Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Intensive insulin therapy in the ICU—reconciling the evidence

Nature Reviews Endocrinology volume 8, pages 374–378 (2012)Cite this article

Subjects

Abstract

Hyperglycaemia during critical illness unequivocally correlates with adverse outcome. Three proof-of-concept randomized controlled trials have shown that preventing hyperglycaemia in patients admitted to the intensive care unit (ICU) reduces organ failure and mortality. A subsequent multicentre, randomized controlled trial found that targeting normoglycaemia in this patient population does not affect organ function differently than targeting an intermediate glucose level (7.8–10.0 mmol/l). However, an intermediate glucose target evoked less hypoglycaemia and, for currently unexplained reasons, also fewer deaths than a normoglycaemic target. Moreover, tolerating a caloric deficit, rather than providing nutrients parenterally, accelerated recovery from critical illness in the presence of normoglycaemia. Whether macronutrient restriction renders moderate hyperglycaemia less harmful remains to be investigated. Hence, if adequate monitoring tools and expertise are available, normoglycaemia remains the only proven effective target for insulin treatment of hyperglycaemia in ICU patients. However, if these conditions are not fulfilled in clinical practice, is an intermediate target range preferable? In the absence of hard evidence, common sense supports such an intermediate blood glucose target.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Different designs of key intervention trials and expected outcome benefits.
Figure 2: Balance between damage induction and removal in critical illness.

Similar content being viewed by others

References

  1. Van den Berghe, G. et al. Clinical review: Intensive insulin therapy in critically ill patients: NICE-SUGAR or Leuven blood glucose target? J. Clin. Endocrinol. Metab. 94, 3163–3170 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Kosiborod, M. et al. Glucose normalization and outcomes in patients with acute myocardial infarction. Arch. Intern. Med. 169, 438–446 (2009).

    Article  CAS  PubMed  Google Scholar 

  3. The Endocrine Society. The Endocrine Society statement to providers on the American College of Physicians guidelines on intensive insulin therapy [online], (2011).

  4. American Diabetes Association. Executive summary: standards of medical care in diabetes—2011. Diabetes Care 34 (Suppl 1.), S4–S10 (2011).

  5. Qaseem, A., Humphrey, L. L., 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. 154, 260–267 (2011).

    Article  PubMed  Google Scholar 

  6. Dellinger, R. P. et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit. Care Med. 36, 296–327 (2008). Erratum in: Crit. Care Med. 36, 1394–1396 (2008).

    Article  PubMed  Google Scholar 

  7. Skyler, J. S. et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA Diabetes Trials: a position statement of the American Diabetes Association and a Scientific Statement of the American College of Cardiology Foundation and the American Heart Association. J. Am. Coll. Cardiol. 53, 298–304 (2009).

    Article  PubMed  Google Scholar 

  8. Van den Berghe, G. et al. Intensive insulin therapy in the critically ill patients. N. Engl. J. Med. 345, 1359–1367 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Kreymann, K. G. et al. ESPEN guidelines on enteral nutrition: intensive care. Clin. Nutr. 25, 210–223 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Singer, P. et al. ESPEN guidelines on parenteral nutrition: intensive care. Clin. Nutr. 28, 387–400 (2009).

    Article  PubMed  Google Scholar 

  11. Van den Berghe, G. et al. Outcome benefit of intensive insulin therapy in the critically ill: Insulin dose versus glycemic control. Crit. Care Med. 31, 359–366 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Van den Berghe, G. et al. Intensive insulin therapy in mixed medical/surgical intensive care units: benefit versus harm. Diabetes 55, 3151–3159 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Ellger, B. et al. Survival benefits of intensive insulin therapy in critical illness: impact of maintaining normoglycaemia versus glycemia-independent actions of insulin. Diabetes 55, 1096–1105 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Van den Berghe, G. et al. Intensive insulin therapy in the medical ICU. N. Engl. J. Med. 354, 449–461 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Schetz, M., Vanhorebeek, I., Wouters, P. J., Wilmer, A. & Van den Berghe, G. Tight blood glucose control is renoprotective in critically ill patients. J. Am. Soc. Nephrol. 19, 571–578 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Vlasselaers, D. et al. Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomized controlled study. Lancet 373, 547–556 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. Furnary, A. P., Cheek, D. B., Holmes, S. C., Howell, W. L. & Kelly, S. P. 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. 18, 339–345 (2006).

    Article  PubMed  Google Scholar 

  18. Krinsley, J. S. Effect of an intensive glucose management protocol on the mortality of critically ill adult patients. Mayo Clin. Proc. 79, 992–1000 (2004). Erratum in: Mayo Clin. Proc. 80, 1101 (2005).

    Article  PubMed  Google Scholar 

  19. Reed, C. C. et al. Intensive insulin protocol improves glucose control and is associated with a reduction in intensive care unit mortality. J. Am. Coll. Surg. 204, 1048–1054; discussion 1054–1055 (2007).

    Article  PubMed  Google Scholar 

  20. Lecomte, P. 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 12, R154 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Finfer, S. et al. Intensive versus conventional glucose control in critically ill patients. N. Engl. J. Med. 360, 1283–1297 (2009).

