(Stroke. 2004;35:2498.)
© 2004 American Heart Association, Inc.
Original Contributions |
Editorial Comment—Prime Time for Proactive Blood Glucose Control?
There is overwhelming evidence that hyperglycemia is detrimental in cerebral ischemia, not only from experimental research but also from an increasing number of clinical studies.1,2 Elevated admission glucose levels are associated with increased mortality and worse functional outcome from ischemic stroke.3,4 In human magnetic resonance imaging studies, tissue at risk will progress to infarction in the presence of high blood glucose level, and diffusion-weighted imaging lesion will grow even in recanalized patients receiving thrombolytic therapy.5–7 The mechanisms of hyperglycemic cellular injury have been largely clarified.8 Although experimental ischemic damage is made worse by hyperglycemia and reduced by lowering the blood glucose level, the therapeutic effect of rapidly acting insulin still remains to be proven in clinical trials.8
This article complements the original observation published last year by the same group: the deleterious effect of hyperglycemia depends on reperfusion in patients receiving recombinant tissue plasminogen activator (rtPA) treatment.9 Moderately elevated admission blood glucose (>140 mg/dL) emerged as the only independent predictor of poor outcome in patients recanalized by rtPA when controlled for stroke severity.
Also in a re-analysis of the National Institute for Neurological Disorders (NINDS) rtPA Trial, increased admission blood glucose level was independently associated with decreased odds for neurological improvement and the risk of symptomatic intracerebal hemorrhage was increased by 75% per each 100 mg/dL of blood glucose.3
In accordance with these studies, the data from Helsinki showed an increased risk of hemorrhagic change by 42% per each mmol/L of admission blood glucose in a logistic regression model.10
This year, Leigh et al found that in patients recanalized by rtPA, blood glucose was higher in those who deteriorated, compared with those who improved, and moderately elevated blood glucose was more common in those with poor outcome (OR, 5.67; P=0.009). Of recanalized patients with elevated blood glucose and a poor outcome, the majority (55%) had diabetes as compared with those with good outcome (42%).11 From their earlier work, Alvarez-Sabin et al concluded that admission hyperglycemia is associated with a lesser degree of neurological improvement, greater infarct size, and worse outcome after rtPA-induced recanalization.9
One limitation of the current study is the case series design with no randomization to intensive glucose lowering therapy. Stroke severity as well as timing of recanalization were unrelated to admission blood glucose levels, emphasizing that both the level blood glucose and stroke severity, as measured by National Institutes of Health Stroke Scale (NIHSS) score, were independent predictors of poor outcome at 3 months. However, hyperglycemic patients were two times more likely to have diabetes (50%) than normoglycemic patients (25%). Although there was no difference in the proportion of diabetics in patients with good or poor outcome, it is impossible to completely exclude the possibility that diabetes with associated angiopathic end-organ manifestations would have partially explained the worse outcome in hyperglycemic patients with early recanalization.
The key result from this study is that even a moderate degree of admission hyperglycemia predicts poor outcome in patients recanalized by 6 hours after onset of stroke, and the blood glucose level has an inverse correlation with the degree of improvement in the NIHSS score at 24 hours only in patients recanalized within the first 3 hours, as demonstrated by transcranial Doppler ultrasound.
What are the clinical implications? Significantly decreased mortality by aggressive blood glucose lowering has already been proven in non-neurological intensive care, and has already been widely adopted.12 High admission blood glucose is certainly a risk factor for poor outcome in ischemic stroke patients receiving rtPA. Several questions remain unanswered, however. Does the risk disappear if blood glucose is rapidly lowered, or does it remain high because of a pre-existing metabolic disturbance at the cellular level? Should untreated hyperglycemia, with or without diabetes, be a relative contraindication to rtPA?
Finally, rapidly accumulating evidence inevitably casts some doubts on current guidelines recommending active treatment of only extreme degrees of hyperglycemia (European Stroke Initiative, >10 mmol/L; American Stroke Association, >300 mg/dL [16.63 mmol/L]).13 The relationship between admission hyperglycemia and worse outcome is supported by substantial evidence, both in diabetic and nondiabetic stroke patients.14,15 Although randomized therapeutic trials are still awaited,16 we should ask whether it is time for a more proactive blood glucose control.
 |
References |
|---|
 Top References |
|---|
1. Pulsinelli WA, Waldman S, Rawlinson D, Plum F. Moderate hyperglycemia augments ischemic brain damage: a neuropathologic study in rats. Neurology. 1982; 32: 1239–1246.
