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Dyslipidemia: a prospective controlled randomized trial of intensive glycemic control in sepsis

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Abstract

Purpose

Metabolic disturbances are quite common in critically ill patients. Glycemic control appears to be an important adjuvant therapy in such patients. In addition, disorders of lipid metabolism are associated with worse prognoses. The purpose of this study was to investigate the effects that two different glycemic control protocols have on lipid profile and metabolism.

Methods

We evaluated 63 patients hospitalized for severe sepsis or septic shock, over the first 72 h of intensive care. Patients were randomly allocated to receive conservative glycemic control (target range 140–180 mg/dl) or intensive glycemic control (target range 80–110 mg/dl). Serum levels of low-density lipoprotein, high-density lipoprotein, triglycerides, total cholesterol, free fatty acids, and oxidized low-density lipoprotein were determined.

Results

In both groups, serum levels of low-density lipoprotein, high-density lipoprotein, and total cholesterol were below normal, whereas those of free fatty acids, triglycerides, and oxidized low-density lipoprotein were above normal. At 4 h after admission, free fatty acid levels were higher in the conservative group than in the intensive group, progressively decreasing in both groups until hour 48 and continuing to decrease until hour 72 only in the intensive group. Oxidized low-density lipoprotein levels were elevated in both groups throughout the study period.

Conclusions

Free fatty acids respond to intensive glycemic control and, because of their high toxicity, can be a therapeutic target in patients with sepsis.

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References

  1. Wang HE, Shapiro NI, Angus DC, Yealy DM (2007) National estimates of severe sepsis in United States emergency departments. Crit Care Med 35:1928–1936

    Article  PubMed  Google Scholar 

  2. Vincent JL (2000) Update on sepsis: pathophysiology and treatment. Acta Clin Belg 55:79–87

    PubMed  CAS  Google Scholar 

  3. Mesotten D, Swinnen JV, Vanderhoydonc F, Wouters PJ, Van den Berghe G (2004) Contribution of circulating lipids to the improved outcome of critical illness by glycemic control with intensive insulin therapy. J Clin Endocrinol Metab 89:219–226

    Article  PubMed  CAS  Google Scholar 

  4. McCowen KC, Malhotra A, Bistrian BR (2001) Stress-induced hyperglycemia. Crit Care Clin 17:107–124

    Article  PubMed  CAS  Google Scholar 

  5. Mizock BA (1995) Alterations in carbohydrate metabolism during stress: a review of the literature. Am J Med 98:75–84

    Article  PubMed  CAS  Google Scholar 

  6. Scott JF, Robinson GM, French JM, O’Connell JE, Alberti KG, Gray CS (1999) Glucose potassium insulin infusions in the treatment of acute stroke patients with mild to moderate hyperglycemia: the glucose insulin in stroke trial (GIST). Stroke 30:793–799

    Article  PubMed  CAS  Google Scholar 

  7. Wendel M, Paul R, Heller AR (2007) Lipoproteins in inflammation and sepsis. II. Clinical aspects. Intensive Care Med 33:25–35

    Article  PubMed  CAS  Google Scholar 

  8. Gordon BR, Parker TS, Levine DM, Saal SD, Wang JC, Sloan BJ, Barie PS, Rubin AL (1996) Low lipid concentrations in critical illness: implications for preventing and treating endotoxemia. Crit Care Med 24:584–589

    Article  PubMed  CAS  Google Scholar 

  9. Barlage S, Gnewuch C, Liebisch G, Wolf Z, Audebert FX, Gluck T, Frohlich D, Kramer BK, Rothe G, Schmitz G (2009) Changes in HDL-associated apolipoproteins relate to mortality in human sepsis and correlate to monocyte and platelet activation. Intensive Care Med 35:1877–1885

    Article  PubMed  CAS  Google Scholar 

  10. Pittet YK, Berger MM, Pluess TT, Voirol P, Revelly JP, Tappy L, Chiolero RL (2010) Blunting the response to endotoxin in healthy subjects: effects of various doses of intravenous fish oil. Intensive Care Med 36:289–295

    Article  PubMed  CAS  Google Scholar 

  11. Navab M, Hama SY, Cooke CJ, Anantharamaiah GM, Chaddha M, Jin L, Subbanagounder G, Faull KF, Reddy ST, Miller NE, Fogelman AM (2000) Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: step 1. J Lipid Res 41:1481–1494

    PubMed  CAS  Google Scholar 

  12. Navab M, Hama SY, Hough GP, Hedrick CC, Sorenson R, La Du BN, Kobashigawa JA, Fonarow GC, Berliner JA, Laks H, Fogelman AM (1998) High density associated enzymes: their role in vascular biology. Curr Opin Lipidol 9:449–456

    Article  PubMed  CAS  Google Scholar 

  13. Watson AD, Berliner JA, Hama SY, La Du BN, Faull KF, Fogelman AM, Navab M (1995) Protective effect of high density lipoprotein associated paraoxonase. Inhibition of the biological activity of minimally oxidized low density lipoprotein. J Clin Invest 96:2882–2891

