Hyperglycemia in acute ischemic stroke: pathophysiology and clinical management

Abstract

Patients with acute ischemic stroke frequently test positive for hyperglycemia, which is associated with a poor clinical outcome. This association between poor glycemic control and an unfavorable prognosis is particularly evident in patients with persistent hyperglycemia, patients without a known history of diabetes mellitus, and patients with cortical infarction. To date, however, only one large clinical trial has specifically investigated the effect of glycemic control on stroke outcome. This trial failed to show a clinical benefit, but had several limitations. Despite a lack of clinical evidence supporting the use of glycemic control in the treatment of patients with stroke, international guidelines recommend treating this subset of critically ill patients for hyperglycemia in the hospital setting. This treatment regime is, however, particularly challenging in patients with stroke, and is associated with an increased risk of the patient developing hypoglycemia. Here we review the available evidence linking hyperglycemia to a poor clinical outcome in patients with ischemic stroke. We highlight the pathophysiological mechanisms that might underlie the deleterious effects of hyperglycemia on acute stroke prognosis and systematically review the literature concerning tight glycemic control after stroke. Finally, we provide directions on the use of insulin treatment strategies to control hyperglycemia in this patient group.

Key Points

  • Hyperglycemia is frequently observed in patients with ischemic stroke, persists throughout the clinical course of the disorder and is associated with an increased infarct size and a poor clinical outcome

  • Several pathophysiological mechanisms could account for the detrimental effect of hyperglycemia observed in patients with acute ischemic stroke

  • No evidence exists that supports the use of glucose lowering therapy for the treatment of hyperglycemia in patients with acute ischemic stroke

  • Establishing glycemic control in patients with acute ischemic stroke is challenging and carries a substantial risk of the patient developing hypoglycemia

  • Studies that establish safe methods of improving glycemic control are awaited before randomized controlled trials that assess clinical outcome measures associated with glycemic control can be initiated

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Figure 1: Mechanisms leading to hyperglycemia in patients with ischemic stroke.
Figure 2: Schematic representation of infarct evolution over time.

References

  1. 1

    Allport, L. et al. Frequency and temporal profile of poststroke hyperglycemia using continuous glucose monitoring. Diabetes Care 29, 1839–1844 (2006).

    CAS  PubMed  Google Scholar 

  2. 2

    Baird, T. A. et al. Persistent poststroke hyperglycemia is independently associated with infarct expansion and worse clinical outcome. Stroke 34, 2208–2214 (2003).

    CAS  PubMed  Google Scholar 

  3. 3

    Capes, S. E., Hunt, D., Malmberg, K., Pathak, P. & Gerstein, H. C. Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke 32, 2426–2432 (2001).

    CAS  PubMed  Google Scholar 

  4. 4

    Christensen, H. & Boysen, G. Blood glucose increases early after stroke onset: a study on serial measurements of blood glucose in acute stroke. Eur. J. Neurol. 9, 297–301 (2002).

    CAS  PubMed  Google Scholar 

  5. 5

    Dora, B. et al. Prolonged hyperglycemia in the early subacute period after cerebral infarction: effects on short term prognosis. Acta Neurol. Belg. 104, 64–67 (2004).

    PubMed  Google Scholar 

  6. 6

    Gray, C. S., Hildreth, A. J., Alberti, G. K. & O'Connell, J. E. Poststroke hyperglycemia: natural history and immediate management. Stroke 35, 122–126 (2004).

    CAS  PubMed  Google Scholar 

  7. 7

    Melamed, E. Reactive hyperglycaemia in patients with acute stroke. J. Neurol. Sci. 29, 267–275 (1976).

    CAS  PubMed  Google Scholar 

  8. 8

    Szczudlik, A. et al. Transient hyperglycemia in ischemic stroke patients. J. Neurol. Sci. 189, 105–111 (2001).

    CAS  PubMed  Google Scholar 

  9. 9

    Wong, A. A., Schluter, P. J., Henderson, R. D., O'Sullivan, J. D. & Read, S. J. Natural history of blood glucose within the first 48 hours after ischemic stroke. Neurology 70, 1036–1041 (2008).

    CAS  PubMed  Google Scholar 

  10. 10

    Berger, L. & Hakim, A. M. The association of hyperglycemia with cerebral edema in stroke. Stroke 17, 865–871 (1986).

