The Long and Winding Road to Personalized Glycemic Control in the Intensive Care Unit

Abstract

In the critically ill adult, dysglycemia is a marker of disease severity and is associated with worse clinical outcomes. Close monitoring of glucose and use of insulin in critically ill patients have been done for more than 2 decades, but the appropriate target glycemic range in critically ill patients remains controversial. Physiological stress response, levels of inflammatory cytokines, nutritional intake, and level of mobility affect glycemic control, and a more personalized approach to patients with dysglycemia is warranted in critically ill intensive care unit (ICU) patients. We discuss the pathophysiology and downstream effects of altered glycemic response in critical illness, management of glycemic control in the ICU, and future strategies toward personalization of critical care glycemic management.

Keywords

hyperglycemia - hypoglycemia - glycemic variability - critical illness - insulin

Disclosures

None.

• References

• 1 Aramendi I, Burghi G, Manzanares W. Dysglycemia in the critically ill patient: current evidence and future perspectives. Rev Bras Ter Intensiva 2017; 29 (03) 364-372
• 2 van den Berghe G, Wouters P, Weekers F. , et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001; 345 (19) 1359-1367
• 3 Van den Berghe G, Wilmer A, Hermans G. , et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006; 354 (05) 449-461
• 4 Brunkhorst FM, Engel C, Bloos F. , et al; German Competence Network Sepsis (SepNet). Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008; 358 (02) 125-139
• 5 Dungan KM, Braithwaite SS, Preiser JC. Stress hyperglycaemia. Lancet 2009; 373 (9677): 1798-1807
• 6 Plummer MP, Bellomo R, Cousins CE. , et al. Dysglycaemia in the critically ill and the interaction of chronic and acute glycaemia with mortality. Intensive Care Med 2014; 40 (07) 973-980
• 7 Cely CM, Arora P, Quartin AA, Kett DH, Schein RM. Relationship of baseline glucose homeostasis to hyperglycemia during medical critical illness. Chest 2004; 126 (03) 879-887
• 8 Lena D, Kalfon P, Preiser JC, Ichai C. Glycemic control in the intensive care unit and during the postoperative period. Anesthesiology 2011; 114 (02) 438-444
• 9 Barth E, Albuszies G, Baumgart K. , et al. Glucose metabolism and catecholamines. Crit Care Med 2007; 35 (9, Suppl): S508-S518
• 10 Andrews RC, Walker BR. Glucocorticoids and insulin resistance: old hormones, new targets. Clin Sci (Lond) 1999; 96 (05) 513-523
• 11 Carré 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 (06) 745-751
• 12 Vanhorebeek I, Gunst J, Derde S. , et al. Insufficient activation of autophagy allows cellular damage to accumulate in critically ill patients. J Clin Endocrinol Metab 2011; 96 (04) E633-E645
• 13 Weir CJ, Murray GD, Dyker AG, Lees KR. Is hyperglycaemia an independent predictor of poor outcome after acute stroke? Results of a long-term follow up study. BMJ 1997; 314 (7090): 1303-1306
• 14 Demchuk AM, Morgenstern LB, Krieger DW. , et al. Serum glucose level and diabetes predict tissue plasminogen activator-related intracerebral hemorrhage in acute ischemic stroke. Stroke 1999; 30 (01) 34-39
• 15 Hirata Y, Tomioka H, Sekiya R. , et al. Association of hyperglycemia on admission and during hospitalization with mortality in diabetic patients admitted for pneumonia. Intern Med 2013; 52 (21) 2431-2438
• 16 Sharif K, Ghadir S, Jakubowicz D. , et al. Improved outcome of patients with diabetes mellitus with good glycemic control in the cardiac intensive care unit: a retrospective study. Cardiovasc Diabetol 2019; 18 (01) 4
• 17 Krinsley JS, Grover A. Severe hypoglycemia in critically ill patients: risk factors and outcomes. Crit Care Med 2007; 35 (10) 2262-2267
• 18 Bagshaw SM, Egi M, George C, Bellomo R. ; Australia New Zealand Intensive Care Society Database Management Committee. Early blood glucose control and mortality in critically ill patients in Australia. Crit Care Med 2009; 37 (02) 463-470
• 19 Krinsley JS, Schultz MJ, Spronk PE. , et al. Mild hypoglycemia is independently associated with increased mortality in the critically ill. Crit Care 2011; 15 (04) R173