    Article  PubMed  CAS  Google Scholar 

  14. Cominacini L, Rigoni A, Pasini AF, Garbin U, Davoli A, Campagnola M, Pastorino AM, Lo Cascio V, Sawamura T (2001) The binding of oxidized low density lipoprotein (ox-LDL) to ox-LDL receptor-1 reduces the intracellular concentration of nitric oxide in endothelial cells through an increased production of superoxide. J Biol Chem 276:13750–13755

    PubMed  CAS  Google Scholar 

  15. Cury-Boaventura MF, Gorjao R, de Lima TM, Piva TM, Peres CM, Soriano FG, Curi R (2006) Toxicity of a soybean oil emulsion on human lymphocytes and neutrophils. JPEN J Parenter Enteral Nutr 30:115–123

    Article  PubMed  CAS  Google Scholar 

  16. Hatanaka E, Levada-Pires AC, Pithon-Curi TC, Curi R (2006) Systematic study on ROS production induced by oleic, linoleic, and gamma-linolenic acids in human and rat neutrophils. Free Radic Biol Med 41:1124–1132

    Article  PubMed  CAS  Google Scholar 

  17. Carantoni M, Abbasi F, Warmerdam F, Klebanov M, Wang PW, Chen YD, Azhar S, Reaven GM (1998) Relationship between insulin resistance and partially oxidized LDL particles in healthy, nondiabetic volunteers. Arterioscler Thromb Vasc Biol 18:762–767

    Article  PubMed  CAS  Google Scholar 

  18. Cury-Boaventura MF, Gorjao R, de Lima TM, Newsholme P, Curi R (2006) Comparative toxicity of oleic and linoleic acid on human lymphocytes. Life Sci 78:1448–1456

    Article  PubMed  CAS  Google Scholar 

  19. Nogueira AC, Kawabata V, Biselli P, Lins MH, Valeri C, Seckler M, Hoshino W, Junior LG, Bernik MM, de AndradeMachado JB, Martinez MB, Lotufo PA, Caldini EG, Martins E, Curi R, Soriano FG (2008) Changes in plasma free fatty acid levels in septic patients are associated with cardiac damage and reduction in heart rate variability. Shock 29:342–348

    PubMed  CAS  Google Scholar 

  20. Oliver MF, Opie LH (1994) Effects of glucose and fatty acids on myocardial ischaemia and arrhythmias. Lancet 343:155–158

    Article  PubMed  CAS  Google Scholar 

  21. Manzella D, Barbieri M, Rizzo MR, Ragno E, Passariello N, Gambardella A, Marfella R, Giugliano D, Paolisso G (2001) Role of free fatty acids on cardiac autonomic nervous system in noninsulin-dependent diabetic patients: effects of metabolic control. J Clin Endocrinol Metab 86:2769–2774

    Article  PubMed  CAS  Google Scholar 

  22. Paolisso G, Manzella D, Rizzo MR, Ragno E, Barbieri M, Varricchio G, Varricchio M (2000) Elevated plasma fatty acid concentrations stimulate the cardiac autonomic nervous system in healthy subjects. Am J Clin Nutr 72:723–730

    PubMed  CAS  Google Scholar 

  23. van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R (2001) Intensive insulin therapy in the critically ill patients. N Engl J Med 345:1359–1367

    Article  PubMed  Google Scholar 

  24. Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V, Bellomo R, Cook D, Dodek P, Henderson WR, Hebert PC, Heritier S, Heyland DK, McArthur C, McDonald E, Mitchell I, Myburgh JA, Norton R, Potter J, Robinson BG, Ronco JJ (2009) Intensive versus conventional glucose control in critically ill patients. N Engl J Med 360:1283–1297

    Article  PubMed  Google Scholar 

  25. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ (2009) Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. 1992. Chest 136:e28

    Article  PubMed  CAS  Google Scholar 

  26. Schulz KF, Altman DG, Moher D, CONSORT statement (2010) (2010) Updated guidelines for reporting parallel group randomized trials. Ann Intern Med 152:726–732

    PubMed  Google Scholar 

  27. Steinberg D (1997) Lewis A. Conner Memorial Lecture. Oxidative modification of LDL and atherogenesis. Circulation 95:1062–1071

    PubMed  CAS  Google Scholar 

  28. Norata GD, Tonti L, Roma P, Catapano AL (2002) Apoptosis and proliferation of endothelial cells in early atherosclerotic lesions: possible role of oxidised LDL. Nutr Metab Cardiovasc Dis 12:297–305

    PubMed  CAS  Google Scholar 

  29. Thomas JP, Kalyanaraman B, Girotti AW (1994) Involvement of preexisting lipid hydroperoxides in Cu(2+)-stimulated oxidation of low-density lipoprotein. Arch Biochem Biophys 315:244–254

