Information de reference pour ce titreAccession Number: | 00003246-201910000-00020.
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Author: | Weiss, Scott L. MD, MSCE 1-3; Zhang, Donglan BS 1,3; Bush, Jenny RNC 1; Graham, Kathryn BS 1; Starr, Jonathan BS 1,3; Tuluc, Florin MD, PhD 4; Henrickson, Sarah MD, PhD 5,6; Kilbaugh, Todd MD 1,3; Deutschman, Clifford S. MD, MS 7; Murdock, Deborah PhD 3; McGowan, Francis X. Jr MD 1,3; Becker, Lance MD 8; Wallace, Douglas C. PhD 3
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Institution: | (1)Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. (2)Pediatric Sepsis Program at the Children's Hospital of Philadelphia, Philadelphia, PA. (3)Center for Mitochondrial and Epigenomic Medicine at the Children's Hospital of Philadelphia, Philadelphia, PA. (4)Flow Cytometry Research Core, Children's Hospital of Philadelphia, Philadelphia, PA. (5)Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. (6)Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. (7)Feinstein Institute for Medical Research at Hofstra-Northwell School of Medicine, Hempstead, NY. (8)Department of Emergency Medicine at Hofstra-Northwell School of Medicine, Hempstead, NY.
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Title: | |
Source: | Critical Care Medicine. 47(10):1433-1441, October 2019.
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Abstract: | Objectives: Limited data exist about the timing and significance of mitochondrial alterations in children with sepsis. We therefore sought to determine if alterations in mitochondrial respiration and content within circulating peripheral blood mononuclear cells were associated with organ dysfunction in pediatric sepsis.
Design: Prospective observational study
Setting: Single academic PICU.
Patients: One-hundred sixty-seven children with sepsis/septic shock and 19 PICU controls without sepsis, infection, or organ dysfunction.
Interventions: None.
Measurements and Main Results: Mitochondrial respiration and content were measured in peripheral blood mononuclear cells on days 1-2, 3-5, and 8-14 after sepsis recognition or once for controls. Severity and duration of organ dysfunction were determined using the Pediatric Logistic Organ Dysfunction score and organ failure-free days through day 28. Day 1-2 maximal uncoupled respiration (9.7 +/- 7.7 vs 13.7 +/- 4.1 pmol O2/s/106 cells; p = 0.02) and spare respiratory capacity (an index of bioenergetic reserve: 6.2 +/- 4.3 vs 9.6 +/- 3.1; p = 0.005) were lower in sepsis than controls. Mitochondrial content, measured by mitochondrial DNA/nuclear DNA, was higher in sepsis on day 1-2 than controls (p = 0.04) and increased in sepsis patients who had improving spare respiratory capacity over time (p = 0.005). Mitochondrial respiration and content were not associated with day 1-2 Pediatric Logistic Organ Dysfunction score, but low spare respiratory capacity was associated with higher Pediatric Logistic Organ Dysfunction score on day 3-5. Persistently low spare respiratory capacity was predictive of residual organ dysfunction on day 14 (area under the receiver operating characteristic, 0.72; 95% CI, 0.61-0.84) and trended toward fewer organ failure-free days although day 28 ([beta] coefficient, -0.64; 95% CI, -1.35 to 0.06; p = 0.08).
Conclusions: Mitochondrial respiration was acutely decreased in peripheral blood mononuclear cells in pediatric sepsis despite an increase in mitochondrial content. Over time, a rise in mitochondrial DNA tracked with improved respiration. Although initial mitochondrial alterations in peripheral blood mononuclear cells were unrelated to organ dysfunction, persistently low respiration was associated with slower recovery from organ dysfunction.
Copyright (C) by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
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Author Keywords: | child; mitochondria; multiple organ failure; sepsis.
