Abstract
Purpose
It is unclear whether tight glycemic control is warranted in all critically ill adults. We employed network meta-analysis to examine the risk of mortality and hypoglycemia associated with different glycemic control targets in critically ill adults.
Methods
Electronic databases were searched up to 2016 for randomized controlled trials comparing various insulin regimens in critically ill adults with hyperglycemia. Two reviewers independently extracted information and evaluated quality with the Cochrane risk-of-bias tool. Four glycemic control groups were compared: tight (blood glucose: 4.4 < 6.1 mmol/l), moderate (6.1 < 7.8 mmol/l), mild (7.8 < 10.0 mmol/l), and very mild (10.0 to < 12.2 mmol/l). Network meta-analysis was performed by a frequentist approach with multivariate random effects meta-analysis.
Results
Thirty-six randomized trials (17,996 patients) were identified. Compared with very mild control, tight control did not reduce the risk of short-term mortality [relative risk (RR) 0.94 (95 % CI 0.83–1.07, p = 0.36)], and neither did mild control [RR 0.88 (0.73–1.06), p = 0.18] or moderate control [RR 1.1 (0.66–1.84), p = 0.72]. However, severe hypoglycemia (<2.2 mmol/l) was more frequent with tight control than very mild control [RR 5.49 (3.22–9.38), p < 0.001] or mild control [RR 4.47 (2.5–8.03), p < 0.001]. Stratified analyses (cause of death, ICU type, time period, or diabetes) did not find significant between-group differences. Ranking analysis revealed the following hierarchy for avoiding death (highest to lowest rank): mild control, tight control, and very mild control.
Conclusions
Network meta-analysis showed no mortality benefit of tight glycemic control in critically ill patients, but fivefold more hypoglycemia versus mild or very mild control.
Similar content being viewed by others
References
Norhammar AM, Rydén L, Malmberg K (1999) Admission plasma glucose. Independent risk factor for long-term prognosis after myocardial infarction even in nondiabetic patients. Diabetes Care 22(11):1827–1831
Kosiborod M, Rathore SS, Inzucchi SE et al (2005) Admission glucose and mortality in elderly patients hospitalized with acute myocardial infarction: implications for patients with and without recognized diabetes. Circulation 111:3078–3086
Svensson AM, McGuire DK, Abrahamsson P et al (2005) Association between hyper- and hypoglycaemia and 2 year all-cause mortality risk in diabetic patients with acute coronary events. Eur Heart J 26:1255–1261
Van den Berghe G, Wouters P, Weekers F et al (2001) Intensive insulin therapy in critically ill patients. N Engl J Med 345(19):1359–1367
Van den Berghe G, Wilmer A, Hermans G et al (2006) Intensive insulin therapy in the medical ICU. N Engl J Med 354(5):449–461
NICE-SUGAR Study Investigators, Finfer S, Chittock DR, Su SY et al (2009) Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 360(13):1283–1297
NICE-SUGAR Study Investigators, Finfer S, Liu B, Chittock DR et al (2012) Hypoglycemia and risk of death in critically ill patients. N Engl J Med 367(12):1108–1118
Krinsley JS, Grover A (2007) Severe hypoglycemia in critically ill patients: risk factors and outcomes. Crit Care Med 35(10):2262–2267
Griesdale DE, de Souza RJ, van Dam RM et al (2009) Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including NICE-SUGAR study data. CMAJ 180(8):821–827
Kramer AH, Roberts DJ, Zygun DA (2012) Optimal glycemic control in neurocritical care patients: a systematic review and meta-analysis. Crit Care 16(5):R203
Friedrich JO, Chant C, Adhikari NK (2010) Does intensive insulin therapy really reduce mortality in critically ill surgical patients? A reanalysis of meta-analytic data. Crit Care 14(5):324
Wiener RS, Wiener DC, Larson RJ (2008) Benefits and risks of tight glucose control in critically ill adults: a meta-analysis. JAMA 300(8):933–944
American Diabetes Association (2015) Standards of medical care in diabetes-2015. Diabetes Care 38(suppl 1):S80–S85
Higgins J, Green S (2011) Cochrane handbook for systematic reviews of interventions. Version 5.1.0. Cochrane Collaboration. http://handbook.cochrane.org/. Accessed 1 Sep 2015
Bangalore S, Toklu B, Kotwal A et al (2014) Anticoagulant therapy during primary percutaneous coronary intervention for acute myocardial infarction: a meta-analysis of randomized trials in the era of stents and P2Y12 inhibitors. BMJ 11(349):g6419
