood Mononuclear Cells of Patients with Sepsis - A Prospective Observational Trial. Ann Am Thorac Soc 2015; 12 (11):1662-6.149. Cooper CE, Giulivi C. Nitric oxide regulation of mitochondrial oxygen consumption II: molecular mechanism and tissue physiology. Am. J. Physiol. Cell Physiol 2007. 292: 1993–2003.150. Galkin A, Abramov AY, Frakich N, et al. Lack of oxygen deactivates mitochondrial Complex I: implications for ischemic injury? J Biol Chem 2009. 284: 36055–36061.151. Forget AP, Mangalaboyi J, Mordon S, et al. Escherichia coli endotoxin reduces cytochrome aa3 redox status in pig skeletal muscle. Crit Care Med 2000; 28: 3491-3497.152. Barth E, Radermacher P, Thiemermann C, et al. Role of inducible nitric oxide synthase in the reduced responsiveness of the myocardium to catecholamines in a hyperdynamic, murine model of septic shock. Crit Care Med 2006; 34: 307-313.153. Poyton RO, Ball KA, Castello PR. Mitochondrial generation of free radicals and hypoxic signaling. Trends Endocrinol. Metab 2009; 7: 332-340.154. Haisch M, Fukagawa NK, Matthews DE. Oxidation of glutamine by the splanchnic bed in humans. Am J Physiol Endocrinol Metab 2000; 278: 593-602.155. Owen OE, Smalley KJ, D’Alessio DA, et al. Protein, fat, and carbohydrate requirements during starvation: anaplerosis and cataplerosis. The American Journal of Clinical Nutrition 1998; 68: 12-34.156. Meléndez-Hevia E, Waddell TG. Cascante M.The puzzle of the Krebs citric acid cycle: Assembling the pieces of chemically feasible reactions, and opportunism in the design of metabolic pathways during evolution. J Mol Evol 1996; 43: 293-303.157. Martin W, Muller M. The hydrogen hypothesis for the first eukaryote. Nature 1998; 392: 37-41158. Randall HM Jr, Cohen JJ. Anaerobic CO2 production by dog kidney in vitro. Am J Physiol 1966; 211: 493-505159. D’Alessandro A, Slaughter AL, Peltz ED, et al. Trauma/hemorrhagic shock instigates aberrant metabolic flux through glycolytic pathways, as revealed by preliminary 13C-glucose labeling metabolomics. J Transl Med 2015; 13: 253-265.160. Randle PJ, England PJ, Denton RM.Control of the tricarboxylate cycle and its interactions with glycolysis during acetate utilization in rat heart. Biochem J 1970; 117: 677-695.161. Guynn RW, Gelberg HJ & Veech RL. Equilibrium constants of the malate dehydrogenase, citrate synthase, citrate lyase, and acetyl coenzyme A hydrolysis reactions under physiological conditions. J. Biol. Chem. 1973; 248: 6957–6965.162. Cooney GJ, Taegtmeyer H, Newsholme EA. Tricarboxylic acid cycle flux and enzyme activities in the isolated working rat heart. Biochem J 1981; 200: 701-703.163. Hochachka PW, Dressendorfer RH. Succinate accumulation in man during exercise. Eur J Appl Physiol Occup Physiol 1976. 35: 235-242.164. Sanborn T, Gavin W, Berkowitz S, et al. Augmented conversion of aspartate and glutamate to succinate during anoxia in rabbit heart. Am J Physiol 1979; 237: H535-H541.165. Shi Q, Gibson GE. Upregulation of the mitochondrial malate dehydrogenase by oxidative stress is mediated by miR-743a. J Neurochem 2011; 118: 440-448.166. Des Rosiers C, Fernandez CA, David F, Brunengraber H. Reversibility of the mitochondrial isocitrate dehydrogenase reaction in the perfused rat liver. Evidence from isotopomer analysis of citric acid cycle intermediates. J Biol Chem 1994; 269: 27179-27182.167. Comte B, Vincent G, Bouchard B, Benderdour M, Des Rosiers C. Reverse flux through cardiac NADP1-isocitrate dehydrogenase under normoxia and ischemia. Am J Physiol Heart Circ Physiol 2002; 