Skip to main content


Log in

A prospective randomised multi-centre controlled trial on tight glucose control by intensive insulin therapy in adult intensive care units: the Glucontrol study

  • Original
  • Published:
Intensive Care Medicine Aims and scope Submit manuscript



An optimal target for glucose control in ICU patients remains unclear. This prospective randomized controlled trial compared the effects on ICU mortality of intensive insulin therapy (IIT) with an intermediate glucose control.


Adult patients admitted to the 21 participating medico-surgical ICUs were randomized to group 1 (target BG 7.8–10.0 mmol/L) or to group 2 (target BG 4.4–6.1 mmol/L).


While the required sample size was 1,750 per group, the trial was stopped early due to a high rate of unintended protocol violations. From 1,101 admissions, the outcomes of 542 patients assigned to group 1 and 536 of group 2 were analysed. The groups were well balanced. BG levels averaged in group 1 8.0 mmol/L (IQR 7.1–9.0) (median of all values) and 7.7 mmol/L (IQR 6.7–8.8) (median of morning BG) versus 6.5 mmol/L (IQR 6.0–7.2) and 6.1 mmol/L (IQR 5.5–6.8) for group 2 (p < 0.0001 for both comparisons). The percentage of patients treated with insulin averaged 66.2 and 96.3%, respectively. Proportion of time spent in target BG was similar, averaging 39.5% and 45.1% (median (IQR) 34.3 (18.5–50.0) and 39.3 (26.2–53.6)%) in the groups 1 and 2, respectively. The rate of hypoglycaemia was higher in the group 2 (8.7%) than in group 1 (2.7%, p < 0.0001). ICU mortality was similar in the two groups (15.3 vs. 17.2%).


In this prematurely stopped and therefore underpowered study, there was a lack of clinical benefit of intensive insulin therapy (target 4.4–6.1 mmol/L), associated with an increased incidence of hypoglycaemia, as compared to a 7.8–10.0 mmol/L target. ( # NCT00107601, EUDRA-CT Number: 200400391440).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others


  1. 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 345:1359–1367

    Article  PubMed  Google Scholar 

  2. Angus DC, Abraham E (2005) Intensive insulin therapy in critical illness. Am J Respir Crit Care Med 172:1358–1359

    Article  PubMed  Google Scholar 

  3. Devos P, Preiser JC (2007) Current controversies around tight glucose control in critically ill patients. Curr Opin Clin Nutr Metab Care 10:206–209

    Article  PubMed  Google Scholar 

  4. Aragon D (2006) Evaluation of nursing work effort and perceptions about blood glucose testing in tight glycemic control. Am J Crit Care 15:370–377

    PubMed  Google Scholar 

  5. Krinsley JS, Grover A (2007) Severe hypoglycemia in critically ill patients: risk factors and outcomes. Crit Care Med 35:2262–2267

    Article  PubMed  Google Scholar 

  6. Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, Van Wijngaerden E, Bobbaers H, Bouillon R (2006) Intensive insulin therapy in the medical ICU. N Engl J Med 354:449–461

    Article  PubMed  Google Scholar 

  7. Brunkhorst FM, Engel C, Bloos F, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, Moerer O, Gruending 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) (2008) Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 358:125–139

    Article  PubMed  CAS  Google Scholar 

  8. Devos P, Preiser JC, Melot C (2007) Impact of tight glucose control by intensive insulin therapy on ICU mortality and the rate of hypoglycaemia: final results of the Glucontrol study. Intensive Care Med 33:S189

    Google Scholar 

  9. Devos P, Ledoux D, Preiser JC (2005) Current practice of glycaemia control in European intensive care units (ICUS). Intensive Care Med 31:S203

    Google Scholar 

  10. Vogelzang M, van der Horst ICC, Nijsten MWN (2004) Hyperglycaemic index as a tool to assess glucose control: a retrospective study. Crit Care 8:R122–R127

    Article  PubMed  Google Scholar 

  11. Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985) APACHE II: a severity of disease classification system. Crit Care Med 13:818–829

    Article  PubMed  CAS  Google Scholar 

  12. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG (1996) The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the working group on sepsis-related problems of the European Society of Intensive Care Medicine. Intensive Care Med 22:707–710

    Article  PubMed  CAS  Google Scholar 

  13. Grey NJ, Predrizet GA (2004) Reduction of nosocomial infections in the surgical intensive-care unit by strict glycemic control. Endocr Pract 10:46–52

    PubMed  Google Scholar 

  14. De La Rosa GC, Donado JH, Restrepo AH, Quintero AM, Gonzalez LG, Saldarriaga NE, Bedoya M, Toro JM, Velasquez JB, Valencia JC, Arango CM, Aleman PH, Vasquez EM, Chavarriaga JC, Yepes A, Pulido W, Cadavid CA, Grupo de Investigacion en Cuidado intensivo: GICI-HPTU (2008) Strict glycaemic control in patients hospitalised in a mixed medical and surgical intensive care unit: a randomised clinical trial. Crit Care 12:R120