• 20 Egi M, Bellomo R, Stachowski E. , et al. Hypoglycemia and outcome in critically ill patients. Mayo Clin Proc 2010; 85 (03) 217-224
• 21 Finfer S, Liu B, Chittock DR. , et al; NICE-SUGAR Study Investigators. Hypoglycemia and risk of death in critically ill patients. N Engl J Med 2012; 367 (12) 1108-1118
• 22 Krinsley J, Schultz MJ, Spronk PE. , et al. Mild hypoglycemia is strongly associated with increased intensive care unit length of stay. Ann Intensive Care 2011; 1: 49
• 23 Uijtendaal EV, Zwart-van Rijkom JE, de Lange DW, Lalmohamed A, van Solinge WW, Egberts TC. Influence of a strict glucose protocol on serum potassium and glucose concentrations and their association with mortality in intensive care patients. Crit Care 2015; 19: 270
• 24 Yatabe T, Inoue S, Sakaguchi M, Egi M. The optimal target for acute glycemic control in critically ill patients: a network meta-analysis. Intensive Care Med 2017; 43 (01) 16-28
• 25 Yamada T, Shojima N, Noma H, Yamauchi T, Kadowaki T. Glycemic control, mortality, and hypoglycemia in critically ill patients: a systematic review and network meta-analysis of randomized controlled trials. Intensive Care Med 2017; 43 (01) 1-15
• 26 Vriesendorp TM, van Santen S, DeVries JH. , et al. Predisposing factors for hypoglycemia in the intensive care unit. Crit Care Med 2006; 34 (01) 96-101
• 27 Mahmoodpoor A, Hamishehkar H, Beigmohammadi M. , et al. Predisposing factors for hypoglycemia and its relation with mortality in critically ill patients undergoing insulin therapy in an intensive care unit. Anesth Pain Med 2016; 6 (01) e33849
• 28 Kosiborod M, Inzucchi SE, Goyal A. , et al. Relationship between spontaneous and iatrogenic hypoglycemia and mortality in patients hospitalized with acute myocardial infarction. JAMA 2009; 301 (15) 1556-1564
• 29 Saliba L, Cook CH, Dungan KM, Porter K, Murphy CV. Medication-induced and spontaneous hypoglycemia carry the same risk for hospital mortality in critically ill patients. J Crit Care 2016; 36: 13-17
• 30 Lacherade JC, Jacqueminet S, Preiser JC. An overview of hypoglycemia in the critically ill. J Diabetes Sci Technol 2009; 3 (06) 1242-1249
• 31 Schächinger H, Port J, Brody S. , et al. Increased high-frequency heart rate variability during insulin-induced hypoglycaemia in healthy humans. Clin Sci (Lond) 2004; 106 (06) 583-588
• 32 Gill GV, Woodward A, Casson IF, Weston PJ. Cardiac arrhythmia and nocturnal hypoglycaemia in type 1 diabetes--the ‘dead in bed’ syndrome revisited. Diabetologia 2009; 52 (01) 42-45
• 33 Braithwaite SS. Glycemic variability in hospitalized patients: choosing metrics while awaiting the evidence. Curr Diab Rep 2013; 13 (01) 138-154
• 34 Meyfroidt G. Blood glucose amplitude variability in critically ill patients. Minerva Anestesiol 2015; 81 (09) 1010-1018
• 35 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 (02) 244-252
• 36 Krinsley JS. Glycemic variability: a strong independent predictor of mortality in critically ill patients. Crit Care Med 2008; 36 (11) 3008-3013
• 37 Bagshaw SM, Bellomo R, Jacka MJ, Egi M, Hart GK, George C. ; ANZICS CORE Management Committee. The impact of early hypoglycemia and blood glucose variability on outcome in critical illness. Crit Care 2009; 13 (03) R91
• 38 Bardia A, Khabbaz K, Mueller A. , et al. The association between preoperative hemoglobin A1C and postoperative glycemic variability on 30-day major adverse outcomes following isolated cardiac valvular surgery. Anesth Analg 2017; 124 (01) 16-22
• 39 Arnold P, Paxton RA, McNorton K, Szpunar S, Edwin SB. The effect of a hypoglycemia treatment protocol on glycemic variability in critically ill patients. J Intensive Care Med 2015; 30 (03) 156-160
• 40 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 (11) 2795-2804
• 41 Ceriello A, Esposito K, Piconi L. , et al. Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients. Diabetes 2008; 57 (05) 1349-1354
• 42 Monnier L, Mas E, Ginet C. , et al. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA 2006; 295 (14) 1681-1687
• 43 Sechterberger MK, van Steen SC, Boerboom EM. , et al. Higher glucose variability in type 1 than in type 2 diabetes patients admitted to the intensive care unit: a retrospective cohort study. J Crit Care 2017; 38: 300-303