283: H1505-H1514.168. Mullen AR, Wheaton WW, Jin ES, et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 2012; 481: 385-388.169. Phillips D, Aponte AM, French SA, Chess DJ, Balaban RS. Succinyl-CoA synthetase is a phosphate target for the activation of mitochondrial metabolism. Biochemistry 2009; 48: 7140-7149.170. Siegel JH, Cerra FB, Coleman B, et al. Physiologic and metabolic correlations in human sepsis. Surgery 1979; 85:163.171. Cerra FB, Siegel JH, Coleman B, et al. Septic autocannibalism a failure of exogenous nutritional support. Ann Surg 1980; 192: 570-579.172. Infantino V, Convertini P, Cucci L, et al. The mitochondrial citrate carrier: a new player in inflammation. Biochem. J. 2011; 438: 433–436.173. Infantino V, Iacobazzi V, Menga A, et al. A key role of the mitochondrial citrate carrier (SLC25A1) in TNFα- and IFNγ-triggered inflammation. Biochimica et biophysica acta 2014; 1839:1217-1225.174. Cimen H, Han MJ, Yang Y, et al. Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria. Biochemistry 2010; 49: 304-311.175. Mills E, O'Neill LA. Succinate: a metabolic signal in inflammation. Trends Cell Biol 2014; 24:313-320.176. Rubic T, Lametschwandtner G, Hinteregger S, et al. Triggering the succinate receptor GPR91 on dendritic cells enhances immunity. Nat Immunol 2008; 9: 1261-1269.177. Zhang Z1, Tan M, Xie Z, et al. Identification of lysine succinylation as a new post-translational modification. Nat Chem Biol. 2011; 7: 58-63.178. Selak MA, Armour SM, MacKenzie ED, et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF- prolylhydroxylase. Cancer Cell 2005;7: 77-85.179. Reisz JA, Wither MJ, Moore EE, Slaughter AL, Moore HB, Ghasabyan A, et al. All animals are equal but some animals are more equal than others: plasma lactate and succinate in hemorrhagic shock-A comparison in rodents, swine, nonhuman primates, and injured patients. J Trauma Acute Care Surg. 2018;84(3):537–41.180. Hatib F, Jansen JRC, Pinsky MR. Peripheral vascular decoupling in porcine endotoxic shock. J Appl Physiol. 2011; 111:853–60.181. Parkin WG, Leaning MS. Therapeutic control of the circulation. J Clin Comput Monit. 2008; 22:391.182. Forni LG, McKinnon W, Lord GA, et al. Circulating anions usually associated with the Krebs cycle in patients with metabolic acidosis. Crit Care. 2005; 9: R591-R595.183. McKinnon W, Lord GA, Forni LG, et al: A rapid LC-MS method for determination of plasma anion profiles of acidotic patients. J Chromatogr 2006, B833: 179-185.184. Shurubor YI, Cooper AJ, Isakova EP, Deryabina YI, Beal MF, Krasnikov BF. Simultaneous determination of tricarboxylic acid cycle metabolites by high-performance liquid chromatography with ultraviolet detection. Analytical Biochemistry. 2017; 503: 8-10.185. Mycielska ME, Patel A, Rizaner A, Mazurek MP, Keun H, Patel A, et al. Citrate transport and metabolism in mammalian cells: prostate epithelial cells and prostate cancer. Bioessays 2009; 31 (1): 10–20.186. Dabek M, Kruszewska D, Filip R, Hotowy A, Pierzynowski L, Wojtasz-Pajak A, et al. Alpha-Ketoglutarate (AKG) absorption from pig intestine and plasma pharmacokinetics. J. Anim. Physiol. Anim. Nutr. 2005; 89: 419–426.187. Hofmann GF, Meier-Augenstein W, Stöckler S, Surtees R, Rating D, Nyhan WL. Physiology and pathophysiology of organic acids in cerebrospinal fuid. Journal of Inherited Metabolic Disease 1993; 16 (4): 648–669.188. Mongan, PD, Fontana, JL, Chen, R, Bünger, R. Intravenous pyruvate prolongs survival during hemorrhagic shock in swine. Am J Physiol Heart Circ Physiol 1999; 277: H2253–63.189. Hofmaier F., Dinger K., Braun R., Sterner-Kock A. Range of blood lactate values in farm pigs prior to experimental surgery. Lab. Anim. 2013; 47: 130–132.190. Jakob SM, Suistomaa M, Takala J. Lactate, Lactate/Pyruvate Ratio, Low Tissue Perfusion and Outcome. En: Vincent JL editor, Yearbook of Intensive Care and Emergency Medicine 2001. Berlin, Heidelberg: Springer; 2001:268-277.191. Hess M, Hastillo A, Greenfield L. Spectrum of cardiovascular function during gram negative sepsis. Progress in cardiovascular diseases. 1980;23(4):279-289192. Pinsky M Rico P. Cardiac Contractility Is Not Depressed in Early Canine Endotoxic Shock. Am. J. Respir. 1999; 161:4193. Fink MP, Heard SO. Laboratory models of sepsis and septic shock. J. Surg. Res. 1990; 49: 186–196.194. Schmidhammer R, Wassermann E, Germann P, Redl H, Ullrich R. Infusion of increasing doses of endotoxin induces progressive acute lung injury but prevents early pulmonary hypertension in pigs. Shock 2006;25(4):389-94.195. Houser B, Vogt J, Wachter U, Brückner UB, Fink MP. Ethyl pyruvate improves systemic and hepatosplanchnic hemodynamics and prevents lipid peroxidation in a porcine model of resuscitated hyperdynamic endotoxemia. Crit Care Med 2005;33(9):2034-42.196. Cunha-Goncalves, Perez-de-sa V. Inotropic support during experimental endotoxemic shock: part I. The effects of levosimendan on splanchnic perfusion. Anesth Analg 2009;109(5):1568-75.197. Udhoji VN, Weil MH. Hemodynamic and metabolic studies on shock associated with bacteremia. Ann Intern Med. 1985; 62: 966-978.198. van Genderen, J De Jonge, Visser SS, Voorbeijtel J. Microvascular Perfusion as a Target for Fluid Resuscitation in Experimental Circulatory Shock. Crit Care Med 2014;42(2):e96-e105.199. Byrne L, Obonyo NG, Diab S, Dunster K, Passmore M. An ovine model of hyperdynamic endotoxemia and vital organ metabolism. Shock 2018;49(1):99-107.200. Cunha-Goncalves Perez-de-sa V. Inotropic support during experimental endotoxemic shock: part II. A comparison of levosimendan with dobutamine Anesth Analg 2009 Nov;109(5):1576-83.201. Natanson C, Danner RL, Fink MP, MacVittie TJ, Walker RI, Conklin JJ, Parrillo JE. Cardiovascular performance with E. coli challenges in a canine model of human sepsis. Am J Physiol. 1988; 254: H558-H569.202. Shoemaker WC. Cardiorespiratory patterns in complicated uncomplicated septic shock. Ann Surg. 1971; 174: 119-125.203. Natanson C, Fink MP, Ballantyne HK, MacVittie TJ, Conklin JJ, Parrillo JE. Gram-negative bacteremia produces both severe systolic and diastolic cardiac dysfunction in a canine model that simulates human septic shock. J Clin Invest. 1986;78(1):259-270.204. Chittock DR, Ronco JJ, Rusell JA. Monitoring of oxygen transport and oxygen consumption. En: Tobin JM editor, Principles and practice of intensive care monitoring. New York: McGraw-Hill; 1998. 317-344.205. Chemla D, Coirault C, Hebert JL, Lecarpentier Yves. Mechanics of relaxation of the human heart. Physiology 2000; 15: 2: 78-83.206. Schumacker PT, Cain SM. The concept of a critical oxygen delivery. Intensive Care Med 1987; 13: 223–9.207. Friedman G, De Backer D, Shahla M, Vincent JL. Oxygen supply dependency can characterize septic shock Intensive Care Medicine 1998; 24 (2): 118–123.208. Walley KR. Heterogeneity of oxygen delivery impairs oxygen extraction by peripheral tissues: theory. J Appl Physiol 1996; 81: 885–894.209. Grist G. Oxygen pressure field theory: a detailed description of vital gas exchange, at the capillary level for perfusionist. Progress in