Is reducing variability of blood glucose the real but hidden target of intensive insulin therapy?

Moritoki Egi, Rinaldo Bellomo, Michael C Reade, Moritoki Egi, Rinaldo Bellomo, Michael C Reade

Abstract

Since the first report that intensive insulin therapy reduced mortality in selected surgical critically ill patients, lowering of blood glucose levels has been recommended as a means of improving patient outcomes. In this initial Leuven trial, blood glucose control by protocol using insulin was applied to 98.7% of patients in the intensive group but to only 39.2% (P < 0.0001) of patients in the control group. If appropriately applied, such protocols should decrease both the mean blood glucose concentration and its variability (variation of blood glucose concentration). Thus, it is logically possible that the benefit of intensive insulin therapy in the first Leuven trial was due to a decrease in mean glucose levels, a decrease in their variability, or both. Several recent studies have confirmed significant associations between variability of blood glucose levels and patient outcomes. Decreasing the variability of blood glucose levels might be an important dimension of glucose management, a possible mechanism by which an intensive insulin protocol exerts its putative beneficial effects, and an important goal of glucose management in the intensive care unit. Clinicians need to be aware of this controversy when considering the application of intensive insulin therapy and interpreting future trials.

Figures

Figure 1
Figure 1
Graphic representations of glycemic control with a high mean glucose level and high (a) or low (b) variability.

