Critical Care Management of Stress-Induced Hyperglycemia
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Purpose of Review
We discuss key studies that have set the scene for the debate on the efficacy and safety of tight glycemic control in critically ill patients, highlighting important differences among them, and describe the ensuing search towards strategies for safer glucose control.
Differences in level of glycemic control, glucose measurement and insulin administration, expertise, and nutritional management may explain the divergent outcomes of the landmark studies on tight glycemic control in critical illness. Regarding strategies towards safer glucose control, several computerized algorithms have shown promise, but lack validation in adequately powered outcome studies. Real-time continuous glucose monitoring and closed loop blood glucose control systems are not up to the task yet due to technical challenges, though recent advances are promising. Alternatives for insulin have only been investigated in small feasibility studies.
Severe hyperglycemia in critically ill patients generally is not tolerated anymore, but the optimal blood glucose target may depend on the specific patient and logistic context.
KeywordsCritical illness Intensive care Hyperglycemia Hypoglycemia Insulin Clinical outcome
This study was funded by structural research financing via the Methusalem program funded by the Flemish Government (grant number METH08/07 to GVdB and METH14/06 to GVdB and IV) through the University of Leuven, by a European Research Council Advanced Grant (grant number AdvG-2012- 321670) from the Ideas Programme of the EU FP7 (to GVdB), by a grant from the Research Foundation-Flanders (grant number T003617N to GVdB and JG), and by a postdoctoral research fellowship supported by the Clinical Research and Education Council of the University Hospitals Leuven (KOOR to JG).
Compliance with Ethical Standards
Conflict of Interest
Ilse Vanhorebeek, Jan Gunst, and Greet Van den Berghe declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: ••Of major importance
- 5.Ingels C, Debaveye Y, Milants I, Buelens E, Peeraer A, Devriendt Y, et al. Strict blood glucose control with insulin during intensive care after cardiac surgery: impact on 4-years survival, dependency on medical care and quality of life. Eur Heart J. 2006;27:2716–24. https://doi.org/10.1093/eurheartj/ehi855.CrossRefPubMedGoogle Scholar
- 7.Van den Berghe G, Wouters PJ, Kesteloot K, Hilleman DE. Analysis of healthcare resource utilization with intensive insulin therapy in critically ill patients. Crit Care Med. 2006;34:612–6. https://doi.org/10.1097/01.CCM.0000201408.15502.24q.CrossRefPubMedGoogle Scholar
- 9.Hermans G, Wilmer A, Meersseman W, Milants I, Wouters PJ, Bobbaers H, et al. Impact of intensive insulin therapy on neuromuscular complications and ventilator dependency in the medical intensive care unit. Am J Respir Crit Care Med. 2007;175:480–9. https://doi.org/10.1164/rccm.200605-665OC.CrossRefPubMedGoogle Scholar
- 12.Furnary AP, Cheek DB, Holmes SC, Howell WL, Kelly SP. Achieving tight glycemic control in the operating room: lessons learned from 12 years in the trenches of a paradigm shift in anesthetic care. Semin Thorac Cardiovasc Surg. 2006;18:339–45. https://doi.org/10.1053/j.semtcvs.2007.01.004.CrossRefPubMedGoogle Scholar
- 13.Lecomte P, Van Vlem B, Coddens J, Cammu G, Nollet G, et al. Tight perioperative glucose control is associated with a reduction in renal impairment and renal failure in non-diabetic cardiac surgical patients. Crit Care. 2008;12:R154. https://doi.org/10.1186/cc7145.CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Preiser JC, Devos P, Ruiz-Santana S, Mélot C, Annane D, Groeneveld J, 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;35:1738–48. https://doi.org/10.1007/s00134-009-1585-2.CrossRefPubMedGoogle Scholar
- 21.Lazar HL, McDonnell M, Chipkin SR, Furnary AP, Engelman RM, Sadhu AR, et al. The Society of Thoracic Surgeons practice guideline series: blood glucose management during adult cardiac surgery. Ann Thorac Surg. 2009;87:663–9. https://doi.org/10.1016/j.athoracsur.2008.11.011.CrossRefPubMedGoogle Scholar
- 23.Qaseem A, Humphrey LL, Chou R, Snow V, Shekelle P, Clinical Guidelines Committee of the American College of Physicians. Use of intensive insulin therapy for the management of glycemic control in hospitalized patients: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2011;154:260–7. https://doi.org/10.7326/0003-4819-154-4-201102150-00007.CrossRefPubMedGoogle Scholar
- 27.The Endocrine Society. The Endocrine Society statement to providers on the American College of Physicians guidelines on intensive insulin therapy [online], http://www.endo-society.org/advocacy/insider/2011/upload/TES-Statement-about-ACP-Guidelines-23-FEB-11-2.pdf. (2011).