Pediatric Cardiology; 24 (2): 89-99210. Donati A, Damiani E, Domizi R, Romano R, Adrario E, Pelaia P, et al. Alteration of the sublingual microvascular glycocalyx in critically ill patients. Microvasc Res. 2013; 90: 86-89.211. Siegemund M, van Bommel J, Schwarte LA, Studer W, Girard T, Marsch S, Radermacher P, Ince C. Inducible nitric oxide synthase inhibition improves intestinal microcirculatory oxygenation and CO2 balance during endotoxemia in pigs. Intensive Care Med 2005; 31: 985–992,212. Stratton HH, Feustel PJ, Newell JC: Regression of calculated variables in the presence of shared measurement error. J Appl Physiol. 1987; 62: 2083-2093.213. Ronco JJ, Phang PT, Walley KR, et al: Oxygen consumption is independent of changes in oxygen delivery in severe adult respiratory distress syndrome. Am Rev Respir Dis. 1991; 143:1267-1273.214. Vincent JL, Roman A, De Backer D, Kahn RJ. Oxygen uptake/supply dependency: effects of short-term dobutamine infusion. Am Rev Respir Dis. 1990; 142: 2–8.215. Liu MS, GF Kang. Liver glycogen metabolism in endotoxin shock. I. Endotoxin administration decreases glycogen synthase activities in dog livers. Biochem. Med. Metab. Biol 1987; 37: 61–72.216. van der Crabben SN, Blümer RM, Stegenga ME, Ackermans MT, Endert E, Tanck MW, et al. Early endotoxemia increases peripheral and hepatic insulin sensitivity in healthy humans. J Clin Endocrinol Metab. 2009 Feb; 94 (2): 463-8.217. Hagar JA, Edin ML, Lih FB, Thurlow LR, Koller BH, Cairns BA, et al. Lipopolysaccharide potentiates insulin-driven hypoglycemic shock. The Journal of Immunology. 2017; 199 (10): 3634-3643.218. Breadley D, Singer M. Hyperglicemia in critical illness: A review J Diabetes Sci Technol 2009; 3 (6):1250-1260.219. Kvidera SK, Horst EA, Mayorga EJ, Sanz-Fernandez MV, Abuajamieh M, Baumgard LH. Estimating glucose requirements of an activated immune system in growing pigs. J Anim Sci. 2017; 11: 5020-5029.220. Raetzsch CF, Brooks NL, Alderman JM, Moore KS, Hosick PA, Klebanov S, et al. Lipopolysaccharide inhibition of glucose production through the Toll-like receptor-4, myeloid differentiation factor 88, and nuclear factor kappa b pathway Hepatology 2009; 50: 592–600.221. Tanaka H, Nishikawa Y, Fukushima T, Taniguchi A, Fujita Y, Tsuda K, et al. Lipopolysaccharide inhibits hepatic gluconeogenesis in rats: The role of immune cells. Journal of diabetes investigation 2017; 9 (3): 494–504.222. Lv S, Qiu X, Li J, Li W, Zhang C, Zhang ZN et al. Suppression of CRTC2-mediated hepatic gluconeogenesis by TRAF6 contributes to hypoglicemia in septic shock. Cell Discov 2016; 2: 16046.223. Clendenen N, Nunns GR, Moore EE, Reisz JA, Gonzalez E, Peltz E, et al. Hemorrhagic shock and tissue injury drive distinct plasma metabolome derangements in swine. J Trauma Acute Care Surg. 2017; 83(4): 635–642.224. Varvarousis D, Xanthos T, Ferino G, Noto A, Iacovidou N, Mura M, Scano P, Chalkias A, Papalois A, De-Giorgio F, Baldi A, Mura P, Staikou C, Stocchero M, Finco G, d'Aloja E, Locci E. Metabolomics profiling reveals different patterns in an animal model of asphyxial and dysrhythmic cardiac arrest. Sci Rep 2017; 7:16575.225. Solberg R, Enot D, Deigner HP, Koal T, Scholl-Bürgi S, Saugstad OD,Matthias K. Metabolomic analyses of plasma reveals new insights into asphyxia and resuscitation in pigs. PLoS One. 2010; 5: e9606.226. Chinopoulos C. Succinate in ischemia: Where does it come from? Int J Biochem Cell Biol. 2019; 115:105580.227. Lukyanova LD, Kirova YI, Germanova, EL. The Role of Succinate in Regulation of Immediate HIF-1α Expression in Hypoxia. Bulletin of Experimental Biology and Medicine, 2018; 164(3): 298–303.228. Zhang J, Wang YT, MillerJH, DayMM, Munger JC, Brookes PS. Accumulation of succinate in cardiac ischemia primarily occurs via canonical krebs cycle activity. Cell Rep. 2018; 23: 2617 - 2628.229. Hunter FE. Anaerobic phosphorylation due to a coupled oxidation-reduction between alpha-ketoglutaric acid and oxalacetic acid. J. Biol. Chem. 1949; 177: 361–372.230. Kiss G, Konrad C, Pour-Ghaz I, Mansour JJ, Nemeth B, Starkov AA, et al. Mitochondrial diaphorases as NAD(+) donors to segments of the citric acid cycle that support substrate-level phosphorylation yielding ATP during respiratory inhibition. FASEB J. 2014; 28: 1682–1697.231. Tugtekin IF, Radermacher P, Theisen M, Matejovic M, Stehr A, Ploner K, et al. Increased ileal-mucosal-arterial PCO2 gap is associated with impaired villus microcirculation in endotoxic pigs. Intensive Care Med. 2001; 27:757-766.232. Langenberg C, Wan L, Egi M, May CN, Bellomo R. Renal blood flow in experimental septic acute renal failure. Kidney Int 2006; 69: 1996–2002.233. Cossu AP, Suelzu S, Piu P, Orecchioni M, Bazzu G, Padua G. Do on- and off-pump coronary bypass surgery differently affect perioperative peripheral tissue metabolism? Minerva Anestesiol 2012;78(1):26-33.234. Sahuquillo J, Merino M-A, Sánchez-Guerrero A, Arikan F, Vidal-Jorge M, Martínez-Valverde T. Lactate and the Lactate-to-Pyruvate Molar Ratio Cannot Be Used as Independent Biomarkers for Monitoring Brain Energetic Metabolism: A Microdialysis Study in Patients with Traumatic Brain Injuries. PLoS ONE 9(7): e102540.235. von Platen A, D`Souza M. Evaluation of Intrahepatic Lactate / Pyruvate Ratio As a Marker for Ischemic Complications. Transplant Direct. 2019; 5(12): e505236. Kilgour E, Vernon RG. Catecholamine activation of pyruvate dehydrogenase in white adipose tissue of the rat in vivo. Biochem J 1987;241:415–9.237. Kuyper AC, Mattill HA. Some aspects of citric acid metabolism. J. Biol. Chem. 103: 51-60.238. Costello LC, Franklin RB. Plasma citrate homeostasis, how it is regulated, and its physiological and clinical implications. An important, but neglected, relationship in medicine. HSOA J. Hum. Endocrinol. 2016; 1: 5.239. Mycielska ME, Milenkovic VM, Wetzel CH, Rümmele P, Geissler E.K. Extracellular Citrate in Health and Disease. Curr. Mol. Med. 2015; 15: 884–891.240. Jha AK, Huang SC, Sergushichev A, Lampropoulou V, Ivanova Y, Loginicheva E, Chmielewski K. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization.Immunity. 2015; 42: 419-430.241. Williams NC, O’Neill LA. A role for the Krebs cycle intermediate citrate in metabolic reprogramming in innate immunity and inflammation. Front. Immunol. 2018: 9: 141.242. Fensterheim BA, Young JD, Luan L, Kleinbard RR, Stothers CL, Patil NK, et al. The TLR4 Agonist Monophosphoryl Lipid A Drives Broad Resistance to Infection via Dynamic Reprogramming of Macrophage Metabolism. J Immunol 2018;200(11):3777-3789.243. Lampropoulou V, Sergushichev A, Bambouskova M, Nair S, Vincent EE, Loginicheva E, et al. Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab. 2016; 24: 158–166.244. Mcbride MA, Owen AM, Stothers CL, Hernandez A, Luan L, Burelbach KR, et al. The Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma. Front Immunol 2020;11:1–21.245. Vary TC, Siegel JH, Nakatani T, Sato T, Aoyama H: Effect of sepsis on the activity of the pyruvate dehydrogenase complex in skeletal muscle and liver. Am J Physiol. 1986; 250: E634-E640.246. Beloborodova NV, Pautova AK, Sergeev, Fedotcheva NI. Serum Levels of Mitochondrial and Microbial Metabolites Reflect Mitochondrial Dysfunction in Different Stages of Sepsis. Metabolites. 2019; 9 (10):196.247. Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010; 303: 739-46.248. Puskarich MA, Trzeciak S, Shapiro NI, Arnold RC, Heffner AC, Kline JA, et al. Prognostic value and agreement of achieving lactate clearance or central venous oxygen saturation goals during early sepsis resuscitation. Acad Emerg Med. 2012; 19: 252-258.249. Hernandez G, Ospina-Tascón GA, Damiani LP, et al. Effect of a resuscitation strategy targeting peripheral perfusion status vs serum lactate levels on 28-day mortality among patients with septic shock: the ANDROMEDA-SHOCK randomized clinical trial. JAMA. 2019; 321: 654-64.250. Hernandez G, Bellomo R, Bakker J. The ten pitfalls of lactate clearance in sepsis. Intensive Care Med. 2019; 45 (1): 82-85.251. Huckabee WE. Relationships of pyruvate and lactate during anaerobic metabolism. 1. Effects of infusion of pyruvate or glucose and of hyperventilation. J Clin Invest. 1958; 37:244-254252. Broder G, Weil MH. Excess Lactate: An Index of Reversibility of Shock in Human Patients. Science. 1964; 143:1457–1459.253. Howell MD, Donnino M, Clardy P, Talmor D, Shapiro NI. Occult hypoperfusion and mortality in patients with suspected infection. Intensive Care Med. 2007 Nov; 33(11): 1892–1899.254. Gattinoni L, Vasques F, Camporota L, Meessen J, Romitti F, Pasticci I, et al. Understanding lactatemia in human sepsis: potential impact for early management. Am J Respir Crit Care Med. 2019; 200: 582–589.255. Takala J, Uusaro A, Parviainen I, Ruokonen E. Lactate metabolism and regional lactate exchange after cardiac surgery. New Horiz 1996; 4: 483-492.256. Mizock BA. The hepatosplanchnic area and hyperlactatemia: A tale of two lactates. Crit Care Med. 2001; 29 (2): 447–449.257. Bellomo R. Bench-to-bedside review: Lactate and the kidney. Crit Care. 2002; 6(4): 322-326.258. Revelly JP, Tappy L, Martinez A, Bollmann M, Cayeux MC, Berger MM, et al. Lactate and glucose metabolism in severe sepsis and cardiogenic shock. Crit Care Med. 2005; 33: 2235-40.259. Myburgh JA, Higgins A, Jovanovska A, Lipman J, Ramakrishnan N, Santamaria J CAT Study Investigators. A comparison of epinephrine and norepinephrine in critically ill patients. Intensive Care Med. 2008;34:2226–2234.260. Levy B, Sadoune LO, Gelot AM, Bollaert PE, Nabet P, Larcan A: Evolution of lactate/pyruvate and arterial ketone body ratios in the early course of catecholamine-treated septic shock. Crit Care Med. 2000; 28: 114-119.261. Rimachi R, De Carvahlo FB, Orellano-Jimenez C, Cotton F, Vincent JL, De Backer D. Lactate/Pyruvate Ratio as a Marker of Tissue Hypoxia in Circulatory and Septic Shock. Anaesthesia and Intensive Care. 2012; 40 (3): 427-432.262. Huckabee W. Abnormal resting blood lactate. Am. J. Med 1961;30: 833-839263. Brandt S, Regueira T, Bracht H, Porta F, Djafarzadeh S, Takala J, et al. Effect of fluid resuscitation on mortality and organ function in experimental sepsis models Crit Care. 2009; 13(6): R186.264. Khodakova A, Beloborodova N. Mitochondrial metabolites in the blood patients with sepsis. Crit Care 2007; 11 (4): P5.265. Fedotcheva NI, Kazakov RE, Kondrashova MN, Beloborodova NV. Toxic effects of microbial phenolic acids on the functions of mitochondria. Toxycol. Lett. 2008; 180: 182-188.266. Cordes T, Wallace M, Michelucci A, Divakaruni AS, Sapcariu SC, Sousa C, et al. Immunoresponsive gene 1 and itaconate inhibit succinate dehydrogenase to modulate intracellular succinate levels. J. Biol. Chem. 2016; 291: 14274-14284.267. Meiser J, Kraemer L, Jaeger C,Madry H, Link A, Lepper PM, Hiller K, Schneider JG. Itaconic acid indicates cellular but not systemic immune system activation. Oncotarget. 