The Role of Hyperglycemia in Acute

Stroke
Nadya Kagansky, MD; Shmuel Levy, MD; Hilla Knobler, MD
Author Affiliations Article Information
Arch Neurol. 2001;58(8):1209-1212. doi:10.1001/archneur.58.8.1209

Abstract
Background Ischemic stroke is a leading cause of death and long-term disability,
and hyperglycemia is believed to aggravate cerebral ischemia.

Objectives To review animal and human studies on the relationship between

hyperglycemia and brain ischemia that elucidate some of the mechanisms for the
deleterious effect of hyperglycemia. To discuss present and future clinical
recommendations for glucose control.

Methods Computerized data sources and published indexes and articles from 1976
through 2000 were searched for human studies that evaluated the association
between stroke and hyperglycemia, and studies focused on experimental models of
hyperglycemic animals with focal and global brain ischemia.

Results Most human studies have shown that in acute stroke, admission
hyperglycemia in patients with or without diabetes is associated with a worse
clinical outcome than in patients without hyperglycemia. This association is more
consistent in the nonlacunar type of stroke. Animal studies support these findings
by showing both in global and in focal postischemic models that hyperglycemia
exaggerates the following damaging processes: intracellular acidosis, accumulation
of extracellular glutamate, brain edema formation, blood-brain barrier disruption,
and tendency for hemorrhagic transformation. Insulin treatment of hyperglycemic
animals was found to have a beneficial effect in focal and global brain ischemia,
which may be mediated by the glucose-reduction effect or by a direct
neuroprotection.

Conclusions Most studies show the deleterious effect of early hyperglycemia,

especially in patients with nonlacunar focal or global ischemia. Clinical trials of
intensive insulin treatment are needed. Meanwhile simple measures to avoid
excessive hyperglycemia are recommended.

DIABETES MELLITUS is associated with increased risk of stroke and coronary heart
disease and remains an independent risk factor for both after adjusting for other
known risk factors.1- 3 Many studies have shown that patients with diabetes have a
less favorable course than those without following myocardial infarction
(MI).4,5 Furthermore, stress hyperglycemia in patients without diabetes was found
to be associated with increased in-hospital mortality after MI.6 The Diabetes and
Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) Study has recently
provided compelling evidence that achieving euglycemia during acute MI resulted in
a significant reduction of long-term mortality.7 These results have revolutionized
the standard care of patients with diabetes and acute MI.

Stroke, the most prevalent disabling disorder in western countries,8 and MI have
many similarities. Hyperglycemia has also been associated with worse outcome of
ischemic stroke in many human and animal studies. However the associations
between diabetes, hyperglycemia, and hyperglycemic control and stroke outcome
are still controversial issues. In addition, there are no established guidelines based
on controlled studies that define optimal glucose control during acute brain
ischemia. These issues will be discussed in this review.

Hyperglycemia vs diabetes
Several studies9- 12 showed that patients with diabetes who develop stroke have a
less favorable outcome than those without; however, a few other studies did not
confirm these findings.13,14Interestingly, most studies, including large trials, have
shown that admission hyperglycemia is a risk factor for poor outcome following
focal and global cerebral ischemia.15- 19 Weir et al17 performed a long-term follow-up
of 750 nondiabetic patients with acute stroke and, after adjusting for age, sex, type
of stroke, smoking, and blood pressure, admission hyperglycemia remained a
significant independent predictor of long-term higher mortality and morbidity. Data
from a multicenter trial (ORG 10172 in acute Stroke Treatment [TOAST]) that
included 1259 patients found that in patients with nonlacunar stroke, higher blood
glucose levels were associated with worse outcome at 3 months.18 Adjustments for
age, stroke severity on admission, other vascular risk factors, and diabetes mellitus
did not alter this result. One possibility is that these studies may have included
patients with undiagnosed diabetes, and some smaller studies support this
possibility by performing additional laboratory tests for glycosylated hemoglobin
showing that prestroke hyperglycemia was a predictor of worse outcome.9,10 Other
studies, which did not confirm these findings, suggested that admission
hyperglycemia is a marker of extensive brain damage leading to a greater increase
in stress hormones resulting in hyperglycemia.13,19,20 However, van Kooten et
al,21 who also found a significant association between hyperglycemia on admission
and stroke outcome, did not find a correlation between catecholamine and glucose
levels, implying that increased stress was not responsible for the hyperglycemia. In
conclusion, although the association between admission hyperglycemia and worse
outcome in acute stroke has been shown in most studies, it is still unclear whether it
is related to diabetes (diagnosed or undiagnosed previously) or to a stress reaction.