    CAS  PubMed  Google Scholar 

  11. 11

    Candelise, L., Landi, G., Orazio, E. N. & Boccardi, E. Prognostic significance of hyperglycemia in acute stroke. Arch. Neurol. 42, 661–663 (1985).

    CAS  PubMed  Google Scholar 

  12. 12

    Els, T. et al. Hyperglycemia in patients with focal cerebral ischemia after intravenous thrombolysis: influence on clinical outcome and infarct size. Cerebrovasc. Dis. 13, 89–94 (2002).

    CAS  PubMed  Google Scholar 

  13. 13

    Murros, K., Fogelholm, R., Kettunen, S., Vuorela, A. L. & Valve, J. Blood glucose, glycosylated haemoglobin, and outcome of ischemic brain infarction. J. Neurol. Sci. 111, 59–64 (1992).

    CAS  PubMed  Google Scholar 

  14. 14

    Parsons, M. W. et al. Acute hyperglycemia adversely affects stroke outcome: a magnetic resonance imaging and spectroscopy study. Ann. Neurol. 52, 20–28 (2002).

    PubMed  Google Scholar 

  15. 15

    Toni, D. et al. Influence of hyperglycaemia on infarct size and clinical outcome of acute ischemic stroke patients with intracranial arterial occlusion. J. Neurol. Sci. 123, 129–133 (1994).

    CAS  PubMed  Google Scholar 

  16. 16

    Furnary, A. P. et al. Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J. Thorac. Cardiovasc. Surg. 125, 1007–1021 (2003).

    CAS  PubMed  Google Scholar 

  17. 17

    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).

    PubMed  Google Scholar 

  18. 18

    Latorre, J. G. et al. Effective glycemic control with aggressive hyperglycemia management is associated with improved outcome in aneurysmal subarachnoid hemorrhage. Stroke 40, 1644–1652 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Lazar, H. L. et al. Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events. Circulation 109, 1497–1502 (2004).

    CAS  PubMed  Google Scholar 

  20. 20

    Malmberg, K. et al. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J. Am. Coll. Cardiol. 26, 57–65 (1995).

    CAS  PubMed  Google Scholar 

  21. 21

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

    CAS  PubMed  Google Scholar 

  22. 22

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

    CAS  PubMed  Google Scholar 

  23. 23

    Brunkhorst, F. M. et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N. Engl. J. Med. 358, 125–139 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

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

    PubMed  PubMed Central  Google Scholar 

  25. 25

    Gray, C. S. et al. Glucose-potassium-insulin infusions in the management of post-stroke hyperglycaemia: the UK Glucose Insulin in Stroke Trial (GIST-UK). Lancet Neurol. 6, 397–406 (2007).

    CAS  PubMed  Google Scholar 

  26. 26

    Yong, M. & Kaste, M. Dynamic of hyperglycemia as a predictor of stroke outcome in the ECASS-II Trial. Stroke 39, 2749–2755 (2008).

    PubMed  Google Scholar 

  27. 27

    Bruno, A., Saha, C., Williams, L. S. & Shankar, R. IV insulin during acute cerebral infarction in diabetic patients. Neurology 62, 1441–1442 (2004).

    PubMed  Google Scholar 

  28. 28

    Bruno, A. et al. Treatment of hyperglycemia in ischemic stroke (THIS). A randomized pilot trial. Stroke 39, 348–349 (2007).

    Google Scholar 

  29. 29

    Gray, C. S., Scott, J. F., French, J. M., Alberti, K. G. & O'Connell, J. E. Prevalence and prediction of unrecognized diabetes mellitus and impaired glucose tolerance following acute stroke. Age Ageing 33, 71–77 (2004).

    PubMed  Google Scholar 

  30. 30

    Kernan, W. N. et al. Prevalence of abnormal glucose tolerance following a transient ischemic attack or ischemic stroke. Arch. Intern. Med. 165, 227–233 (2005).

    PubMed  Google Scholar 

  31. 31

    Matz, K. et al. Disorders of glucose metabolism in acute stroke patients: an underrecognized problem. Diabetes Care 29, 792–797 (2006).

    CAS  PubMed  Google Scholar 

  32. 32

    Vancheri, F. et al. Impaired glucose metabolism in patients with acute stroke and no previous diagnosis of diabetes mellitus. QJM 98, 871–878 (2005).

    CAS  PubMed  Google Scholar 

  33. 33

    Gauna, C., van den Berghe, G. H. & van der Lely, A. J. Pituitary function during severe and life-threatening illnesses. Pituitary 8, 213–217 (2005).

    CAS  PubMed  Google Scholar 

  34. 34

    Vanhorebeek, I., Langouche, L. & van den Berghe, G. Endocrine aspects of acute and prolonged critical illness. Nat. Clin. Pract. Endocrinol. Metab. 2, 20–31 (2006).

    CAS  PubMed  Google Scholar 

  35. 35

    van den Berghe, G. Novel insights into the neuroendocrinology of critical illness. Eur. J. Endocrinol. 143, 1–13 (2000).

    CAS  PubMed  Google Scholar 

  36. 36

    Feibel, J. H., Hardy, P. M., Campbell, R. G., Goldstein, M. N. & Joynt, R. J. Prognostic value of the stress response following stroke. JAMA 238, 1374–1376 (1977).

    CAS  PubMed  Google Scholar 

  37. 37

    Barth, E. et al. Glucose metabolism and catecholamines. Crit. Care Med. 35 (Suppl. 9), S508–S518 (2007).

    CAS  PubMed  Google Scholar 

  38. 38

    Seematter, G., Binnert, C., Martin, J. L. & Tappy, L. Relationship between stress, inflammation and metabolism. Curr. Opin. Clin. Nutr. Metab. Care 7, 169–173 (2004).

    CAS  PubMed  Google Scholar 

  39. 39

    Gearhart, M. M. & Parbhoo, S. K. Hyperglycemia in the critically ill patient. AACN Clin. Issues 17, 50–55 (2006).

    PubMed  Google Scholar 

  40. 40

    Hunt, D. G. & Ivy, J. L. Epinephrine inhibits insulin-stimulated muscle glucose transport. J. Appl. Physiol. 93, 1638–1643 (2002).

    CAS  PubMed  Google Scholar 

  41. 41

    O'Neill, P. A., Davies, I., Fullerton, K. J. & Bennett, D. Stress hormone and blood glucose response following acute stroke in the elderly. Stroke 22, 842–847 (1991).

    CAS  PubMed  Google Scholar 

  42. 42

    Allport, L. E. et al. Insular cortical ischemia is independently associated with acute stress hyperglycemia. Stroke 35, 1886–1891 (2004).

    PubMed  Google Scholar 

  43. 43

    Meyer, S., Strittmatter, M., Fischer, C., Georg, T. & Schmitz, B. Lateralization in autonomic dysfunction in ischemic stroke involving the insular cortex. Neuroreport 15, 357–361 (2004).

    CAS  PubMed  Google Scholar 

  44. 44

    Tarkowski, E. et al. Early intrathecal production of interleukin-6 predicts the size of brain lesion in stroke. Stroke 26, 1393–1398 (1995).

    CAS  PubMed  Google Scholar 

  45. 45

    Vila, N., Castillo, J., Davalos, A. & Chamorro, A. Proinflammatory cytokines and early neurological worsening in ischemic stroke. Stroke 31, 2325–2329 (2000).

    CAS  PubMed  Google Scholar 

  46. 46

    Chrousos, G. P. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N. Engl. J. Med. 332, 1351–1362 (1995).

    CAS  PubMed  Google Scholar 

  47. 47

    del Aguila, L. F., Claffey, K. P. & Kirwan, J. P. TNF-α impairs insulin signaling and insulin stimulation of glucose uptake in C2C12 muscle cells. Am. J. Physiol. 276, E849–E855 (1999).

    CAS  PubMed  Google Scholar 

  48. 48

    Rask-Madsen, C. et al. Tumor necrosis factor-α inhibits insulin's stimulating effect on glucose uptake and endothelium-dependent vasodilation in humans. Circulation 108, 1815–1821 (2003).

    CAS  PubMed  Google Scholar 

  49. 49

    Plomgaard, P. et al. Tumor necrosis factor-α induces skeletal muscle insulin resistance in healthy human subjects via inhibition of Akt substrate 160 phosphorylation. Diabetes 54, 2939–2945 (2005).

    CAS  PubMed  Google Scholar 

  50. 50

    Fuentes, B. et al. The prognostic value of capillary glucose levels in acute stroke: the glycemia in acute stroke (GLIAS) study. Stroke 40, 562–568 (2009).

    CAS  PubMed  Google Scholar 

  51. 51

    Stollberger, C., Exner, I., Finsterer, J., Slany, J. & Steger, C. Stroke in diabetic and non-diabetic patients: course and prognostic value of admission serum glucose. Ann. Med. 37, 357–364 (2005).

    PubMed  Google Scholar 

  52. 52

    Stead, L. G. et al. Hyperglycemia as an independent predictor of worse outcome in non-diabetic patients presenting with acute ischemic stroke. Neurocrit. Care 10, 181–186 (2008).

    Google Scholar 

  53. 53

    Dungan, K. M., Braithwaite, S. S. & Preiser, J. C. Stress hyperglycaemia. Lancet 373, 1798–1807 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Egi, M. et al. Blood glucose concentration and outcome of critical illness: the impact of diabetes. Crit. Care Med. 36, 2249–2255 (2008).

    CAS  PubMed  Google Scholar 

  55. 55

    Umpierrez, G. E. et al. Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J. Clin. Endocrinol. Metab. 87, 978–982 (2002).

    CAS  PubMed  Google Scholar 

  56. 56

    Bruno, A. et al. Acute blood glucose level and outcome from ischemic stroke. Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. Neurology 52, 280–284 (1999).

    CAS  PubMed  Google Scholar 

  57. 57

    Kruyt, N. D. et al. Hyperglycemia and cognitive outcome after ischemic stroke. J. Neurol. Sci. 270, 141–147 (2008).

    CAS  PubMed  Google Scholar 

  58. 58

    Uyttenboogaart, M. et al. Moderate hyperglycaemia is associated with favourable outcome in acute lacunar stroke. Brain 130, 1626–1630 (2007).

    PubMed  Google Scholar 

  59. 59

    Bruno, A. et al. Admission glucose level and clinical outcomes in the NINDS rt-PA Stroke Trial. Neurology 59, 669–674 (2002).

    CAS  PubMed  Google Scholar 

  60. 60

    Alvarez-Sabin, J. et al. Effects of admission hyperglycemia on stroke outcome in reperfused tissue plasminogen activator–treated patients. Stroke 34, 1235–1241 (2003).

    PubMed  Google Scholar 

  61. 61

    Alvarez-Sabin, J. et al. Impact of admission hyperglycemia on stroke outcome after thrombolysis. Risk stratification in relation to time to reperfusion. Stroke 35, 2493–2498 (2004).

    PubMed  Google Scholar 

  62. 62

    Leigh, R. et al. Predictors of hyperacute clinical worsening in ischemic stroke patients receiving thrombolytic therapy. Stroke 35, 1903–1907 (2004).

    CAS  PubMed  Google Scholar 

  63. 63

    Saposnik, G. et al. Lack of improvement in patients with acute stroke after treatment with thrombolytic therapy: predictors and association with outcome. JAMA 292, 1839–1844 (2004).

    CAS  PubMed  Google Scholar 

  64. 64

    Kidwell, C. S., Alger, J. R. & Saver, J. L. Evolving paradigms in neuroimaging of the ischemic penumbra. Stroke 35, 2662–2665 (2004).

    PubMed  Google Scholar 

  65. 65

    Gentile, N. T. et al. Factor VIIa and tissue factor procoagulant activity in diabetes mellitus after acute ischemic stroke: impact of hyperglycemia. Thromb. Haemost. 98, 1007–1013 (2007).

    CAS  PubMed  Google Scholar 

  66. 66

    Rao, A. K., Chouhan, V., Chen, X., Sun, L. & Boden, G. Activation of the tissue factor pathway of blood coagulation during prolonged hyperglycemia in young healthy men. Diabetes 48, 1156–1161 (1999).

    CAS  PubMed  Google Scholar 

  67. 67

    Stegenga, M. E. et al. Hyperglycemia stimulates coagulation, whereas hyperinsulinemia impairs fibrinolysis in healthy humans. Diabetes 55, 1807–1812 (2006).

    CAS  PubMed  Google Scholar 

  68. 68

    Vaidyula, V. R. et al. Effects of hyperglycemia and hyperinsulinemia on circulating tissue factor procoagulant activity and platelet CD40 ligand. Diabetes 55, 202–208 (2006).

    CAS  PubMed  Google Scholar 

  69. 69

    Festa, A. et al. Relative contribution of insulin and its precursors to fibrinogen and PAI-1 in a large population with different states of glucose tolerance. The insulin resistance atherosclerosis study (IRAS). Arterioscler. Thromb. Vasc. Biol. 19, 562–568 (1999).

    CAS  PubMed  Google Scholar 

  70. 70

    Meigs, J. B. et al. Hyperinsulinemia, hyperglycemia, and impaired hemostasis: the Framingham Offspring Study. JAMA 283, 221–228 (2000).

    CAS  Google Scholar 

  71. 71

    Pandolfi, A. et al. Acute hyperglycemia and acute hyperinsulinemia decrease plasma fibrinolytic activity and increase plasminogen activator inhibitor type 1 in the rat. Acta Diabetol. 38, 71–76 (2001).

    CAS  PubMed  Google Scholar 

  72. 72

    Ribo, M. et al. Acute hyperglycemia state is associated with lower tPA-induced recanalization rates in stroke patients. Stroke 36, 1705–1709 (2005).

    CAS  PubMed  Google Scholar 

  73. 73

    Duckrow, R. B., Beard, D. C. & Brennan, R. W. Regional cerebral blood flow decreases during chronic and acute hyperglycemia. Stroke 18, 52–58 (1987).

    CAS  PubMed  Google Scholar 

  74. 74

    Kawai, N., Keep, R. F., Betz, A. L. & Nagao, S. Hyperglycemia induces progressive changes in the cerebral microvasculature and blood-brain barrier transport during focal cerebral ischemia. Acta Neurochir. Suppl. 71, 219–221 (1998).

    CAS  PubMed  Google Scholar 

  75. 75

    Quast, M. J. et al. Perfusion deficit parallels exacerbation of cerebral ischemia/reperfusion injury in hyperglycemic rats. J. Cereb. Blood Flow Metab. 17, 553–559 (1997).

    CAS  PubMed  Google Scholar 

  76. 76

    Yip, P. K. et al. Effect of plasma glucose on infarct size in focal cerebral ischemia-reperfusion. Neurology 41, 899–905 (1991).

    CAS  PubMed  Google Scholar 

  77. 77

    Venables, G. S., Miller, S. A., Gibson, G., Hardy, J. A. & Strong, A. J. The effects of hyperglycaemia on changes during reperfusion following focal cerebral ischaemia in the cat. J. Neurol. Neurosurg. Psychiatry 48, 663–669 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Beckman, J. A., Goldfine, A. B., Gordon, M. B., Garrett, L. A. & Creager, M. A. Inhibition of protein kinase Cβ prevents impaired endothelium-dependent vasodilation caused by hyperglycemia in humans. Circ. Res. 90, 107–111 (2002).

    CAS  PubMed  Google Scholar 

  79. 79

    Williams, S. B. et al. Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo. Circulation 97, 1695–1701 (1998).

    CAS  PubMed  Google Scholar 

  80. 80

    Fleming, I. & Busse, R. Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R1–R12 (2003).

    CAS  PubMed  Google Scholar 

  81. 81

    Vallance, P., Collier, J. & Moncada, S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet 2, 997–1000 (1989).

    CAS  PubMed  Google Scholar 

  82. 82

    Ding, Y., Vaziri, N. D., Coulson, R., Kamanna, V. S. & Roh, D. D. Effects of simulated hyperglycemia, insulin, and glucagon on endothelial nitric oxide synthase expression. Am. J. Physiol. Endocrinol. Metab. 279, E11–E17 (2000).

    CAS  PubMed  Google Scholar 

  83. 83

    Du, X. L. et al. Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J. Clin. Invest. 108, 1341–1348 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Tesfamariam, B., Brown, M. L. & Cohen, R. A. Elevated glucose impairs endothelium-dependent relaxation by activating protein kinase C. J. Clin. Invest. 87, 1643–1648 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Inoguchi, T. et al. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C–dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 49, 1939–1945 (2000).

    CAS  PubMed  Google Scholar 

  86. 86

    Bohlen, H. G. & Nase, G. P. Arteriolar nitric oxide concentration is decreased during hyperglycemia-induced betaII PKC activation. Am. J. Physiol. Heart Circ. Physiol. 280, H621–H627 (2001).

    CAS  PubMed  Google Scholar 

  87. 87

    Cosentino, F., Hishikawa, K., Katusic, Z. S. & Luscher, T. F. High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells. Circulation 96, 25–28 (1997).

    CAS  PubMed  Google Scholar 

  88. 88

    Jawerbaum, A., Franchi, A. M., Gonzalez, E. T., Novaro, V. & de Gimeno, M. A. Hyperglycemia promotes elevated generation of TXA2 in isolated rat uteri. Prostaglandins 50, 47–56 (1995).