Higgins JPT, Jackson D, Barrett JK et al (2012) Consistency and inconsistency in network meta-analysis: concepts and models for multi-arm studies. Res Synth Methods 3:98–110
White IR, Barrett JK, Jackson D et al (2012) Consistency and inconsistency in network meta-analysis: model estimation using multivariate meta-regression. Res Synth Methods 3:111–125
White IR (2009) Multivariate random-effects meta-analysis. Stata J 9:40–56
Chaimani A, Higgins JP, Mavridis D et al (2013) Graphical tools for network meta-analysis in STATA. PLoS ONE 8(10):e76654
Salanti G, Ades AE, Ioannidis JP (2011) Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol 64(2):163–171
Giakoumidakis K, Eltheni R, Patelarou E et al (2013) Effects of intensive glycemic control on outcomes of cardiac surgery. Heart Lung 42(2):146–151
Liberati A, Altman DG, Tetzlaff J et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 6(7):e1000100
Puhan MA, Schünemann HJ, Murad MH et al (2014) GRADE Working Group. A GRADE Working Group approach for rating the quality of treatment effect estimates from network meta-analysis. BMJ 24(349):g5630
Higgins JP, Thompson SG, Deeks JJ et al (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560
Altman DG, Bland JM (2003) Interaction revisited: the difference between two estimates. BMJ 326:219
Iapichino G, Albicini M, Umbrello M et al (2008) Tight glycemic control does not affect asymmetric-dimethylarginine in septic patients. Intensiv Care Med 34(10):1843–1850
Farah R, Samokhvalov A, Zviebel F et al (2007) Insulin therapy of hyperglycemia in intensive care. Isr Med Assoc J 9(3):140–142
Bilotta F, Spinelli A, Giovannini F et al (2007) The effect of intensive insulin therapy on infection rate, vasospasm, neurologic outcome, and mortality in neurointensive care unit after intracranial aneurysm clipping in patients with acute subarachnoid hemorrhage: a randomized prospective pilot trial. J Neurosurg Anesthesiol 19(3):156–160
Savioli M, Cugno M, Polli F et al (2009) Tight glycemic control may favor fibrinolysis in patients with sepsis. Crit Care Med 37(2):424–431
Lazar HL, McDonnell MM, Chipkin S et al (2011) Effects of aggressive versus moderate glycemic control on clinical outcomes in diabetic coronary artery bypass graft patients. Ann Surg 254(3):458–463
Mitchell I, Knight E, Gissane J, Australian and New Zealand Intensive Care Society Clinical Trials Group et al (2006) A phase II randomised controlled trial of intensive insulin therapy in general intensive care patients. Crit Care Resusc 8(4):289–293
McMullin J, Brozek J, McDonald E et al (2007) Lowering of glucose in critical care: a randomized pilot trial. J Crit Care 22(2):112–118
Brunkhorst FM, Engel C, Bloos F et al (2008) German competence network sepsis (SepNet). Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 358(2):125–139
De La Gdel C, Donado JH, Grupo de Investigacion en Cuidado intensivo: GICI-HPTU et al (2008) Strict glycaemic control in patients hospitalised in a mixed medical and surgical intensive care unit: a randomised clinical trial. Crit Care 12(5):R120
Arabi YM, Dabbagh OC, Tamim HM et al (2008) Intensive versus conventional insulin therapy: a randomized controlled trial in medical and surgical critically ill patients. Crit Care Med 36(12):3190–3197
Oksanen T, Skrifvars MB, Varpula T et al (2007) Strict versus moderate glucose control after resuscitation from ventricular fibrillation. Intensiv Care Med 33(12):2093–2100
Bruno A, Kent TA, Coull BM et al (2008) Treatment of hyperglycemia in ischemic stroke (THIS): a randomized pilot trial. Stroke 39(2):384–389
Grey NJ, Perdrizet GA (2004) Reduction of nosocomial infections in the surgical intensive-care unit by strict glycemic control. Endocr Pract 10(Suppl 2):46–52
Preiser JC, Devos P, Ruiz-Santana S et al (2009) A prospective randomised multi-centre controlled trial on tight glucose control by intensive insulin therapy in adult intensive care units: the Glucontrol study. Intensiv Care Med 35(10):1738–1748
Staszewski J, Brodacki B, Kotowicz J et al (2011) Intravenous insulin therapy in the maintenance of strict glycemic control in nondiabetic acute stroke patients with mild hyperglycemia. J Stroke Cerebrovasc Dis 20(2):150–154
Green DM, O’Phelan KH, Bassin SL et al (2010) Intensive versus conventional insulin therapy in critically ill neurologic patients. Neurocrit Care 13(3):299–306
Coester A, Neumann CR, Schmidt MI (2010) Intensive insulin therapy in severe traumatic brain injury: a randomized trial. J Trauma 68(4):904–911
Johnston KC, Hall CE, Kissela BM, GRASP Investigators et al (2009) Glucose regulation in acute stroke patients (GRASP) trial: a randomized pilot trial. Stroke 40(12):3804–3809
Yang M, Guo Q, Zhang X et al (2009) Intensive insulin therapy on infection rate, days in NICU, in-hospital mortality and neurological outcome in severe traumatic brain injury patients: a randomized controlled trial. Int J Nurs Stud 46(6):753–758
Kreisel SH, Berschin UM, Hammes HP et al (2009) Pragmatic management of hyperglycaemia in acute ischaemic stroke: safety and feasibility of intensive intravenous insulin treatment. Cerebrovasc Dis 27(2):167–175
Azevedo JR, Lima ER, Cossetti RJ et al (2007) Intensive insulin therapy versus conventional glycemic control in patients with acute neurological injury: a prospective controlled trial. Arq Neuropsiquiatr 65(3B):733–738
Cappi SB, Noritomi DT, Velasco IT et al (2012) Dyslipidemia: a prospective controlled randomized trial of intensive glycemic control in sepsis. Intensiv Care Med 38(4):634–641
COIITSS Study Investigator, Annane D, Maxime A, Cariou V (2010) Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial. JAMA 303(4):341–348
Rosso C, Corvol JC, Pires C et al (2012) Intensive versus subcutaneous insulin in patients with hyperacute stroke: results from the randomized INSULINFARCT trial. Stroke 43(9):2343–2349
Gandhi GY, Nuttall GA, Abel MD et al (2007) Intensive intraoperative insulin therapy versus conventional glucose management during cardiac surgery: a randomized trial. Ann Intern Med 146(4):233–243
Bilotta F, Caramia R, Paoloni FP et al (2009) Safety and efficacy of intensive insulin therapy in critical neurosurgical patients. Anesthesiology 110(3):611–619
Cao SG, Ren JA, Shen B et al (2011) Intensive versus conventional insulin therapy in type 2 diabetes patients undergoing D2 gastrectomy for gastric cancer: a randomized controlled trial. World J Surg 35(1):85–92
Arabi YM, Tamim HM, Dhar GS et al (2011) Permissive underfeeding and intensive insulin therapy in critically ill patients: a randomized controlled trial. Am J Clin Nutr 93(3):569–577
Desai SP, Henry LL, Holmes SD et al (2012) Strict versus liberal target range for perioperative glucose in patients undergoing coronary artery bypass grafting: a prospective randomized controlled trial. J Thorac Cardiovasc Surg 143(2):318–325
Chan RP, Galas FR, Hajjar LA et al (2009) Intensive perioperative glucose control does not improve outcomes of patients submitted to open-heart surgery: a randomized controlled trial. Clinics (Sao Paulo) 64(1):51–60
Kalfon P, Giraudeau B, Ichai C, CGAO-REA Study Group et al (2014) Tight computerized versus conventional glucose control in the ICU: a randomized controlled trial. Intensiv Care Med 40(2):171–181
Henderson WR, Dhingra V, Chittock D, Canadian Critical Trials Group et al (2009) The efficacy and safety of glucose control algorithms in intensive care: a pilot study of the Survival Using Glucose Algorithm Regulation (SUGAR) trial. Pol Arch Med Wewn 119(7–8):439–446
Whitmer RA, Karter AJ, Yaffe K et al (2009) Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA 301(15):1565–1572
Khan MI, Barlow RB, Weinstock RS (2011) Acute hypoglycemia decreases central retinal function in the human eye. Vision Res 51(14):1623–1626
Moghissi ES, Korytkowski MT, DiNardo M, American Association of Clinical Endocrinologists et al (2009) American Diabetes Association. American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Endocr Pract 15(4):353–369
Mills EJ, Thorlund K, Ioannidis JP (2013) Demystifying trial networks and network meta-analysis. BMJ 14(346):f2914
Stewart LA, Tierney JF (2002) To IPD or not to IPD? Advantages and disadvantages of systematic reviews using individual patient data. Eval Health Prof 25(1):76–97
Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6(6):e1000097. doi:10.1371/journal.pmed1000097
Acknowledgments
There was no acknowledgment in this research.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
T.Yamada was funded by Japan Diabetes Society, Banyu Foundation, KAKENHI (Grants-in-Aid for Scientific Research), Japan Foundation for Applied Enzymology, and Japan Association for Diabetes Education and Care. We declare that these funds have not influenced this research.