A major difficulty in investigating the role of diabetes and hyperglycemia in acute

stroke is the heterogeneous nature of diabetes/hyperglycemia in regard to the site
of ischemia, the degree of vasculopathy, and the state of reperfusion. For example,
in the TOAST trial, higher admission blood glucose levels were associated with
worse outcome in nonlacunar strokes.18 In lacunar strokes, the relationship between
hyperglycemia and outcome was inconsistent and differed between those who did
and did not receive a low-molecular-weight heparinoid. These observations may be
related to the findings in animal models of focal ischemia: in models with
reperfusion, hyperglycemia increased infarct size, while in animals without
reperfusion, hyperglycemia seemed to have no adverse effect and might even have
been beneficial.22- 24These findings may be owing to less blood reaching the
territory of the end arteriesinsufficient blood to cause lactate accumulation and
acidosis.22,23 Under these conditions hyperglycemia might even be beneficial in
maintaining energy metabolism.24End-artery infarctions resemble lacunar strokes,
which are very common in patients with diabetes.25 Therefore, studies aimed at
evaluating the effect of hyperglycemia on stroke outcome but that do not separate
lacunar from nonlacunar strokes may be misleading.

The correlation between hyperglycemia and occurrence of hemorrhagic strokes or

hemorrhagic transformations of ischemic strokes is also controversial. Some studies
point toward lower frequency of intracerebral hemorrhages in patients with
diabetes. In the Copenhagen Stroke Study,15 intracerebral hemorrhages were 6
times less frequent in patients with diabetes than in those without. Other smaller
studies found that hyperglycemia and diabetes may be associated with an increased
incidence of hemorrhagic transformation of ischemic infarcts.26,27 Hyperglycemia
was found to be the only independent predictor of intracerebral hemorrhage in a
study of 138 patients with ischemic stroke treated with tissue plasminogen
activator.28 Serum glucose levels higher than 200 mg/dL (11.1 mmol/L) were
associated with a 25% symptomatic hemorrhage rate.28

Animal models
Animal studies have the advantage of controlling parameters such as timing of
hyperglycemia, site of ischemia, and state of perfusion, and they provide strong
evidence that acute hyperglycemia has a detrimental effect on ischemic brain
damage.29- 33 Mayer and Yamaguchi29 were the first to show that acute
hyperglycemia in monkeys accentuated hypoxic-ischemic brain damage. In their
study, the hyperglycemic animals suffered greater neurological deficit with
extensive brain damage and widespread necrosis involving the cerebral cortex,
basal ganglia, brainstem, and cerebellum than nonhyperglycemic
animals.29 Pulsinelli et al30 described severe neuropathological changes with brain
edema in ischemic brains of hyperglycemic rats. In another study of rats with
experimental global brain ischemia, acute hyperglycemia was associated with
extensive lesions in the neocortex and striatum compared with only mild damage in
normoglycemic rats.31 Hyperglycemic rats had a marked reduction in neuronal
counts compared with the normoglycemic animals, with prominent changes in the
vascular endothelium and perivascular reactive microglia. These data suggest that
the detrimental influence of hyperglycemia is initially mediated by an action on the
vascular endothelium leading to widespread foci of infarction and neuronal loss.31 In
animals with focal ischemia, the results are less consistent; however, hyperglycemia
has been shown to increase brain damage in models with temporary ischemia and
reperfusion.32,33

Animal models elucidated some of the mechanisms of the deleterious effects of

hyperglycemia on the brain. The most consistent finding in animal studies is the
correlation between hyperglycemia and acidosis.34- 36 During an ischemic event,
local increase in anaerobic glycolysis leads to intracellular acidosis occurring shortly
after the ischemic insult. Animals with acute hyperglycemia developed the most
acidic mean cortical pH as well as higher cerebral lactate concentration, leading to
an increase in neuronal and glial damage.34- 36 Enhanced acidosis may exaggerate
ischemic damage by mechanisms such as increasing free-radical formation,
perturbing intracellular signal transduction, and activating endonucleases.35 A direct
effect of lactic acid accumulation has been proposed, based on studies in which
injection of lactic acid into the cerebral cortex led to histological changes
resembling ischemic infarction.37,38

The second mechanism that links hyperglycemia to increased brain damage is the
effect of hyperglycemia on excitatory amino acids. It has been established that
excitatory amino acids, notably glutamate, play a central role in neuronal death by
activation of postsynaptic glutamate receptors, particularly N-methyl-D-aspartate
(NMDA) receptors.39- 41 This activation leads to an excessive influx of calcium
through ion channels, mitochondrial injury, and eventual cell death. Recently, it was
shown in hyperglycemic rats that the rise in extracellular glutamate concentrations
following forebrain ischemia was more pronounced than in normoglycemic animals.
The difference was observed in the neocortical regions of the brain and correlated
with exaggerated cell damage.42

Hyperglycemia in animal models of brain ischemia was found to exaggerate edema

formation,30,43 blood-brain barrier injury,44and hemorrhagic transformation of the
infarct. In a model of middle cerebral artery occlusion, a 5-fold increase in
hemorrhagic infarct and a 25-fold increase in extensive hemorrhages were observed
in hyperglycemic cats compared with the normoglycemic animals.45

Treatment
The "ischemic penumbra" is the region surrounding a focal cerebral infarct showing
selective neuronal damage with loss of electrical activity while retaining some
metabolic viability.46 This area might be rescued by improving the metabolic milieu
and arresting the ischemic cascade.47 An accumulating body of evidence derived
from animal models shows that during acute focal and global ischemia, insulin
therapy reduces ischemic brain damage and may be neuroprotective.48- 55 In a
model of forebrain ischemia in rats, insulin not only reduced histological injury but
improved neurobehavioral outcome.49,50

It is still unclear whether this effect is due only to the effect of insulin on reducing
glucose levels or is a direct effect.48 In a global ischemic model, it was found that
insulin has an effect in reducing neuronal necrosis in the major brain regions
regardless of its effect on glucose levels.51 In addition, insulin, and to a lesser extent
insulinlike growth factor 1 (IGF-1), reduced ischemic damage when injected directly
into the brain ventricles.52 Therefore, it was suggested that in transient global
ischemia, insulin and IGF-1 have a direct neuroprotective effect on central nervous
system parenchyma. In contrast to global ischemia, in focal ischemia most of the
neuroprotective effects of insulin are due to its effect on glucose levels, and
administration of a glucose infusion concomitant with insulin abolished most of its
effect.53 In minimizing acute brain ischemia, insulin may also have a beneficial
synergistic effect when, for example, used concomitantly with dizocilpine, a
noncompetitive NMDA antagonist.54 A study comparing treatment of diabetic rats
during acute ischemic events with dizocilpine alone or with a combination of
dizocilpine and insulin found an additive neuroprotective effect.54

We do not yet have the results from controlled clinical trials evaluating the effect of
insulin in stroke. Recently, a randomized clinical controlled trial (The Glucose Insulin
in Stroke Trial [GIST]) was started.55 This study is designed to determine whether
glucose-potassium-insulin infusion and maintaining euglycemia in patients with
acute stroke and mild to moderate hyperglycemia can improve outcome.

Recommendations for glucose management in

hospitalized patients with stroke
Although results from controlled clinical trials assessing insulin therapy in patients
with stroke are still lacking, the data presented from animal experimental studies
and human observational studies advocate the need for avoiding early
hyperglycemia in patients with nonlacunar stroke and global ischemia. It is
therefore advisable to preclude administration of intravenous dextrose-containing
solutions during the first 24 hours of hospitalization. In accord with this suggestion,
the current American Heart Association guidelines state that during
cardiopulmonary resuscitation, drugs should be given in nonglucose-containing
solutions to avoid worsening of the neurological outcome.56 In addition,
glucocorticoids should be given only if clearly indicated and under close monitoring
to avoid hyperglycemia. When treating hyperglycemia with insulin, care should be
taken to ensure that hypoglycemia is prevented, as it can also cause brain
damage.57 Until further data are available, it is difficult to define the optimal glucose
concentrations. The GIST55 evaluated the safety of 24 hours of glucose-insulin
infusion with the aim of keeping glucose levels between 72 and 126 mg/dL (4 and 7
mmol/L). This study showed that lowering plasma glucose levels was safe without
significant risk of hypoglycemia or 4-week excess mortality. However, until further
results prove the effectivness of this approach, it cannot be regarded as standard
practice. A reasonable target in most cases is to lower blood glucose levels to
between 100 and 200 mg/dL (5.5 and 11 mmol/L).58 The decision whether to treat
the individual patient intensively with insulin, aiming at normalizition of blood
glucose levels, has also to take into account the clinical setting, ie, the ability of the
medical staff to provide frequent glucose monitoring.

Accepted for publication April 3, 2001.

Corresponding author and reprints: Hilla Knobler, MD, Metabolic Service, Kaplan
Medical Center, Rehovot, Israel, 76100 (e-mail: knobler@inter.net.il).
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