    CAS  PubMed  Google Scholar 

  89. 89

    Natarajan, R. et al. Elevated glucose and angiotensin II increase 12-lipoxygenase activity and expression in porcine aortic smooth muscle cells. Proc. Natl Acad. Sci. USA 90, 4947–4951 (1993).

    CAS  PubMed  Google Scholar 

  90. 90

    el-Kashef, H. Hyperglycemia increased the responsiveness of isolated rabbit's pulmonary arterial rings to serotonin. Pharmacology 53, 151–159 (1996).

    CAS  PubMed  Google Scholar 

  91. 91

    McCord, J. M. Oxygen-derived free radicals in postischemic tissue injury. N. Engl. J. Med. 312, 159–163 (1985).

    CAS  PubMed  Google Scholar 

  92. 92

    Kamada, H., Yu, F., Nito, C. & Chan, P. H. Influence of hyperglycemia on oxidative stress and matrix metalloproteinase-9 activation after focal cerebral ischemia/reperfusion in rats: relation to blood–brain barrier dysfunction. Stroke 38, 1044–1049 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Wei, J., Huang, N. C. & Quast, M. J. Hydroxyl radical formation in hyperglycemic rats during middle cerebral artery occlusion/reperfusion. Free Radic. Biol. Med. 23, 986–995 (1997).

    CAS  PubMed  Google Scholar 

  94. 94

    Suh, S. W. et al. Glucose and NADPH oxidase drive neuronal superoxide formation in stroke. Ann. Neurol. 64, 654–663 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Bemeur, C. et al. Dehydroascorbic acid normalizes several markers of oxidative stress and inflammation in acute hyperglycemic focal cerebral ischemia in the rat. Neurochem. Int. 46, 399–407 (2005).

    CAS  PubMed  Google Scholar 

  96. 96

    Bemeur, C., Ste-Marie, L. & Montgomery, J. Increased oxidative stress during hyperglycemic cerebral ischemia. Neurochem. Int. 50, 890–904 (2007).

    CAS  PubMed  Google Scholar 

  97. 97

    Li, S., Zheng, J. & Carmichael, S. T. Increased oxidative protein and DNA damage but decreased stress response in the aged brain following experimental stroke. Neurobiol. Dis. 18, 432–440 (2005).

    CAS  PubMed  Google Scholar 

  98. 98

    Muralikrishna, A. R. & Hatcher, J. F. Phospholipase A2, reactive oxygen species, and lipid peroxidation in cerebral ischemia. Free Radic. Biol. Med. 40, 376–387 (2006).

    Google Scholar 

  99. 99

    Brownlee, M. Biochemistry and molecular cell biology of diabetic complications. Nature 414, 813–820 (2001).

    CAS  Google Scholar 

  100. 100

    Esposito, K. et al. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation 106, 2067–2072 (2002).

    CAS  PubMed  Google Scholar 

  101. 101

    Martini, S. R. & Kent, T. A. Hyperglycemia in acute ischemic stroke: a vascular perspective. J. Cereb. Blood Flow Metab. 27, 435–451 (2007).

    CAS  PubMed  Google Scholar 

  102. 102

    Garg, R., Chaudhuri, A., Munschauer, F. & Dandona, P. Hyperglycemia, insulin, and acute ischemic stroke: a mechanistic justification for a trial of insulin infusion therapy. Stroke 37, 267–273 (2006).

    CAS  PubMed  Google Scholar 

  103. 103

    Schurr, A. Lactate: the ultimate cerebral oxidative energy substrate? J. Cereb. Blood Flow Metab. 26, 142–152 (2006).

    CAS  PubMed  Google Scholar 

  104. 104

    Siesjo, B. K. Acidosis and ischemic brain damage. Neurochem. Pathol. 9, 31–88 (1988).

    CAS  PubMed  Google Scholar 

  105. 105

    Katsura, K., Asplund, B., Ekholm, A. & Siesjo, B. K. Extra- and intracellular pH in the brain during ischaemia, related to tissue lactate content in normo- and hypercapnic rats. Eur. J. Neurosci. 4, 166–176 (1992).

    PubMed  Google Scholar 

  106. 106

    Anderson, R. E., Tan, W. K., Martin, H. S. & Meyer, F. B. Effects of glucose and PaO2 modulation on cortical intracellular acidosis, NADH redox state, and infarction in the ischemic penumbra. Stroke 30, 160–170 (1999).

    CAS  PubMed  Google Scholar 

  107. 107

    [No authors listed] Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. The NINDS t-PA Stroke Study Group. Stroke 28, 2109–2118 (1997).

