Skip to main content
Top
Published in: Intensive Care Medicine 4/2012

01-04-2012 | Original

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

Authors: Sylas B. Cappi, Danilo T. Noritomi, Irineu T. Velasco, Rui Curi, Tatiana C. A. Loureiro, Francisco G. Soriano

Published in: Intensive Care Medicine | Issue 4/2012

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
go back to reference Wang HE, Shapiro NI, Angus DC, Yealy DM (2007) National estimates of severe sepsis in United States emergency departments. Crit Care Med 35:1928–1936PubMedCrossRef Wang HE, Shapiro NI, Angus DC, Yealy DM (2007) National estimates of severe sepsis in United States emergency departments. Crit Care Med 35:1928–1936PubMedCrossRef
2.
go back to reference Vincent JL (2000) Update on sepsis: pathophysiology and treatment. Acta Clin Belg 55:79–87PubMed Vincent JL (2000) Update on sepsis: pathophysiology and treatment. Acta Clin Belg 55:79–87PubMed
3.
go back to reference 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 89:219–226PubMedCrossRef 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 89:219–226PubMedCrossRef
4.
go back to reference McCowen KC, Malhotra A, Bistrian BR (2001) Stress-induced hyperglycemia. Crit Care Clin 17:107–124PubMedCrossRef McCowen KC, Malhotra A, Bistrian BR (2001) Stress-induced hyperglycemia. Crit Care Clin 17:107–124PubMedCrossRef
5.
go back to reference Mizock BA (1995) Alterations in carbohydrate metabolism during stress: a review of the literature. Am J Med 98:75–84PubMedCrossRef Mizock BA (1995) Alterations in carbohydrate metabolism during stress: a review of the literature. Am J Med 98:75–84PubMedCrossRef
6.
go back to reference 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 30:793–799PubMedCrossRef 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 30:793–799PubMedCrossRef
7.
go back to reference Wendel M, Paul R, Heller AR (2007) Lipoproteins in inflammation and sepsis. II. Clinical aspects. Intensive Care Med 33:25–35PubMedCrossRef Wendel M, Paul R, Heller AR (2007) Lipoproteins in inflammation and sepsis. II. Clinical aspects. Intensive Care Med 33:25–35PubMedCrossRef
8.
go back to reference 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 24:584–589PubMedCrossRef 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 24:584–589PubMedCrossRef
9.
go back to reference 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 35:1877–1885PubMedCrossRef 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 35:1877–1885PubMedCrossRef
10.
go back to reference 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 36:289–295PubMedCrossRef 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 36:289–295PubMedCrossRef
11.
go back to reference 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 41:1481–1494PubMed 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 41:1481–1494PubMed
12.
go back to reference 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 9:449–456PubMedCrossRef 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 9:449–456PubMedCrossRef
13.
go back to reference 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 96:2882–2891PubMedCrossRef 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 96:2882–2891PubMedCrossRef
14.
go back to reference 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 276:13750–13755PubMed 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 276:13750–13755PubMed
15.
go back to reference 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 30:115–123PubMedCrossRef 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 30:115–123PubMedCrossRef
16.
go back to reference 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 41:1124–1132PubMedCrossRef 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 41:1124–1132PubMedCrossRef
17.
go back to reference 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 18:762–767PubMedCrossRef 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 18:762–767PubMedCrossRef
18.
go back to reference 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 78:1448–1456PubMedCrossRef 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 78:1448–1456PubMedCrossRef
19.
go back to reference 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 29:342–348PubMed 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 29:342–348PubMed
20.
go back to reference Oliver MF, Opie LH (1994) Effects of glucose and fatty acids on myocardial ischaemia and arrhythmias. Lancet 343:155–158PubMedCrossRef Oliver MF, Opie LH (1994) Effects of glucose and fatty acids on myocardial ischaemia and arrhythmias. Lancet 343:155–158PubMedCrossRef
21.