    Article  PubMed  CAS  Google Scholar 

  30. Cominacini L, Pasini AF, Garbin U, Davoli A, Tosetti ML, Campagnola M, Rigoni A, Pastorino AM, LoCascio V, Sawamura T (2000) Oxidized low density lipoprotein (ox-LDL) binding to ox-LDL receptor-1 in endothelial cells induces the activation of NF-kappaB through an increased production of intracellular reactive oxygen species. J Biol Chem 275:12633–12638

    Article  PubMed  CAS  Google Scholar 

  31. Ling W, Lougheed M, Suzuki H, Buchan A, Kodama T, Steinbrecher UP (1997) Oxidized or acetylated low density lipoproteins are rapidly cleared by the liver in mice with disruption of the scavenger receptor class A type I/II gene. J Clin Invest 100:244–252

    Article  PubMed  CAS  Google Scholar 

  32. Luangrath V, Brodeur MR, Rhainds D, Brissette L (2008) Mouse CD36 has opposite effects on LDL and oxidized LDL metabolism in vivo. Arterioscler Thromb Vasc Biol 28:1290–1295

    Article  PubMed  CAS  Google Scholar 

  33. Ficker ES, Maranhao RC, Chacra AP, Neves VC, Negrao CE, Martins VC, Vinagre CG (2010) Exercise training accelerates the removal from plasma of LDL-like nanoemulsion in moderately hypercholesterolemic subjects. Atherosclerosis 212:230–236

    Google Scholar 

  34. Soriano FG, Nogueira AC, Caldini EG, Lins MH, Teixeira AC, Cappi SB, Lotufo PA, Bernik MM, Zsengeller Z, Chen M, Szabo C (2006) Potential role of poly(adenosine 5′-diphosphate-ribose) polymerase activation in the pathogenesis of myocardial contractile dysfunction associated with human septic shock. Crit Care Med 34:1073–1079

    Article  PubMed  CAS  Google Scholar 

  35. Miles JM (1993) Lipid fuel metabolism in health and disease. Curr Opin Gen Surg: 78–84

  36. Andersen SK, Gjedsted J, Christiansen C, Tonnesen E (2004) The roles of insulin and hyperglycemia in sepsis pathogenesis. J Leukoc Biol 75:413–421

    Article  PubMed  CAS  Google Scholar 

  37. Voerman HJ, van Strack Schijndel RJ, Groeneveld AB, de Boer H, Nauta JP, Thijs LG (1992) Pulsatile hormone secretion during severe sepsis: accuracy of different blood sampling regimens. Metabolism 41:934–940

    Article  PubMed  CAS  Google Scholar 

  38. Zuurbier CJ, Hoek FJ, van Dijk J, Abeling NG, Meijers JC, Levels JH, de Jonge E, de Mol BA, Van Wezel HB (2008) Perioperative hyperinsulinaemic normoglycaemic clamp causes hypolipidaemia after coronary artery surgery. Br J Anaesth 100:442–450

    Article  PubMed  CAS  Google Scholar 

  39. Chaudhuri A, Janicke D, Wilson M, Ghanim H, Wilding GE, Aljada A, Dandona P (2007) Effect of modified glucose-insulin-potassium on free fatty acids, matrix metalloproteinase, and myoglobin in ST-elevation myocardial infarction. Am J Cardiol 100:1614–1618

    Article  PubMed  CAS  Google Scholar 

  40. Russell RO Jr, Rogers WJ, Mantle JA, McDaniel HG, Rackley CE (1976) Glucose-insulin-potassium, free fatty acids and acute myocardial infarction in man. Circulation 53:I207–I209

    PubMed  Google Scholar 

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Acknowledgments

The São Paulo Research Foundation (FAPESP)- 04/02161-2.

Author information

Authors and Affiliations

  1. Laboratório da Disciplina de Emergências Clínicas, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo 455, sala 3187, São Paulo, SP, 01246-913, Brazil

    Sylas B. Cappi, Danilo T. Noritomi, Irineu T. Velasco & Francisco G. Soriano

  2. Intensive Care Unit, University of São Paulo University Hospital, São Paulo, Brazil

    Francisco G. Soriano

  3. Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil

    Rui Curi & Tatiana C. A. Loureiro

Authors
  1. Sylas B. Cappi
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  2. Danilo T. Noritomi
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  3. Irineu T. Velasco
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  4. Rui Curi
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  5. Tatiana C. A. Loureiro
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  6. Francisco G. Soriano
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Corresponding author

Correspondence to Francisco G. Soriano.

Additional information

Clinical trial registered with http://www.clinicaltrials.gov as NCT01013662.

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Cappi, S.B., Noritomi, D.T., Velasco, I.T. et al. Dyslipidemia: a prospective controlled randomized trial of intensive glycemic control in sepsis. Intensive Care Med 38, 634–641 (2012). https://doi.org/10.1007/s00134-011-2458-z

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  • DOI: https://doi.org/10.1007/s00134-011-2458-z

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