    Article  Google Scholar 

  15. Treggiari MM, Karir V, Yanez ND, Weiss NS, Daniel S, Deem SA (2008) Intensive insulin therapy and mortality in critically ill patients. Crit Care 12:R29

    Article  PubMed  Google Scholar 

  16. Walters MR, Weir CJ, Lees KR (2006) A randomised, controlled pilot study to investigate the potential benefit of intervention with insulin in hyperglycaemic acute ischaemic stroke patients. Cerebrovasc Dis 22:116–122

    Article  PubMed  CAS  Google Scholar 

  17. Mitchell I, Knight E, Gissane J, Tamhane R, Kolli R, Leditschke IA, Bellomo R, Finfer S, Australian, New Zealand Intensive Care Society Clinical Trials Group (2006) A phase II randomised controlled trial of intensive insulin therapy in general intensive care patients. Crit Care Resusc 8:289–293

    PubMed  Google Scholar 

  18. Arabi YM, Dabbagh OC, Tamim HM, Al-Shimemeri AA, Memish ZA, Haddad SH, Syed SJ, Giridhar HR, Rishu AH, Al-Daker MO, Kahoul SH, Britts RJ, Sakkijha MH (2008) Intensive versus conventional insulin therapy: a randomized controlled trial in medical and surgical critically ill patients. Crit Care Med 36:3190–3197

    Article  PubMed  CAS  Google Scholar 

  19. NICE-SUGAR Study Investigators, 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 2009(360):1346–1349

    Google Scholar 

  20. Wiener RS, Wiener DC, Larson RJ (2008) Benefits and risks of tight glucose control in critically ill adults: a meta-analysis. JAMA 300:933–944

    Article  PubMed  CAS  Google Scholar 

  21. Griesdale DEG, de Souza RJ, van Dam RM, Heyland DK, Cook DJ, Malhotra A, Dhaliwal R, Henderson WR, Chittock DR, Finfer S, Talmor D (2009) Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including NICE-SUGAR study data. CMAJ 2009(180):821–827

    Google Scholar 

  22. Dungan K, Braithwaite SS, Preiser JC (2009) Stress hyperglycaemia. Lancet 373:1798–1807

    Article  PubMed  CAS  Google Scholar 

  23. Inzucchi SE (2006) Clinical practice. Management of hyperglycemia in the hospital setting. N Engl J Med 355:1903–1911

    Article  PubMed  CAS  Google Scholar 

  24. Finney SJ, Zekveld C, Elia A, Evans TW (2003) Glucose control and mortality in critically ill patients. JAMA 290:2041–2047

    Article  PubMed  CAS  Google Scholar 

  25. Krinsley JS (2003) Association between hyperglycemia and increased hospital mortality in a heterogeneous population of critically ill patients. Mayo Clin Proc 78:1471–1478

    Article  PubMed  Google Scholar 

  26. Van der Voort PH, Feenstra RA, Bakker AJ, Heide L, Boerma EC, der Horst IC (2006) Intravenous glucose intake independently related to intensive care unit and hospital mortality: an argument for glucose toxicity in critically ill patients. Clin Endocrinol 64:141–145

    Article  CAS  Google Scholar 

  27. Ahrens CL, Barletta JF, Kanji S, Tyburski JG, Wilson RF, Janisse JJ, Devlin JW (2005) Effect of low-calorie parenteral nutrition on the incidence and severity of hyperglycemia in surgical patients: a randomized, controlled trial. Crit Care Med 33:2507–2512

    Article  PubMed  CAS  Google Scholar 

  28. Muniyappa R, Montagnani M, Koh KK, Quon MJ (2007) Cardiovascular actions of insulin. Endocr Rev 28:463–491

    Article  PubMed  CAS  Google Scholar 

  29. Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, Vanhole C, Palmer CR, van Weissenbruch M, Midgley P, Thompson M, Thio M, Cornette L, Ossuetta I, Iglesias I, Theyskens C, de Jong M, Ahluwalia JS, de Zegher F, Dunger DB (2008) Early insulin therapy in very-low-birth-weight infants. N Engl J Med 359:1873–1884

    Article  PubMed  CAS  Google Scholar 

  30. Cryer PE (2007) Hypoglycaemia, functional brain failure, and brain death. J Clin Invest 117:868–870

    Article  PubMed  CAS  Google Scholar 

  31. Gandhi GY, Nuttall GA, Abel MD, Mullany CJ, Schaff HV, O’Brien PC, Johnson MG, Williams AR, Cutshall SM, Mundy LM, Rizza RA, McMahon MM (2007) Intensive intra-operative insulin therapy versus conventional glucose management during cardiac surgery: a randomized trial. Ann Intern Med 146:233–243