References

    1. Wolfe RR, Allsop JR, Burke JF. Glucose metabolism in man: responses to intravenous glucose infusion. Metabolism. 1979;28:210–220. doi: 10.1016/0026-0495(79)90066-0.
    1. Shangraw RE, Jahoor F, Miyoshi H, Neff WA, Stuart CA, Herndon DN, Wolfe RR. Differentiation between septic and postburn insulin resistance. Metabolism. 1989;38:983–989. doi: 10.1016/0026-0495(89)90010-3.
    1. Robinson LE, van Soeren MH. Insulin resistance and hyperglycemia in critical illness: role of insulin in glycemic control. AACN Clin Issues. 2004;15:45–62.
    1. Coursin DB, Connery LE, Ketzler JT. Perioperative diabetic and hyperglycemic management issues. Crit Care Med. 2004;32(4 Suppl):S116–125. doi: 10.1097/01.CCM.0000115623.52021.C0.
    1. Malmberg K, Ryden L, Efendic S, Herlitz J, Nicol P, Waldenstrom A, Wedel H, Welin L. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol. 1995;26:57–65. doi: 10.1016/0735-1097(95)00126-K.
    1. Malmberg K. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. BMJ. 1997;314:1512–1515.
    1. Berghe G van den, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345:1359–1367. doi: 10.1056/NEJMoa011300.
    1. Berghe G Van den, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, Van Wijngaerden E, Bobbaers H, Bouillon R. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;354:449–461. doi: 10.1056/NEJMoa052521.
    1. Berghe G Van den, Wilmer A, Milants I, Wouters PJ, Bouckaert B, Bruyninckx F, Bouillon R, Schetz M. Intensive insulin therapy in mixed medical/surgical intensive care units: benefit versus harm. Diabetes. 2006;55:3151–3159. doi: 10.2337/db06-0855.
    1. Berghe G Van den, Wouters PJ, Bouillon R, Weekers F, Verwaest C, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P. Outcome benefit of intensive insulin therapy in the critically ill: insulin dose versus glycemic control. Crit Care Med. 2003;31:359–366. doi: 10.1097/01.CCM.0000045568.12881.10.
    1. Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM, Surviving Sepsis Campaign Management Guidelines Committee Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004;32:858–873. doi: 10.1097/01.CCM.0000117317.18092.E4.
    1. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med. 2008;34:17–60. doi: 10.1007/s00134-007-0934-2.
    1. Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, Moerer O, Gruendling M, Oppert M, Grond S, Olthoff D, Jaschinski U, John S, Rossaint R, Welte T, Schaefer M, Kern P, Kuhnt E, Kiehntopf M, Hartog C, Natanson C, Loeffler M, Reinhart K, German Competence Network Sepsis (SepNet) Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358:125–139. doi: 10.1056/NEJMoa070716.
    1. Wiener RS, Wiener DC, Larson RJ. Benefits and risks of tight glucose control in critically ill adults: a meta-analysis. JAMA. 2008;300:933–944. doi: 10.1001/jama.300.8.933.
    1. Egi M, Bellomo R, Stachowski E, French CJ, Hart G, Stow P. Circadian rhythm of blood glucose values in critically ill patients. Crit Care Med. 2007;35:416–421. doi: 10.1097/01.CCM.0000253814.78836.43.
    1. Egi M, Bellomo R, Stachowski E, French CJ, Hart G. Variability of blood glucose concentration and short-term mortality in critically ill patients. Anesthesiology. 2006;105:244–252. doi: 10.1097/00000542-200608000-00006.
    1. Ali NA, O'Brien JM, Jr, Dungan K, Phillips G, Marsh CB, Lemeshow S, Connors AF, Jr, Preiser JC. Glucose variability and mortality in patients with sepsis. Crit Care Med. 2008;36:2316–2321. doi: 10.1097/CCM.0b013e3181810378.
    1. Hirshberg E, Larsen G, Van Duker H. Alterations in glucose homeostasis in the pediatric intensive care unit: hyperglycemia and glucose variability are associated with increased mortality and morbidity. Pediatr Crit Care Med. 2008;9:361–366. doi: 10.1097/PCC.0b013e318172d401.
    1. Dossett LA, Cao H, Mowery NT, Dortch MJ, Morris JM, Jr, May AK. Blood glucose variability is associated with mortality in the surgical intensive care unit. Am Surg. 2008;74:679–685. discussion 685.
    1. Waeschle RM, Moerer O, Hilgers R, Herrmann P, Neumann P, Quintel M. The impact of the severity of sepsis on the risk of hypoglycaemia and glycaemic variability. Crit Care. 2008;12:R129. doi: 10.1186/cc7097.
    1. Krinsley JS. Glycemic variability: a strong independent predictor of mortality in critically ill patients. Crit Care Med. 2008;36:3008–3013. doi: 10.1097/CCM.0b013e31818b38d2.
    1. Service FJ, Molnar GD, Rosevear JW, Ackerman E, Gatewood LC, Taylor WF. Mean amplitude of glycemic excursions, a measure of diabetic instability. Diabetes. 1970;19:644–655.
    1. Monnier L, Colette C, Boegner C, Pham TC, Lapinski H, Boniface H. Continuous glucose monitoring in patients with type 2 diabetes: Why? When? Whom? Diabetes Metab. 2007;33:247–252. doi: 10.1016/j.diabet.2006.11.007.
    1. Zhou J, Jia W, Bao Y, Ma X, Lu W, Li H, Hu C, Xiang K. Glycemic variability and its responses to intensive insulin treatment in newly diagnosed type 2 diabetes. Med Sci Monit. 2008;14:CR552–558.
    1. Wentholt IM, Kulik W, Michels RP, Hoekstra JB, DeVries JH. Glucose fluctuations and activation of oxidative stress in patients with type 1 diabetes. Diabetologia. 2008;51:183–190. doi: 10.1007/s00125-007-0842-6.
    1. Quagliaro L, Piconi L, Assaloni R, Martinelli L, Motz E, Ceriello A. Intermittent high glucose enhances apoptosis related to oxidative stress in human umbilical vein endothelial cells: the role of protein kinase C and NAD(P)H-oxidase activation. Diabetes. 2003;52:2795–2804. doi: 10.2337/diabetes.52.11.2795.
    1. Monnier L, Mas E, Ginet C, Michel F, Villon L, Cristol JP, Colette C. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA. 2006;295:1681–1687. doi: 10.1001/jama.295.14.1681.
    1. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414:813–820. doi: 10.1038/414813a.
    1. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005;54:1615–1625. doi: 10.2337/diabetes.54.6.1615.
    1. Watada H, Azuma K, Kawamori R. Glucose fluctuation on the progression of diabetic macroangiopathy – new findings from monocyte adhesion to endothelial cells. Diabetes Res Clin Pract. 2007;77(Suppl 1):S58–61. doi: 10.1016/j.diabres.2007.01.034.
    1. Azuma K, Kawamori R, Toyofuku Y, Kitahara Y, Sato F, Shimizu T, Miura K, Mine T, Tanaka Y, Mitsumata M, Watada H. Repetitive fluctuations in blood glucose enhance monocyte adhesion to the endothelium of rat thoracic aorta. Arterioscler Thromb Vasc Biol. 2006;26:2275–2280. doi: 10.1161/01.ATV.0000239488.05069.03.
    1. Risso A, Mercuri F, Quagliaro L, Damante G, Ceriello A. Intermittent high glucose enhances apoptosis in human umbilical vein endothelial cells in culture. Am J Physiol Endocrinol Metab. 2001;281:E924–930.
    1. Bellomo R, Egi M. Glycemic control in the intensive care unit: why we should wait for NICE-SUGAR. Mayo Clin Proc. 2005;80:1546–1548. doi: 10.4065/80.12.1546.

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