2018; 9: 32098-32107.268. Liu MS, Zhang JN. Glycolytic and tricarboxylic acid cycle intermediates in dog livers during endotoxic shock. Biochemical medicine 1985; 34 (3): 335-343.269. Plummer MP, Deane AM. Dysglycemia and Glucose Control During Sepsis. Clinics in Chest Medicine 2016; 37(2): 309-319.270. Ferreira FBD, dos Santos C, Bruxel MA, Nunes EA, Spiller F, Rafacho A. Glucose homeostasis in two degrees of sepsis lethality induced by caecum ligation and puncture in mice. Int J Exp Pathol 2017; 98: 98-40.271. Yang S, Cioffi WG, Bland KI, Chaudry IH, Wang P. Differential alterations in systemic and regional oxygen delivery and consumption during the early and late stages of sepsis. J Trauma 1999; 47: 706-12.272. Morita Y, Chin-Yee I, Yu P, Sibbald WJ, Martin CM. Critical Oxygen Delivery in Conscious Septic Rats under Stagnant or Anemic Hypoxia. American Journal of Respiratory and Critical Care Medicine 2003; 167(6): 868–872.273. Tao W, Deyo DJ, Traber DL, Johnston WE, Sherwood ER. Hemodynamic and Cardiac Contractile Function During Sepsis Caused by Cecal Ligation and Puncture in Mice. Shock 2004; 21(1): 31–37.274. Hotchkiss RS, Song SK, Neil JJ, Chen RD, Manchester JK, Karl IE, et al. Sepsis does not impair tricarboxylic acid cycle in the heart. Am J Physiol Cell Physiol 1991; 260 (1):C50–C57.275. Lado-Abeal J, Martinez-Sánchez N, Cocho JA, Martín-Pastor M, Castro-Piedras I, Couce-Pico ML, et al. Lipopolysaccharide (LPS)-induced septic shock causes profound changes in myocardial energy metabolites in pigs. Metabolomics 2018; 14 (10): 131.276. Liu Z, Yin P, Amathieu R, Savarin P, Xu G. Application of LC-MS-based metabolomics method in differentiating septic survivors from non-survivors. Analytical and Bioanalytical Chemistry 2016; 408 (27): 7641-7649.277. Cerra FB. The hypermetabolism organ failure complex. World J. Surg. 1987; 11: 173-181.278. Muleme HM, Walpole AC, Staples JF. Mitochondrial metabolism in hibernation: metabolic suppression, temperature effects, and substrate preferences. Physiol Biochem Zool 2006; 79: 474-483.279. Fedotcheva NI, Litvinova EG, Kamzolova SV, Morguno IG, Amerkhanov ZG. Mitochondrial metabolites in tissues as indicators of metabolic alterations during hibernation. Cryo Lett 2010; 31: 392-400.280. Zhao Z, Oort A, Tao Z, O’Brien WG, Lee CC. Metabolite profiling of 5′-AMP induced hypometabolism. Metabolomics. 2014; 10: 63-76.281. Lei Z, Huhman DV, Sumner L.W. Mass spectrometry strategies in metabolomics. J. Biol. Chem. 2011; 286: 25435–25442.282. Al Kadhi O, Melchini A, Mithen R, Saha S. Development of a LC-MS-MS method for the simultaneous detection of tricarboxylic acid cycle intermediates in a range of biological matrices.Journal of Analytical Methods in Chemistry. 2017, 5391832.283. Beloborodova NV, Sarshor YN, Bedova AY, Chernevskaya EA, Pautova AK. Involvement of aromatic metabolites in the pathogenesis of septic shock. Shock 2018, 50, 273–279.284. Ospina-Tascón GA, Umaña M, Bermudez W, Bautista-Rincon DF, Hernandez G, Bruhn A. et al. Combination of arterial lactate levels and venous-arterial CO2 to arterial-venous O 2 content difference ratio as markers of resuscitation in patients with septic shock. 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