  108. 108

    Demchuk, A. M. et al. Serum glucose level and diabetes predict tissue plasminogen activator-related intracerebral hemorrhage in acute ischemic stroke. Stroke 30, 34–39 (1999).

    CAS  PubMed  Google Scholar 

  109. 109

    Tanne, D. et al. Markers of increased risk of intracerebral hemorrhage after intravenous recombinant tissue plasminogen activator therapy for acute ischemic stroke in clinical practice: the multicenter rt-PA stroke survey. Circulation 105, 1679–1685 (2002).

    CAS  Google Scholar 

  110. 110

    Hawkins, B. T., Lundeen, T. F., Norwood, K. M., Brooks, H. L. & Egleton, R. D. Increased blood–brain barrier permeability and altered tight junctions in experimental diabetes in the rat: contribution of hyperglycaemia and matrix metalloproteinases. Diabetologia 50, 202–211 (2007).

    CAS  PubMed  Google Scholar 

  111. 111

    Griesdale, D. E. et al. Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including NICE-SUGAR study data. CMAJ 180, 821–827 (2009).

    PubMed  Google Scholar 

  112. 112

    Malmberg, K. et al. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur. Heart J. 26, 650–661 (2005).

    CAS  PubMed  Google Scholar 

  113. 113

    Ceremuzynski, L. et al. Low-dose glucose-insulin-potassium is ineffective in acute myocardial infarction: results of a randomized multicenter Pol-GIK trial. Cardiovasc. Drugs Ther. 13, 191–200 (1999).

    CAS  PubMed  Google Scholar 

  114. 114

    Diaz, R. et al. Metabolic modulation of acute myocardial infarction. The ECLA (Estudios Cardiologicos Latinoamerica) Collaborative Group. Circulation 98, 2227–2234 (1998).

    CAS  PubMed  Google Scholar 

  115. 115

    Mehta, S. R. et al. Effect of glucose-insulin-potassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction: the CREATE-ECLA randomized controlled trial. JAMA 293, 437–446 (2005).

    PubMed  Google Scholar 

  116. 116

    Cheung, N. W., Wong, V. W. & McLean, M. The hyperglycemia: intensive insulin infusion in infarction (HI-5) study: a randomized controlled trial of insulin infusion therapy for myocardial infarction. Diabetes Care 29, 765–770 (2006).

    CAS  PubMed  Google Scholar 

  117. 117

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

    CAS  PubMed  Google Scholar 

  118. 118

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

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    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).

    CAS  PubMed  Google Scholar 

  120. 120

    Kruyt, N. D. et al. High mean fasting glucose levels independently predict poor outcome and delayed cerebral ischemia after aneurysmal subarachnoid haemorrhage. J. Neurol. Neurosurg. Psychiatry 79, 1382–1385 (2008).

    CAS  PubMed  Google Scholar 

  121. 121

    Kruyt, N. D. et al. Hyperglycemia and clinical outcome in aneurysmal subarachnoid hemorrhage: a meta-analysis. Stroke 40, e424–e430 (2009).

    PubMed  Google Scholar 

  122. 122

    Ringleb, P. A. et al. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc. Dis. 25, 457–507 (2008).

    Google Scholar 

  123. 123

    Adams, H. P. Jr et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Circulation 115, e478–e534 (2007).

    PubMed  PubMed Central  Google Scholar 

  124. 124

    Casaubon, L. K. et al. Variability in physician care practices for glucose treatment in stroke patients. Can. J. Neurol. Sci. 35, 573–582 (2008).

    PubMed  Google Scholar 

  125. 125

    Hirsch, I. B. Sliding scale insulin—time to stop sliding. JAMA 301, 213–214 (2009).

    CAS  PubMed  Google Scholar 

  126. 126

    Queale, W. S., Seidler, A. J. & Brancati, F. L. Glycemic control and sliding scale insulin use in medical inpatients with diabetes mellitus. Arch. Intern. Med. 157, 545–552 (1997).

    CAS  PubMed  Google Scholar 

  127. 127

    Umpierrez, G. E., Palacio, A. & Smiley, D. Sliding scale insulin use: myth or insanity? Am. J. Med. 120, 563–567 (2007).

    PubMed  Google Scholar 

  128. 128

    Hassan, E. Hyperglycemia management in the hospital setting. Am. J. Health Syst. Pharm. 64 (Suppl. 6), S9–S14 (2007).

    PubMed  Google Scholar 

  129. 129

    Inzucchi, S. E. Clinical practice. Management of hyperglycemia in the hospital setting. N. Engl. J. Med. 355, 1903–1911 (2006).

    CAS  PubMed  Google Scholar 

  130. 130

    Weng, J. et al. Effect of intensive insulin therapy on beta-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-group trial. Lancet 371, 1753–1760 (2008).

    CAS  PubMed  Google Scholar 

  131. 131

    Kruyt, N. D. et al. Subjecting acute ischemic stroke patients to continuous tube feeding and an intensive computerized protocol establishes tight glycemic control. Neurocrit. Care doi:10.1007/s12028-009-9230-z.

    PubMed  Google Scholar 

  132. 132

    Morris, A. et al. An electronic protocol for translation of research results to clinical practice: a preliminary report. J. Diabetes Sci. Technol. 2, 802–808 (2008).

    PubMed  PubMed Central  Google Scholar 

  133. 133

    Rood, E., Bosman, R. J., van der Spoel, J. I., Taylor, P. & Zandstra, D. F. Use of a computerized guideline for glucose regulation in the intensive care unit improved both guideline adherence and glucose regulation. J. Am. Med. Inform. Assoc. 12, 172–180 (2005).

    PubMed  PubMed Central  Google Scholar 

  134. 134

    Vogelzang, M. et al. Computer-assisted glucose control in critically ill patients. Intensive Care Med. 34, 1421–1427 (2008).

    PubMed  PubMed Central  Google Scholar 

  135. 135

    Vriesendorp, T. M. et al. Efficacy and safety of two 5-day insulin dosing regimens to achieve strict glycaemic control in patients with acute ischemic stroke. J. Neurol. Neurosurg. Psychiatry 80, 1040–1043 (2009).

    CAS  PubMed  Google Scholar 

  136. 136

    Hemmen, T. M., Meyer, B. C., McClean, T. L. & Lyden, P. D. Identification of nonischemic stroke mimics among 411 code strokes at the University of California, San Diego, Stroke Center. J. Stroke Cerebrovasc. Dis. 17, 23–25 (2008).

    PubMed  Google Scholar 

  137. 137

    de Courten-Meyers, G. M., Kleinholz, M., Wagner, K. R. & Myers, R. E. Normoglycemia (not hypoglycemia) optimizes outcome from middle cerebral artery occlusion. J. Cereb. Blood Flow Metab. 14, 227–236 (1994).

    Google Scholar 

  138. 138

    Zhu, C. Z. & Auer, R. N. Optimal blood glucose levels while using insulin to minimize the size of infarction in focal cerebral ischemia. J. Neurosurg. 101, 664–668 (2004).

    CAS  PubMed  Google Scholar 

  139. 139

    Walters, M. R., Weir, C. J. & Lees, K. R. 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 (2006).

    CAS  PubMed  Google Scholar 

  140. 140

    Gentile, N. T., Seftchick, M. W., Huynh, T., Kruus, L. K. & Gaughan, J. Decreased mortality by normalizing blood glucose after acute ischemic stroke. Acad. Emerg. Med. 13, 174–180 (2006).

    PubMed  Google Scholar 

  141. 141

    Johnston, K. C., Hall, C. E., Kissela, B. M., Bleck, T. P. & Conaway, M. R. Glucose regulation in acute stroke patients (GRASP) Trial. A randomized pilot trial. Stroke 40, 3804–3809 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Kreisel, S. H. et al. Pragmatic management of hyperglycaemia in acute ischaemic stroke: safety and feasibility of intensive intravenous insulin treatment. Cerebrovasc. Dis. 27, 167–175 (2008).

    PubMed  Google Scholar 

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Acknowledgements

The authors wish to thank the following authors for providing additional data on their studies: N. Gentile, K. Johnston, N. MacDougall, Y. Samson and M. Walters. The research of N. D. K. and G. J. B. is supported by a grant from the Academic Medical Center, University of Amsterdam and the University Medical Center Utrecht, The Netherlands. The research of G. J. B. is also supported by grant 907-00-140 from the Netherlands Organization of Scientific Research (ZonMw).

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Correspondence to Nyika D. Kruyt.

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Kruyt, N., Biessels, G., DeVries, J. et al. Hyperglycemia in acute ischemic stroke: pathophysiology and clinical management. Nat Rev Neurol 6, 145–155 (2010). https://doi.org/10.1038/nrneurol.2009.231

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