    PubMed  Google Scholar 

  32. Vespa P, Boonyaputthikul R, McArthur DL, Miller C, Etchepare M, Bergsneider M, Glenn T, Martin N, Hovda D (2006) Intensive insulin therapy reduces micro dialysis glucose values without altering glucose utilization or improving the lactate/pyruvate ratio after traumatic brain injury. Crit Care Med 34:850–856

    Article  PubMed  CAS  Google Scholar 

  33. Zimmerman CR, Mlynarek ME, Jordan JA (2004) An insulin infusion protocol in critically ill cardiothoracic surgery patients. Ann Pharmacother 38:1123–1129

    Article  PubMed  CAS  Google Scholar 

  34. Goldberg PA, Siegel MD, Sherwin RS, Halickman JI, Lee M, Bailey VA, Lee SL, Dziura JD, Inzucchi SE (2004) Implementation of a safe and effective insulin infusion protocol in a medical intensive care unit. Diabetes Care 27:461–467

    Article  PubMed  CAS  Google Scholar 

  35. Kanji S, Singh A, Tierney M, Meggison H, McIntyre L, Hebert PC (2004) Standardization of intravenous insulin therapy improves the efficiency and safety of blood glucose control in critically ill adults. Intensive Care Med 30:804–810

    Article  PubMed  Google Scholar 

  36. Preiser JC, Devos P (2007) Steps for the implementation and validation of tight glucose control. Intensive Care Med 33:570–571

    Article  PubMed  Google Scholar 

  37. Kanji S, Buffie J, Hutton B, Bunting PS, Singh A, McDonald K, Fergusson D, McIntyre LA, Hebert PC (2005) Reliability of point-of-care testing for glucose measurement in critically ill adults. Crit Care Med 33:2778–2785

    Article  PubMed  Google Scholar 

  38. Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, Whitten P, Margolis BD, Byrne DW, Ely EW, Rocha MG, SEDCOM (Safety, Efficacy of Dexmedetomidine Compared With Midazolam) Study Group (2009) Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA 301:489–499

    Article  PubMed  CAS  Google Scholar 

Download references


Supported by a grant from the ‘Communauté Française Wallonie-Bruxelles’ (Belgium).

We are indebted to Dr Daniel De Backer (Erasme University Hospital Brussels, Belgium), Dr Mette Berger (Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland) and Prof. Pedro Saavedra (University of Las Palmas de Gran Canaria, Spain).

The members of the independent Data and Safety monitoring board were Christian Mélot, Peter Radermacher and Greet Van den Berghe.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Jean-Charles Preiser.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 56 kb)

Appendix 1: list of participants

Appendix 1: list of participants


University Clinic of Innsbruck

(M Joannidis)

13 patients


Regional Centre Hospital of Citadelle, Liege (F Damas, V Fraipont)

40 patients

University Hospital Centre, Liege (JL Canivet, P Damas, B Lambermont, D Ledoux)

4 units: 141 + 158 + 16 + 110 patients


Raymond Poincaré Hospital, Garches (D Annane)

74 patients

Gustave-Roussy Institute, Villejuif (G Nitenberg)

12 patients


Rabin Medical Centre, Petah Tiqva (P Singer)

85 patients

The Netherlands

Free University Medical Centre, Amsterdam (J Groeneveld)

10 patients


University Medical Centre, Ljubljana (A Stecher, L Kompan)

112 patients


University General Hospital, Alicante (J Acosta Escribano, S Almanza; R Carrasco Moreno, M Fernández Vivas, V Ortolá Vercher)

15 patients

University Hospital Germans Trias i Pujol, Badalona (ML Bordejé, P Marcos Neira, S Martínez Vega, H Pérez Moltó)

53 patients

Dr Josep Trueta University Hospital, Girona (A Bonet Sarís, N López de Arbina, P Ortiz Ballugera)

28 patients

Dr. Negrín University Hospital, Las Palmas de Gran Canaria (S Ruiz-Santana, P Saavedra, Hípola Escalada, MA Hernández Viera, R Manzanedo Velasco, JJ Díaz Díaz)

101 patients

Hospital Severo Ochoa, Leganés (J López Martinez, R Díaz Abad)

35 patients

University Hospital 12 October, Madrid (JC Montejo, T Grau Carmona, C García Fuentes)

2 units: 15 + 40 patients

Provincial Hospital of Toledo (B García Vila, ML Rodríguez Blanco, MC Martín Parra)

19 patients

Dr Peset Hospital, Valencia (M Cervera Montes, C Campos, A Castillo, S Sancho, JM Simón)

24 patients

Rights and permissions

Reprints and permissions

About this article

Cite this article

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 35, 1738–1748 (2009).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: