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Hyperglycemia in Acute Stroke

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 Hyperglycemia in Acute Stroke
Perttu J. Lindsberg and Risto O. Roine

Stroke. 2004;35:363-364
doi: 10.1161/01.STR.0000115297.92132.84
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 Advances in Stroke 2003
Hyperglycemia in Acute Stroke
Perttu J. Lindsberg, MD, PhD; Risto O. Roine, MD, PhD
E
levated blood glucose is common in the early phase of
stroke. The prevalence of hyperglycemia, defined as blood
glucose level ⬎6.0 mmol/L (108 mg/dL), has been ob-
served in two thirds of all ischemic stroke subtypes on admission
and in at least 50% in each subtype including lacunar strokes.1
Extensive experimental evidence in stroke models supports that
hyperglycemia has adverse effects on tissue outcome, and an
association between blood glucose and functional outcome has been
found in an increasing number of clinical studies. Although no
interventional stroke studies have addressed the acute reversal of
hyperglycemia, active lowering of elevated blood glucose by
rapidly acting insulin is recommended in most published guidelines,
even in nondiabetic patients (European Stroke Initiative [EUSI]
guidelines ⬎10 mmol/L, American Stroke Association [ASA]
guidelines ⬎300 mg/dL).2
Causes of Acute Hyperglycemia
Although up to one third of acute stroke patients have either
diagnosed or newly diagnosed diabetes, probably a major propor-
tion of patients have stress hyperglycemia mediated partly by the
release of cortisol and norepinephrine. It is also a manifestation of
relative insulin deficiency, which is associated with increased
lipolysis. Even in nondiabetic patients, stress hyperglycemia may be
a marker of deficient glucose regulation in individuals with insulin
resistance and developing diabetes mellitus.
How Elevated Glucose Injures the
Ischemic Brain
By provoking anaerobic metabolism, lactic acidosis, and free
radical production, hyperglycemia may exert direct mem-
brane lipid peroxidation and cell lysis in metabolically
challenged tissue. Moderately and severely increased blood
glucose has been found to further the metabolic state and
mitochondrial function in the area of ischemic penumbra.3
Insulin resistance is a known risk factor for the onset of stroke
acting through a number of intermediate vascular disease risk
factors (ie, thrombophilia, endothelial dysfunction, and in-
flammation).4 The evolution of an acute infarction may be
expedited by the very same vascular factors, explaining why
ischemia time seems to fly faster with patients with diabetes
The opinions expressed in this editorial are not necessarily those of the
editors or of the American Stroke Association.
Received November 25, 2003; accepted December 3, 2003.
From the Department of Neurology (P.J.L., R.O.R), Helsinki University
Central Hospital; and Neurosciences Programme (P.J.L.), Biomedicum Helsinki,
Helsinki, Finland.
Correspondence to P.J. Lindsberg, Neurosciences Programme, Biomedicum
Helsinki, PO Box 700, FIN 00029 HUS, Helsinki, Finland. E-mail
perttu.lindsberg@hus.fi
(Stroke. 2004;35:363-364.)
© 2004 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
DOI: 10.1161/01.STR.0000115297.92132.84
363
Downloaded from http://stroke.ahajournals.org/ by guest on June 9, 2013
or grave hyperglycemia. Relative insulin deficiency liberates
circulating free fatty acids, which, together with hyperglyce-
mia, reportedly diminishes vascular reactivity.5,6 Further-
more, lowering glucose with insulin has been reported to
reduce ischemic brain damage in an animal model.7
The evolution of an infarction is accompanied by glutamate
release mediating repeated waves of spreading depression (SD),
another mechanism believed to propagate the necrosis of the
penumbral tissue. Although hyperglycemia alone did not trigger
early-response genes in the cortical tissue of rats, in conjunction
with induced SD, the expression of c-fos and cyclooxygenase-2
were substantially increased.8 This suggests that elevated glucose
may trigger untoward intracellular biochemical cascades also by
altering early gene expression in metabolically challenged neurons.
The blood-brain barrier is well known to be vulnerable to
hyperglycemia, presumably through the liberation of lactic acid and
free radicals. The recent experimental study by Song et al in a rat
model of collagenase-induced intracerebral hemorrhage (ICH) adds
that hyperglycemia aggravates edema formation in a zone surround-
ing cerebral hemorrhages.9 The study also documented increased
cell death measured by the TUNEL staining. It is conceivable that
hemorrhages are surrounded by a zone of similarly challenged
tissue as infarctions are, where the availability of glucose influences
the metabolic state.
Clinical Correlation of Hyperglycemia and
Infarct Progression
Although experimental studies have clarified several mechanisms
by which hyperglycemia influences the destiny of ischemic brain
tissue, studies bridging the gap between clinical stroke and experi-
mental models have been scarce. Recent advances in MRI tech-
niques have permitted correlation of loss of penumbral tissue with
elevated blood glucose, which was linked to increased brain lactate
production.10 Using a subcutaneous glucose sensor for continuous
monitoring up to 72 hours, the same group could reproduce the
finding that the infarcts expanded more in hyperglycemic patients,
and that hyperglycemia was independently associated with the
infarct volume change.11 This suggests that elevated glucose not
only reflects the initial volume of infarcted tissue in the acute stage
but is one of the true determinants of early infarct progression in
man.
Prognosis and Hyperglycemia
Already ample literature has demonstrated that hyperglycemia on
admission is associated with worsened clinical outcome, as re-
viewed in a systematic overview of 33 studies.12 Glycemic control
may be indicated also in nondiabetic patients, in which stress
hyperglycemia was associated with a 3-fold risk of fatal 30-day
outcome and 1.4-fold risk of poor functional outcome, as compared
with normoglycemic patients. Good glycemic control seems war-
ranted also in hemorrhagic stroke,9 although more clinical informa-
tion is needed in this area. At least 2 clinical trials have recently been
 364 Stroke February 2004
Summary of Evidence Supporting a Detrimental Role for
Elevated Glucose in Stroke
1. Experimental ischemic damage is worsened by hyperglycemia.
2. Experimental ischemic damage is reduced by glucose reduction.
3. Early hyperglycemia is associated with clinical infarct progression in brain
imaging.
4. Early hyperglycemia is associated with hemorrhagic conversion in stroke.
5. Early hyperglycemia is associated with poor clinical outcome.
6. Early hyperglycemia may reduce the benefit from recanalization.
7. Immediate insulin therapy reported beneficial in acute myocardial
infarction and surgical critical illness.
initiated to examine the efficacy of early insulin therapy in acute
stroke.11,13 Still, there is no evidence to prove that reversal of
hyperglycemia improves the prognosis, as it has been demonstrated
to do in acute myocardial infarction and in critically ill postsurgical
patients.14,15
Hyperglycemia and Thrombolytic Therapy of
Acute Ischemic Stroke
In several thrombolysis trials, hyperglycemia has been found to be
associated with hemorrhagic events16 and was reconfirmed recent-
ly17 as well as in a re-analysis of the NINDS rt-PA trial.18 In the
latter study, an increase of admission glucose level was indepen-
dently associated with decreased odds for neurologic improvement
(odds ratio [OR]⫽0.76 per 100-mg/dL increase in admission
glucose) and the OR for symptomatic ICH was 1.75 per 100-mg/dL
increase in admission glucose (95% CI 1.11 to 2.78, P⫽0.02). The
relationship was weaker after excluding patients with ICH, suggest-
ing that admission hyperglycemia may exert its hazards in part
through hemorrhagic events. However, another recent study by
Alvarez-Sabin et al found admission glucose ⬎140 mg/dL (OR 8.4,
CI 1.8 to 40.0) to be the sole independent predictor of poor
functional outcome at 3 months in patients with recanalization
within 6 hours, even after excluding the patients with symptomatic
ICH.19 The same was not true for the patients who did not
recanalize, which leads to speculation that hyperglycemia might
partially preclude the beneficial effect of rtPA and early reperfusion.
Conclusions
This recent evidence supports that acutely elevated, predominantly
stress-related hyperglycemia is associated with poor outcomes such
as dependent state or intracerebral hemorrhage. Through several
different biochemical mechanisms, elevated glucose in the setting of
cerebrovascular insults probably accelerates the course of ischemic
injury, also in the boundary regions with milder perfusion deficit.
Although admission hyperglycemia has been clearly demonstrated
to be a risk factor for symptomatic hemorrhage and worsened
outcome after thrombolytic therapy, there is perhaps not enough
evidence to withhold thrombolysis from hyperglycemic patients
within the 3-hour time window. However, restoration of normogly-
cemia as soon as possible should be encouraged, although conclu-
sive evidence of decreased risk with this approach is lacking.
Especially the nondiabetic patients may be at risk of further brain
damage if hyperglycemia prevails. The recent evidence summa-
rized above and in the Table urges corroboration in randomized
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controlled trials of the efficacy of immediate glycemic control, and
determination of where the level of target glucose concentrations of
the relatively different current target values in the published guide-
lines (EUSI: ⬍10 mmol/L, ASA: ⬍300 mg/dL⫽16.63 mmol/L)2
should be set. In the interim, we should fare well with adhering to
good general stroke management, including control of blood glu-
cose, normalization of body temperature, fluid balance and hemo-
dynamics, or we may otherwise risk the favorable outcome even in
the patient with early recanalization.
References
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KEY WORDS: Advances in Stroke 䡲 hyperglycemia 䡲 stroke, acute