- 29.Srinivasan V, Spinella PC, Drott HR, Roth CL, Helfaer MA, Nadkarni V. Association of timing, duration, and intensity of hyperglycemia with intensive care unit mortality in critically ill children. Pediatr Crit Care Med. 2004;5:329–36. https://doi.org/10.1097/01.PCC.0000128607.68261.7C.CrossRefPubMedGoogle Scholar
- 31.Vlasselaers D, Milants I, Desmet L, Wouters PJ, Vanhorebeek I, van den Heuvel I, et al. Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study. Lancet. 2009;373:547–56. https://doi.org/10.1016/S0140-6736(09)60044-1.CrossRefPubMedGoogle Scholar
- 34.Sadhwani A, Asaro LA, Goldberg C, Ware J, Butcher J, Gaies M, et al. Impact of tight glycemic control on neurodevelopmental outcomes at 1 year of age for children with congenital heart disease: a randomized controlled trial. J Pediatr. 2016;174:193–198.e2. https://doi.org/10.1016/j.jpeds.2016.03.048.CrossRefPubMedPubMedCentralGoogle Scholar
- 41.Food and Drug Administration. Blood glucose monitoring test systems for prescription point-of-care use. Guidance for industry and Food and Drug Administration Staff. http://ww.fda.gov.downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm380325.pdf.
- 44.•• Fivez T, Kerklaan D, Mesotten D, Verbruggen S, Wouters PJ, Vanhorebeek I, et al. Early versus late parenteral nutrition in critically ill children. N Engl J Med. 2016;374:1111–22. https://doi.org/10.1056/NEJMoa1514762. Adequately powered RCT showing improved clinical outcome with early macronutrient restriction during critical illness in children as compared with early full feeding. Combined with studies on impact of early full feeding versus early macronutrient restriction on autophagy, this study may implicate nutritional management as an important factor in explaining different outcomes in key RCTs on glycemic control. CrossRefPubMedGoogle Scholar
- 47.•• Vanhorebeek I, Verbruggen S, Casaer MP, Gunst J, Wouters PJ, Hanot J, et al. Effect of early supplemental parenteral nutrition in the paediatric ICU: a preplanned observational study of post-randomisation treatments in the PEPaNIC trial. Lancet Respir Med. 2017;5:475–83. https://doi.org/10.1016/S2213-2600(17)30186-8. Study refuting the criticism that the benefits of strict glycemic control in the Leuven studies would be simply explained by counteracting the harm by administering high doses of glucose in the early phase of critical illness. Harm by early parenteral nutrition was not explained by a higher glucose load, but rather by giving more amino acids. CrossRefPubMedGoogle Scholar
- 51.Gunst J, Derese I, Aertgeerts A, Ververs EJ, Wauters A, van den Berghe G, et al. Insufficient autophagy contributes to mitochondrial dysfunction, organ failure, and adverse outcome in an animal model of critical illness. Crit Care Med. 2013;41:182–94. https://doi.org/10.1097/CCM.0b013e3182676657.CrossRefPubMedGoogle Scholar
- 53.Hermans G, Casaer MP, Clerckx B, Güiza F, Vanhullebusch T, Derde S, et al. Effect of tolerating macronutrient deficit on the development of intensive-care unit acquired weakness: a subanalysis of the EPaNIC trial. Lancet Respir Med. 2013;1:621–9. https://doi.org/10.1016/S2213-2600(13)70183-8.CrossRefPubMedGoogle Scholar
- 58.McKinlay CJD, Alsweiler JM, Anstice NS, Burakevych N, Chakraborty A, Children With Hypoglycemia and Their Later Development (CHYLD) Study Team, et al. Association of neonatal glycemia with neurodevelopmental outcomes at 4.5 years. JAMA Pediatr. 2017;171:972–83. https://doi.org/10.1001/jamapediatrics.2017.1579.CrossRefPubMedGoogle Scholar
- 61.Meyfroidt G, Keenan DM, Wang X, Wouters PJ, Veldhuis JD, Van den Berghe G. Dynamic characteristics of blood glucose time series during the course of critical illness: effects of intensive insulin therapy and relative association with mortality. Crit Care Med. 2010;38:1021–9. https://doi.org/10.1097/CCM.0b013e3181cf710e.CrossRefPubMedGoogle Scholar
- 62.Krinsley JS, Egi M, Kiss A, Devendra AN, Schuetz P, Maurer PM, 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:R37. https://doi.org/10.1186/cc12547.CrossRefPubMedPubMedCentralGoogle Scholar
- 67.Van Herpe T, Mesotten D, Wouters PJ, Herbots J, Voets E, et al. LOGIC-insulin algorithm-guided versus nurse-directed blood glucose control during critical illness: the LOGIC-1 single-center, randomized, controlled clinical trial. Diabetes Care. 2013;36:188–94. https://doi.org/10.2337/dc12-0584.CrossRefPubMedPubMedCentralGoogle Scholar
- 68.•• Dubois J, Van Herpe T, van Hooijdonk RT, Wouters R, Coart D, et al. Software-guided versus nurse-directed blood glucose control in critically ill patients: the LOGIC-2 multicenter randomized controlled clinical trial. Crit Care. 2017;21:212. https://doi.org/10.1186/s13054-017-1799-6. Study demonstrating efficacy and safety of the computerized LOGIC-Insulin algorithm in a multinational setting, where the participating centers used different glucose targets and had varying levels of experience in glycemic control, illustrating robust applicability of the algorithm. CrossRefPubMedPubMedCentralGoogle Scholar
- 69.Desai SP, Henry LL, Holmes SD, Hunt SL, Martin CT, Hebsur S, et al. Strict versus liberal target range for perioperative glucose in patients undergoing coronary artery bypass grafting: a prospective randomized controlled trial. J Thorac Cardiovasc Surg. 2012;143:318–25. https://doi.org/10.1016/j.jtcvs.2011.10.070.CrossRefPubMedGoogle Scholar
- 70.Umpierrez G, Cardona S, Pasquel F, Jacobs S, Peng L, Unigwe M, et al. Randomized controlled trial of intensive versus conservative glucose control in patients undergoing coronary artery bypass graft surgery: GLUCO-CABG Trial. Diabetes Care. 2015;38:1665–72. https://doi.org/10.2337/dc15-0303.CrossRefPubMedPubMedCentralGoogle Scholar
- 73.Boom DT, Sechterberger MK, Rijkenberg S, Kreder S, Bosman RJ, Wester JPJ, et al. Insulin treatment guided by subcutaneous continuous glucose monitoring compared to frequent point-of-care measurement in critically ill patients: a randomized controlled trial. Crit Care. 2014;18:453. https://doi.org/10.1186/s13054-014-0453-9.CrossRefPubMedPubMedCentralGoogle Scholar
- 74.De Block CE, Gios J, Verheyen N, Manuel-y-Keenoy B, Rogiers P, et al. Randomized evaluation of glycemic control in the medical intensive care unit using real-time continuous glucose monitoring (REGIMEN Trial). Diabetes Technol Ther. 2015;17:889–98. https://doi.org/10.1089/dia.2015.0151.CrossRefPubMedGoogle Scholar
- 77.Deane AM, Chapman MJ, Fraser RJ, Burgstad CM, Bedanko LK, Horowitz M. The effect of exogenous glucagon-like peptide-1 on the glycaemic response to small intestinal nutrient in the critically ill: a randomised double-blind placebo-controlled cross over study. Crit Care. 2009;13:R67. https://doi.org/10.1186/cc7874.CrossRefPubMedPubMedCentralGoogle Scholar
- 78.Kar P, Cousins CE, Annink CE, Jones KL, Chapman MJ, Meier JJ, et al. Effects of glucose-dependent insulinotropic polypeptide on gastric emptying, glycaemia and insulinaemia during critical illness: a prospective, double blind, randomised, crossover study. Crit Care. 2015;19:20. https://doi.org/10.1186/s13054-014-0718-3.CrossRefPubMedPubMedCentralGoogle Scholar
- 79.Kohl BA, Hammond MS, Cucchiara AJ, Ochroch EA. Intravenous GLP-1 (7-36) amide for prevention of hyperglycemia during cardiac surgery: a randomized, double-blind, placebo-controlled study. J Cardiothorac Vasc Anesth. 2014;28:618–25. https://doi.org/10.1053/j.jvca.2013.06.021.CrossRefPubMedGoogle Scholar
- 80.Lips M, Mraz M, Klouckova J, Kopecky P, Dobias M, et al. Effect of continuous exenatide infusion on cardiac function and peri-operative glucose control in patients undergoing cardiac surgery: a single-blind, randomized controlled trial. Diabetes Obes Metab. 2017;19:18181–1822. https://doi.org/10.1111/dom.13029.CrossRefGoogle Scholar
- 81.Wiberg S, Hassager C, Schmidt H, Thomsen JH, Frydland M, Lindholm MG, et al. Neuroprotective effects of the glucagon-like peptide-1 analog exenatide after out-of-hospital cardiac arrest: a randomized controlled trial. Circulation. 2016;134:2115–24. https://doi.org/10.1161/CIRCULATIONAHA.116.024088.CrossRefPubMedGoogle Scholar
- 82.Jeschke MG, Abdullahi A, Burnett M, Rehou S, Stanojcic M. Glucose control in severely burned patients using metformin: an interim safety and efficacy analysis of a phase II randomized controlled trial. Ann Surg. 2016;264:518–27. https://doi.org/10.1097/SLA.0000000000001845.CrossRefPubMedGoogle Scholar
- 83.Htike ZZ, Zaccardi S, Papamargaritis D, Webb DR, Khunti K, Davies MJ. Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: a systematic review and mixed-treatment comparison analysis. Diabetes Obes Metab. 2017;19:524–36. https://doi.org/10.1111/dom.12849.CrossRefPubMedGoogle Scholar
- 86.Mesotten D, Swinnen JV, Vanderhoydonc F, Wouters PJ, Van den Berghe G. Contribution of circulating lipids to the improved outcome of critical illness by glycemic control with intensive insulin therapy. J Clin Endocrinol Metab. 2004;89:219–26. https://doi.org/10.1210/jc.2003-030760.CrossRefPubMedGoogle Scholar
- 98.Derde S, Vanhorebeek I, Ververs EJ, Vanhees I, Darras VM, van Herck E, et al. Increasing intravenous glucose load in the present of normoglycemia: effect on outcome and metabolism in critically ill rabbits. Crit Care Med. 2010;38:602–11. https://doi.org/10.1097/CCM.0b013e3181c03f65.CrossRefPubMedGoogle Scholar
- 101.Fisher JG, Sparks EA, Khan FA, Alexander JL, Asaro LA, Wypij D, et al. Tight glycemic control with insulin does not affect skeletal muscle degradation during the early postoperative period following pediatric cardiac surgery. Pediatr Crit Care Med. 2015;16:515–21. https://doi.org/10.1097/PCC.0000000000000413.CrossRefPubMedPubMedCentralGoogle Scholar
- 102.Hatzakorvian R, Shum-Tim D, Wykes L, Hülshoff A, Bui H, et al. Glucose and insulin administration while maintaining normoglycemia inhibits whole body protein breakdown and synthesis after cardiac surgery. J Appl Physiol (1985). 2014;117:1380–7. https://doi.org/10.1152/japplphysiol.00175.2014.CrossRefGoogle Scholar
- 105.Gielen M, Mesotten D, Wouters PJ, Desmet L, Vlasselaers D, Vanhorebeek I, et al. Effect of tight glucose control with insulin on the thyroid axis of critically ill children and its relation with outcome. J Clin Endocrinol Metab. 2012;97:3569–76. https://doi.org/10.1210/jc.2012-2240.CrossRefPubMedPubMedCentralGoogle Scholar
- 109.Hansen TK, Thiel S, Wouters PJ, Christiansen JS, Van den Berghe G. Intensive insulin therapy exerts antiinflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels. J Clin Endocrinol Metab. 2003;88:1082–8. https://doi.org/10.1210/jc.2002-021478.CrossRefPubMedGoogle Scholar