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References: | 1. Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 2016; 315:801-810
2. Vincent JL, Nelson DR, Williams MD. Is worsening multiple organ failure the cause of death in patients with severe sepsis? Crit Care Med 2011; 39:1050-1055
3. Weiss SL, Balamuth F, Hensley J, et al. The epidemiology of hospital death following pediatric severe sepsis: When, why, and how children with sepsis die. Pediatr Crit Care Med 2017; 18:823-830
4. Singer M. The role of mitochondrial dysfunction in sepsis-induced multi-organ failure. Virulence 2014; 5:66-72
5. Belikova I, Lukaszewicz AC, Faivre V, et al. Oxygen consumption of human peripheral blood mononuclear cells in severe human sepsis. Crit Care Med 2007; 35:2702-2708
6. Crouser ED. Mitochondrial dysfunction in septic shock and multiple organ dysfunction syndrome. Mitochondrion2004; 4:729-741
7. Levy RJ, Deutschman CS. Cytochrome c oxidase dysfunction in sepsis. Crit Care Med 2007; 35:S468-S475
8. Weiss SL, Selak MA, Tuluc F, et al. Mitochondrial dysfunction in peripheral blood mononuclear cells in pediatric septic shock. Pediatr Crit Care Med 2015; 16:e4-e12
9. Brealey D, Karyampudi S, Jacques TS, et al. Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure. Am J Physiol Regul Integr Comp Physiol 2004; 286:R491-R497
10. Sjovall F, Morota S, Hansson MJ, et al. Temporal increase of platelet mitochondrial respiration is negatively associated with clinical outcome in patients with sepsis. Crit Care 2010; 14:R214
11. Japiassu AM, Santiago AP, d'Avila JC, et al. Bioenergetic failure of human peripheral blood monocytes in patients with septic shock is mediated by reduced F1Fo adenosine-5'-triphosphate synthase activity. Crit Care Med 2011; 39:1056-1063
12. Brealey D, Brand M, Hargreaves I, et al. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 2002; 360:219-223
13. Garrabou G, Moren C, Lopez S, et al. The effects of sepsis on mitochondria. J Infect Dis 2012; 205:392-400
14. Carre JE, Orban JC, Re L, et al. Survival in critical illness is associated with early activation of mitochondrial biogenesis. Am J Respir Crit Care Med 2010; 182:745-751
15. Haden DW, Suliman HB, Carraway MS, et al. Mitochondrial biogenesis restores oxidative metabolism during Staphylococcus aureus sepsis. Am J Respir Crit Care Med 2007; 176:768-777
16. Sjovall F, Morota S, Persson J, et al. Patients with sepsis exhibit increased mitochondrial respiratory capacity in peripheral blood immune cells. Crit Care 2013; 17:R152
17. Karlsson M, Hara N, Morata S, et al. Diverse and tissue-specific mitochondrial respiratory response in a mouse model of sepsis-induced multiple organ failure. Shock 2016; 45:404-410
18. Karamercan MA, Weiss SL, Villarroel JP, et al. Can peripheral blood mononuclear cells be used as a proxy for mitochondrial dysfunction in vital organs during hemorrhagic shock and resuscitation? Shock 2013; 40:476-484
19. Goldstein B, Giroir B, Randolph A. International pediatric sepsis consensus conference: Definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 2005; 6:2-8
20. Pollack MM, Patel KM, Ruttimann UE. PRISM III: An updated Pediatric Risk of Mortality score. Crit Care Med 1996; 24:743-752
21. Leteurtre S, Martinot A, Duhamel A, et al. Validation of the Paediatric Logistic Organ Dysfunction (PELOD) score: Prospective, observational, multicentre study. Lancet 2003; 362:192-197
22. Gaies MG, Gurney JG, Yen AH, et al. Vasoactive-inotropic score as a predictor of morbidity and mortality in infants after cardiopulmonary bypass. Pediatr Crit Care Med 2010; 11:234-238
23. Brand MD, Nicholls DG. Assessing mitochondrial dysfunction in cells. Biochem J 2011; 435:297-312
24. Larsen S, Nielsen J, Hansen CN, et al. Biomarkers of mitochondrial content in skeletal muscle of healthy young human subjects. J Physiol 2012; 590:3349-3360
25. Kirby DM, Thorburn DR, Turnbull DM, et al. Biochemical assays of respiratory chain complex activity Methods Cell Biol 2007; 80:93-119
26. Malik AN, Czajka A. Is mitochondrial DNA content a potential biomarker of mitochondrial dysfunction? Mitochondrion 2013; 13:481-492