• 44 Krinsley JS, Egi M, Kiss A. , et al. Diabetic status and the relation of the three domains of glycemic control to mortality in critically ill patients: an international multicenter cohort study. Crit Care 2013; 17 (02) R37
• 45 Krinsley JS. Glycemic control in the critically ill: what have we learned since NICE-SUGAR?. Hosp Pract (1995) 2015; 43 (03) 191-197
• 46 Preiser JC, Devos P, Ruiz-Santana S. , et al. A prospective randomised multi-centre controlled trial on tight glucose control by intensive insulin therapy in adult intensive care units: the Glucontrol study. Intensive Care Med 2009; 35 (10) 1738-1748
• 47 Chase JG, Pretty CG, Pfeifer L. , et al. Organ failure and tight glycemic control in the SPRINT study. Crit Care 2010; 14 (04) R154
• 48 Signal M, Le Compte A, Shaw GM, Chase JG. Glycemic levels in critically ill patients: are normoglycemia and low variability associated with improved outcomes?. J Diabetes Sci Technol 2012; 6 (05) 1030-1037
• 49 Krinsley JS, Preiser JC. Time in blood glucose range 70 to 140 mg/dl >80% is strongly associated with increased survival in non-diabetic critically ill adults. Crit Care 2015; 19: 179
• 50 De La Rosa Gdel C, Donado JH, Restrepo AH. , et al; Grupo de Investigacion en Cuidado intensivo: GICI-HPTU. Strict glycaemic control in patients hospitalised in a mixed medical and surgical intensive care unit: a randomised clinical trial. Crit Care 2008; 12 (05) R120
• 51 Finfer S, Chittock DR, Su SY. , et al; NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009; 360 (13) 1283-1297
• 52 Kalfon P, Giraudeau B, Ichai C. , et al; CGAO-REA Study Group. Tight computerized versus conventional glucose control in the ICU: a randomized controlled trial. Intensive Care Med 2014; 40 (02) 171-181
• 53 Qaseem A, Chou R, Humphrey LL, Shekelle P. ; Clinical Guidelines Committee of the American College of Physicians. Inpatient glycemic control: best practice advice from the Clinical Guidelines Committee of the American College of Physicians. Am J Med Qual 2014; 29 (02) 95-98
• 54 American Diabetes Association. 15. Diabetes care in the hospital: Standards of Medical Care in Diabetes-2019 . Diabetes Care 2019; 42 (Suppl. 01) S173-S181
• 55 Rhodes A, Evans LE, Alhazzani W. , et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med 2017; 45 (03) 486-552
• 56 Mojtahedzadeh M, Jafarieh A, Najafi A, Khajavi MR, Khalili N. Comparison of metformin and insulin in the control of hyperglycaemia in non-diabetic critically ill patients. Endokrynol Pol 2012; 63 (03) 206-211
• 57 Dungan KM. Hyperglycemia in the intensive care unit: is insulin the only option?. Crit Care 2013; 17 (06) 1012
• 58 Umpierrez GE, Gianchandani R, Smiley D. , et al. Safety and efficacy of sitagliptin therapy for the inpatient management of general medicine and surgery patients with type 2 diabetes: a pilot, randomized, controlled study. Diabetes Care 2013; 36 (11) 3430-3435
• 59 Clarke RS. The hyperglycaemic response to different types of surgery and anaesthesia. Br J Anaesth 1970; 42 (01) 45-53
• 60 Rehman HU, Mohammed K. Perioperative management of diabetic patients. Curr Surg 2003; 60 (06) 607-611
• 61 Furnary AP, Wu Y, Bookin SO. Effect of hyperglycemia and continuous intravenous insulin infusions on outcomes of cardiac surgical procedures: the Portland Diabetic Project. Endocr Pract 2004; 10 (Suppl. 02) 21-33
• 62 Okabayashi T, Shima Y, Sumiyoshi T. , et al. Intensive versus intermediate glucose control in surgical intensive care unit patients. Diabetes Care 2014; 37 (06) 1516-1524
• 63 Berríos-Torres SI, Umscheid CA, Bratzler DW. , et al; Healthcare Infection Control Practices Advisory Committee. Centers for Disease Control and Prevention guideline for the prevention of surgical site infection, 2017. JAMA Surg 2017; 152 (08) 784-791
• 64 Deedwania P, Kosiborod M, Barrett E. , et al; American Heart Association Diabetes Committee of the Council on Nutrition, Physical Activity, and Metabolism. Hyperglycemia and acute coronary syndrome: a scientific statement from the American Heart Association Diabetes Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation 2008; 117 (12) 1610-1619
• 65 Steg PG, James SK, Atar D. , et al; Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012; 33 (20) 2569-2619
• 66 Hermanides J, Plummer MP, Finnis M, Deane AM, Coles JP, Menon DK. Glycaemic control targets after traumatic brain injury: a systematic review and meta-analysis. Crit Care 2018; 22 (01) 11
• 67 Kramer AH, Roberts DJ, Zygun DA. Optimal glycemic control in neurocritical care patients: a systematic review and meta-analysis. Crit Care 2012; 16 (05) R203
• 68 Sechterberger MK, Bosman RJ, Oudemans-van Straaten HM. , et al. The effect of diabetes mellitus on the association between measures of glycaemic control and ICU mortality: a retrospective cohort study. Crit Care 2013; 17 (02) R52
• 69 Carpenter DL, Gregg SR, Xu K, Buchman TG, Coopersmith CM. Prevalence and impact of unknown diabetes in the ICU. Crit Care Med 2015; 43 (12) e541-e550
• 70 Kar P, Plummer MP, Bellomo R. , et al. Liberal glycemic control in critically ill patients with type 2 diabetes: an exploratory study. Crit Care Med 2016; 44 (09) 1695-1703
• 71 Egi M. Acute glycemic control in diabetics. How sweet is oprimal? Con: just as sweet as in nondiabetic is better. J Intensive Care 2018; 6: 70
• 72 Stoll B, Puiman PJ, Cui L. , et al. Continuous parenteral and enteral nutrition induces metabolic dysfunction in neonatal pigs. JPEN J Parenter Enteral Nutr 2012; 36 (05) 538-550
• 73 MacGregor IL, Gueller R, Watts HD, Meyer JH. The effect of acute hyperglycemia on gastric emptying in man. Gastroenterology 1976; 70 (02) 190-196
• 74 Chapman MJ, Fraser RJ, Matthews G. , et al. Glucose absorption and gastric emptying in critical illness. Crit Care 2009; 13 (04) R140
• 75 Nguyen N, Ching K, Fraser R, Chapman M, Holloway R. The relationship between blood glucose control and intolerance to enteral feeding during critical illness. Intensive Care Med 2007; 33 (12) 2085-2092
• 76 Rodnick KJ, Piper RC, Slot JW, James DE. Interaction of insulin and exercise on glucose transport in muscle. Diabetes Care 1992; 15 (11) 1679-1689
• 77 Kennedy JW, Hirshman MF, Gervino EV. , et al. Acute exercise induces GLUT4 translocation in skeletal muscle of normal human subjects and subjects with type 2 diabetes. Diabetes 1999; 48 (05) 1192-1197
• 78 Krinsley JS. The long and winding road toward personalized glycemic control in the critically ill. J Diabetes Sci Technol 2018; 12 (01) 26-32
• 79 Pereira AJ, Corrêa TD, de Almeida FP. , et al. Inaccuracy of venous point-of-care glucose measurements in critically ill patients: a cross-sectional study. PLoS One 2015; 10 (06) e0129568
• 80 Shearer A, Boehmer M, Closs M. , et al. Comparison of glucose point-of-care values with laboratory values in critically ill patients. Am J Crit Care 2009; 18 (03) 224-230
• 81 Valgimigli F, Lucarelli F, Scuffi C, Morandi S, Sposato I. Evaluating the clinical accuracy of GlucoMen®Day: a novel microdialysis-based continuous glucose monitor. J Diabetes Sci Technol 2010; 4 (05) 1182-1192
• 82 Wernerman J, Desaive T, Finfer S. , et al. Continuous glucose control in the ICU: report of a 2013 round table meeting. Crit Care 2014; 18 (03) 226
• 83 Bochicchio GV, Nasraway S, Moore L, Furnary A, Nohra E, Bochicchio K. Results of a multicenter prospective pivotal trial of the first inline continuous glucose monitor in critically ill patients. J Trauma Acute Care Surg 2017; 82 (06) 1049-1054
• 84 van Hooijdonk RT, Leopold JH, Winters T. , et al. Point accuracy and reliability of an interstitial continuous glucose-monitoring device in critically ill patients: a prospective study. Crit Care 2015; 19: 34
• 85 Kalmovich B, Bar-Dayan Y, Boaz M, Wainstein J. Continuous glucose monitoring in patients undergoing cardiac surgery. Diabetes Technol Ther 2012; 14 (03) 232-238
• 86 Scrimgeour LA, Potz BA, Sellke FW, Abid MR. Continuous glucose monitoring in the cardiac ICU: current use and future directions. Clin Med Res (N Y) 2017; 6 (06) 173-176
• 87 Chase JG, Desaive T, Bohe J. , et al. Improving glycemic control in critically ill patients: personalized care to mimic the endocrine pancreas. Crit Care 2018; 22 (01) 182
• 88 Arabi YM, Dabbagh OC, Tamim HM. , et al. Intensive versus conventional insulin therapy: a randomized controlled trial in medical and surgical critically ill patients. Crit Care Med 2008; 36 (12) 3190-3197