2. Dietrich WD, Alonso O, Busto R. Moderate hyperglycemia worsens acute blood-barrier injury after forebrain ischemia in rats. Stroke. 1993; 24: 111–116.
3. Bruno A, Levine SR, Frankel MR, Brott TG, Lin Y, Tilley BC, Lyden PD, Broderick JP, Kwiatkowski TG, Fineberg SE, and the NINDS rt-PA Stroke Study Group. Admission glucose level and clinical outcomes in the NINDS rt-PA Stroke Trial. Neurology. 2002; 59: 669–674.
4. Demchuk AM, Morgenstern LB, Krieger DW, Chi TL, Hu W, Wein TH, Hardy RJ, Grotta JC, Buchan AM. Serum glucose and diabetes predict tissue plasminogen activator-related intracerebral hemorrhage in acute ischemic stroke. Stroke. 1999; 30: 34–39.
5. Parsons MW, Barber PA, Chalk J, Darby DG, Rose S, Desmond PM, Gerraty RP, Tress BM, Wright PM, Donnan GA, Davis SM. Diffusion- and perfusion-weighted MRI response to thrombolysis in stroke. Ann Neurol. 2002; 51: 28–37.[CrossRef][Medline] [Order article via Infotrieve]
6. Parsons MW, Barber PA, Desmond PM, Baird TA, Darby DG, Byrnes G, Tress BM, Davis SM. Acute hyperglycemia adversely affects stroke outcome: a magnetic resonance imaging and spectroscopy study. Ann Neurol. 2002; 52: 20–28.[CrossRef][Medline] [Order article via Infotrieve]
7. Els T, Klisch J, Orszagh M, Hetzel A, Schulte-Monting J, Schumacher M, Lucking CH. Hyperglycemia in patients with focal cerebral ischemia after intravenous thrombolysis: influence on clinical outcome and infarct size. Cerebrovasc Dis. 2002; 13: 89–94.[CrossRef][Medline] [Order article via Infotrieve]
8. Lindsberg PJ, Roine RO. Hyperglycemia in acute stroke. Stroke. 2004; 35: 363–364.
9. Alvarez-Sabin J, Molina CA, Montaner J, Arenillas JF, Huertas R, Ribo M, Codina A, Quintana M. Effects of admission hyperglycemia on stroke outcome in reperfused tissue plasminogen activator-treated patients. Stroke. 2003; 34: 1235–1241.
10. Lindsberg PJ, Soinne L, Roine RO, Salonen O, Tatlisumak T, Kallela M, Häppölä O, Tiainen M, Haapaniemi E, Kuisma M, Kaste M. Community-based thrombolytic therapy of acute ischemic stroke in Helsinki. Stroke. 2003; 34: 1443–1449.
11. Leigh R, Zaidat OO, Suri MF, Lynch G, Sundararajan S, Sunshine JL, Tarr R, Selman W, Landis DMD, Suarez JI. Predictors of hyperacute clinical worsening in ischemic stroke patients receiving thrombolytic therapy. Stroke. 2004; 35: 1903–1907.
12. Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001; 345: 1359–1367.
13. Klijn CJM, Hankey GJ. Management of acute ischaemic stroke: new guidelines from the American Stroke Association and European Stroke Initiative. Lancet Neurol. 2003; 2: 698–701.[CrossRef][Medline] [Order article via Infotrieve]
14. Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC. Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke. 2001; 32: 2426–2432.
15. Woo J, Lam CWK, Kay R, Wong AHY, Teoh R, Nicholls MG. The influence of hyperglycemia and diabetes mellitus on immediate and 3-month morbidity and mortality after acute stroke. Arch Neurol. 1990; 47: 1174–1177.
16. Scott JF, Robinson GM, O’Connell JE, Alberti KG, Gray CS. Glucose potassium insulin infusions in the treatment of acute stroke patients with mild to moderate hyperglycemia: the Glucose Insulin in Stroke Trial (GIST). Stroke. 1999; 30: 793–799.
Related Article:
Stroke 2004 35: 2493-2498.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||