27. Kepp O, Galluzzi L, Kroemer G. Mitochondrial control of the NLRP3 inflammasome. Nat Immunol 2011; 12:199-200
28. Lederer DJ, Bell SC, Branson RD, et al. Control of confounding and reporting of results in causal inference studies: Guidance for authors from editors of respiratory, sleep, and critical care journals. Ann Am Thorac Soc2018; 16:22-28
29. Chacko BK, Kramer PA, Ravi S, et al. The bioenergetic health index: A new concept in mitochondrial translational research. Clin Sci (Lond) 2014; 127:367-373
30. Dranka BP, Hill BG, Darley-Usmar VM. Mitochondrial reserve capacity in endothelial cells: The impact of nitric oxide and reactive oxygen species. Free Radic Biol Med 2010; 48:905-914
31. Choi SW, Gerencser AA, Nicholls DG. Bioenergetic analysis of isolated cerebrocortical nerve terminals on a microgram scale: Spare respiratory capacity and stochastic mitochondrial failure. J Neurochem 2009; 109:1179-1191
32. van der Windt GJ, Everts B, Chang CH, et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 2012; 36:68-78
33. Sansbury BE, Jones SP, Riggs DW, et al. Bioenergetic function in cardiovascular cells: The importance of the reserve capacity and its biological regulation. Chem Biol Interact 2011; 191:288-295
34. Cheng SC, Scicluna BP, Arts RJ, et al. Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis. Nat Immunol 2016; 17:406-413
35. Pence BD, Yarbro JR. Aging impairs mitochondrial respiratory capacity in classical monocytes. Exp Gerontol 2018; 108:112-117
36. Fink MP. Cytopathic hypoxia. Is oxygen use impaired in sepsis as a result of an acquired intrinsic derangement in cellular respiration? Crit Care Clin 2002; 18:165-175
37. Pearce EL, Pearce EJ. Metabolic pathways in immune cell activation and quiescence. Immunity 2013; 38:633-643
38. D'Souza AD, Parikh N, Kaech SM, et al. Convergence of multiple signaling pathways is required to coordinately up-regulate mtDNA and mitochondrial biogenesis during T cell activation. Mitochondrion 2007; 7:374-385
39. Zhang Q, Raoof M, Chen Y, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 2010; 464:104-107
40. Kraft BD, Chen L, Suliman HB, et al. Peripheral blood mononuclear cells demonstrate mitochondrial damage clearance during sepsis. Crit Care Med 2019; 47:651-658
41. Cote HC, Day AG, Heyland DK. Longitudinal increases in mitochondrial DNA levels in blood cells are associated with survival in critically ill patients. Crit Care 2007; 11:R88
42. Pyle A, Burn DJ, Gordon C, et al. Fall in circulating mononuclear cell mitochondrial DNA content in human sepsis. Intensive Care Med 2010; 36:956-962
43. Sebastiani M, Giordano C, Nediani C, et al. Induction of mitochondrial biogenesis is a maladaptive mechanism in mitochondrial cardiomyopathies. J Am Coll Cardiol 2007; 50:1362-1369
44. Baur JA, Pearson KJ, Price NL, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006; 444:337-342
45. Viscomi C, Bottani E, Zeviani M. Emerging concepts in the therapy of mitochondrial disease. Biochim Biophys Acta 2015; 1847:544-557
46. Whitaker RM, Corum D, Beeson CC, et al. Mitochondrial biogenesis as a pharmacological target: A new approach to acute and chronic diseases. Annu Rev Pharmacol Toxicol 2016; 56:229-249
47. Hazeldine J, Lord JM, Belli A. Traumatic brain injury and peripheral immune suppression: Primer and prospectus. Front Neurol 2015; 6:235
48. Kilbaugh TJ, Lvova M, Karlsson M, et al. Peripheral blood mitochondrial DNA as a biomarker of cerebral mitochondrial dysfunction following traumatic brain injury in a porcine model. PLoS One 2015; 10:e0130927
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Language: | English.
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Document Type: | Pediatric Critical Care.
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Journal Subset: | Clinical Medicine.
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ISSN: | 0090-3493
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NLM Journal Code: | dtf, 0355501
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DOI Number: | https://dx.doi.org/10.1097/CCM.0...- ouverture dans une nouvelle fenêtre
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