go back to reference 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 86:2769–2774PubMedCrossRef 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 86:2769–2774PubMedCrossRef
22.
go back to reference 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 72:723–730PubMed 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 72:723–730PubMed
23.
go back to reference 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 345:1359–1367PubMedCrossRef 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 345:1359–1367PubMedCrossRef
24.
go back to reference 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 360:1283–1297PubMedCrossRef 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 360:1283–1297PubMedCrossRef
25.
go back to reference 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:e28PubMedCrossRef 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:e28PubMedCrossRef
26.
go back to reference Schulz KF, Altman DG, Moher D, CONSORT statement (2010) (2010) Updated guidelines for reporting parallel group randomized trials. Ann Intern Med 152:726–732PubMed Schulz KF, Altman DG, Moher D, CONSORT statement (2010) (2010) Updated guidelines for reporting parallel group randomized trials. Ann Intern Med 152:726–732PubMed
27.
go back to reference Steinberg D (1997) Lewis A. Conner Memorial Lecture. Oxidative modification of LDL and atherogenesis. Circulation 95:1062–1071PubMed Steinberg D (1997) Lewis A. Conner Memorial Lecture. Oxidative modification of LDL and atherogenesis. Circulation 95:1062–1071PubMed
28.
go back to reference 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 12:297–305PubMed 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 12:297–305PubMed
29.
go back to reference Thomas JP, Kalyanaraman B, Girotti AW (1994) Involvement of preexisting lipid hydroperoxides in Cu(2+)-stimulated oxidation of low-density lipoprotein. Arch Biochem Biophys 315:244–254PubMedCrossRef Thomas JP, Kalyanaraman B, Girotti AW (1994) Involvement of preexisting lipid hydroperoxides in Cu(2+)-stimulated oxidation of low-density lipoprotein. Arch Biochem Biophys 315:244–254PubMedCrossRef
30.
go back to reference 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 275:12633–12638PubMedCrossRef 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 275:12633–12638PubMedCrossRef
31.
go back to reference 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 100:244–252PubMedCrossRef 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 100:244–252PubMedCrossRef
32.
go back to reference 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 28:1290–1295PubMedCrossRef 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 28:1290–1295PubMedCrossRef
33.
go back to reference 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 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
34.
go back to reference 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 34:1073–1079PubMedCrossRef 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 34:1073–1079PubMedCrossRef
35.
go back to reference Miles JM (1993) Lipid fuel metabolism in health and disease. Curr Opin Gen Surg: 78–84 Miles JM (1993) Lipid fuel metabolism in health and disease. Curr Opin Gen Surg: 78–84
36.
go back to reference Andersen SK, Gjedsted J, Christiansen C, Tonnesen E (2004) The roles of insulin and hyperglycemia in sepsis pathogenesis. J Leukoc Biol 75:413–421PubMedCrossRef Andersen SK, Gjedsted J, Christiansen C, Tonnesen E (2004) The roles of insulin and hyperglycemia in sepsis pathogenesis. J Leukoc Biol 75:413–421PubMedCrossRef
37.
go back to reference 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 41:934–940PubMedCrossRef 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 41:934–940PubMedCrossRef
38.
go back to reference 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 100:442–450PubMedCrossRef 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 100:442–450PubMedCrossRef
39.
go back to reference 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 100:1614–1618PubMedCrossRef 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 100:1614–1618PubMedCrossRef
40.
go back to reference 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–I209PubMed 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–I209PubMed
Metadata
Title
Dyslipidemia: a prospective controlled randomized trial of intensive glycemic control in sepsis
Authors
Sylas B. Cappi
Danilo T. Noritomi
Irineu T. Velasco
Rui Curi
Tatiana C. A. Loureiro
Francisco G. Soriano
Publication date
01-04-2012
Publisher
Springer-Verlag
Published in
Intensive Care Medicine / Issue 4/2012
Print ISSN: 0342-4642
Electronic ISSN: 1432-1238
DOI
https://doi.org/10.1007/s00134-011-2458-z

Other articles of this Issue 4/2012

Intensive Care Medicine 4/2012 Go to the issue