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
Conflicts of interest
No potential conflicts of interest relevant to this article were reported.
Additional information
Take-home message:
Network meta-analysis showed no mortality benefit of tight glycemic control in critically ill patients, but fivefold more hypoglycemia versus mild or very mild control.
Electronic supplementary material
Below is the link to the electronic supplementary material.
134_2016_4523_MOESM1_ESM.pptx
Supplementary Figure 1. Flowchart of study selection. Supplementary Figure 2. Summary of the risk of bias: our judgements about the risk of bias for each item in each study. Blue low risk of bias, Yellow unclear risk of bias, Red high risk of bias. Supplementary Figure 3a. Rankogram for short-term mortality. The plot presents the ranking probabilities and their uncertainty. Supplementary Figure 3b. Hierarchy of outcomes for short-term mortality according to surface under the cumulative ranking curve (SUCRA) values. As the SUCRA value becomes higher, the efficacy (no short-term mortality) decreases. Supplementary figure 4. Network plot comparing the different treatment strategies. Nodes and edges are weighted according to the number of studies with the respective interventions. Supplementary Figure 5a. Rankogram for hypoglycemia. The plot presents the ranking probabilities and their uncertainty. Supplementary Figure 5b. Hierarchy of outcomes for hypoglycemia according to surface under the cumulative ranking curve (SUCRA) values. As the SUCRA value becomes higher, the safety (no hypoglycemia) decreases. Supplementary Figure 6. Comparison of various glycemic targets by using the mixed treatment comparison model stratified by the presence of diabetes. Supplementary Figure 7. Comparison of various glycemic targets using the mixed treatment comparison model with stratification by the cause of death (sepsis mortality, cardiovascular mortality, respiratory mortality, or neurological mortality). Supplementary Figure 8. Hierarchy of mortality outcomes according to the surface under the cumulative ranking curve (SUCRA). Mortality increases as the SUCRA value becomes higher. Supplementary Figure 9. Direct comparison meta-analysis between tight control and very mild control. Supplementary Figure 10. Direct comparison meta-analysis between tight control and mild control. Supplementary Figure 11. Funnel plots and the results of Begg’s test and Egger’s test. Supplementary Figure 12a. Direct comparison meta-analysis between tight control and very mild (or mild) control in patients with diabetes. Supplementary Figure 12b. Direct comparison meta-analysis between tight control and very mild (or mild) control in patients without diabetes.Supplementary Figure13. Meta-regression analysis of the relation between diabetes and the relative risk of short-term mortality with tight glycemic control versus mild and very mild control (PPTX 4424 kb)
134_2016_4523_MOESM2_ESM.docx
Supplementary Table 1. Terms used to search the electronic databases. Supplementary Table 2. Type of ICU and cause of death in all trials included in the network meta-analysis (DOCX 26 kb)
Rights and permissions
About this article
Cite this article
Yamada, T., Shojima, N., Noma, H. et al. Glycemic control, mortality, and hypoglycemia in critically ill patients: a systematic review and network meta-analysis of randomized controlled trials. Intensive Care Med 43, 1–15 (2017). https://doi.org/10.1007/s00134-016-4523-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00134-016-4523-0