    Article  PubMed  Google Scholar 

  22. Scott, M. G., Bruns, D. E., Boyd, J. C. & Sacks, D. B. Tight glucose control in the intensive care unit: are glucose meters up to the task? Clin. Chem. 55, 18–20 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. Vlasselaers, D. et al. Blood glucose measurements in arterial blood of intensive care unit patients submitted to tight glycemic control: agreement between bedside tests. J. Diabetes Sci. Technol. 2, 932–938 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Egi, M., Finfer, S. & Bellomo, R. Glycemic control in the ICU. Chest 140, 212–220 (2011).

    Article  PubMed  Google Scholar 

  25. Cembrowski, G. S. et al. Could susceptibility to low hematocrit interference have compromised the results of the NICE-SUGAR trial? Clin. Chem. 56, 1193–1195 (2010).

    Article  CAS  PubMed  Google Scholar 

  26. Boyd, J. C. & Bruns, D. E. Monte Carlo simulation in establishing analytical requirements for clinical laboratory tests: meeting the clinical needs. Methods Enzymol. 467, 411–433 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Karon, B. S., Boyd, J. C. & Klee, G. G. Glucose meter performance criteria for tight glycemic control estimated by simulation modeling. Clin. Chem. 56, 1091–1097 (2010).

    Article  CAS  PubMed  Google Scholar 

  28. Kanji, S. et al. Reliability of point-of-care testing for glucose measurement in critically ill adults. Crit. Care Med. 33, 2778–2785 (2005).

    Article  PubMed  Google Scholar 

  29. Villet, S. et al. Negative impact of hypocaloric feeding and energy balance on clinical outcome in ICU patients. Clin. Nutr. 24, 502–509 (2005).

    Article  PubMed  Google Scholar 

  30. Martindale, R. G. et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Medicine and American Society for Parenteral and Enteral Nutrition: Executive Summary. Crit. Care Med. 37, 1757–1761 (2009).

    Article  PubMed  Google Scholar 

  31. Heyland, D. K., Dhaliwal, R., Drover, J. W., Gramlich, L. & Dodek, P. Canadian clinical practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients. J. Parenter. Enteral. Nutr. 27, 355–373 (2003).

    Article  Google Scholar 

  32. Reid, C. Frequency of under- and overfeeding in mechanically ventilated ICU patients: causes and possible consequences. J. Hum. Nutr. Diet. 19, 13–22 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Dhaliwal, R., Jurewitsch, B., Harrietha, D. & Heyland, D. K. Combination enteral and parenteral nutrition in critically ill patients: harmful or beneficial? A systematic review of the evidence. Intensive Care Med. 30, 1666–1671 (2004).

    Article  PubMed  Google Scholar 

  34. Casaer, M. P. et al. Early versus late parenteral nutrition in critically ill adults. N. Engl. J. Med. 365, 506–517 (2011).

    Article  CAS  PubMed  Google Scholar 

  35. Vanhorebeek, I. et al. Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients. Lancet 365, 53–59 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Langouche, L. et al. Intensive insulin therapy protects the endothelium of critically ill patients. J. Clin. Invest. 115, 2277–2286 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Van den Berghe, G., Schoonheydt, K., Becx, P., Bruyninckx, F. & Wouters, P. J. Insulin therapy protects the central and peripheral nervous system of intensive care patients. Neurology 64, 1348–1353 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Vanhorebeek, I. et al. Tissue-specific glucose toxicity induces mitochondrial damage in a burn injury model of critical illness. Crit. Care Med. 37, 1355–1364 (2009).

    Article  CAS  PubMed  Google Scholar 

  39. Vanhorebeek, I. et al. Hyperglycemic kidney damage in an animal model of prolonged critical illness. Kidney Int. 76, 512–520 (2009).

    Article  CAS  PubMed  Google Scholar 

  40. Van den Berghe, G. How does blood glucose control with insulin save lives in intensive care? J. Clin. Invest. 114, 1187–1195 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Langouche, L. et al. Effect of intensive insulin therapy on insulin sensitivity in the critically ill. J. Clin. Endocrinol. Metab. 92, 3890–3897 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Vanhorebeek, I. et al. Insufficient activation of autophagy allows cellular damage to accumulate in critically ill patients. J. Clin. Endocrinol. Metab. 96, E633–E645 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Rabinowitz, J. D. & White, E. Autophagy and metabolism. Science 330, 1344–1348 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Levine, B. & Kroemer, G. Autophagy in the pathogenesis of disease. Cell 132, 27–42 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The author's work is funded by the Methusalem program of the Flemish government (provided via Catholic University of Leuven).

Author information

Authors and Affiliations

  1. Department of Intensive Care Medicine, Catholic University of Leuven, Herestraat 49, B-3000, Leuven, Belgium

    Greet Van den Berghe

Authors
  1. Greet Van den Berghe
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares an association with the following company: Baxter (grant/research support).

Rights and permissions

Reprints and permissions

About this article

Cite this article

den Berghe, G. Intensive insulin therapy in the ICU—reconciling the evidence. Nat Rev Endocrinol 8, 374–378 (2012). https://doi.org/10.1038/nrendo.2012.14

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2012.14

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing