Hyperglycemia in Acute StrokeElevated 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 observed 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 proportion 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 membrane 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 inflammation).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 or grave hyperglycemia. Relative insulin deficiency liberates circulating free fatty acids, which, together with hyperglycemia, reportedly diminishes vascular reactivity.5,6 Furthermore, 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 surrounding 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 experimental models have been scarce. Recent advances in MRI techniques 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.

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Prognosis and Hyperglycemia

Already ample literature has demonstrated that hyperglycemia on admission is associated with worsened clinical outcome, as reviewed 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 warranted also in hemorrhagic stroke,9 although more clinical information is needed in this area. At least 2 clinical trials have recently been 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 recently17 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 independently 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, suggesting 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.

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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 normoglycemia as soon as possible should be encouraged, although conclusive 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 summarized above and in the Table urges corroboration in randomized 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 guidelines (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 glucose, normalization of body temperature, fluid balance and hemodynamics, or we may otherwise risk the favorable outcome even in the patient with early recanalization.

Preexisting hyperglycemia worsens the clinical outcome of acute stroke. Nondiabetic ischemic stroke patients with hyperglycemia have a 3-fold higher 30-day mortality rate than do patients without hyperglycemia. In diabetic patients with ischemic stroke, the 30-day mortality rate is 2-fold higher.[1]

With regard to hypoglycemia, the condition can mimic acute stroke or symptoms of transient ischemic attack (TIA).[2, 3, 4]

Essential update: ACP guidelines raise glucose target for ICU patients with hyperglycemia

In their new guidelines for the treatment of hyperglycemia in the intensive care unit, the American College of Physicians (ACP) revised the target blood glucose level to 140-200 mg/dL from the previous goal of 80-110 mg/dL. The change is based on evidence that in ICU patients, not only does treatment using intensive insulin therapy and a normoglycemic target appear to lack a short-term mortality benefit, but a target below 140 mg/dL can actually be harmful.[5, 6]

Signs and symptoms

Hyperglycemia in stroke

Patients may come to the attention of clinicians because of preexisting diabetes mellitus

Diabetes may also be seen with other risk factors for stroke, such as hypertension and hypercholesterolemia

High glycemic levels may also be seen in the setting of an acute stroke without a history of diabetes, presumably due to a sympathetic response to the infarct

Retinopathy, neuropathy, and peripheral vascular disease may be found in patients with long-standing diabetes

Hypoglycemia in strokelike occurrences

In the literature, signs of an acute stroke, such as hemiplegia, aphasia, and cortical blindness, have been reported with hypoglycemia.

In individuals presenting with low glycemic levels and strokelike symptoms, diabetes mellitus may have been previously diagnosed, and recent changes in the doses of hypoglycemic agents and insulin may have been instituted. In particular, aggressively tight glucose control, either patient driven or clinician directed, may give rise to chronic or recurrent episodes of hypoglycemia. However, if factitious hypoglycemia is suspected, such behavior may have manifested earlier as similar episodes or other factitious behaviors.

Symptoms caused by hypoglycemia can occur suddenly and fluctuate, suggesting a vascular etiology.

Diagnosis

Laboratory studies

In the setting of acute stroke, obtaining the following is routine practice:

Serum glucose levels Complete blood count (CBC)

Electrolyte values

Prothrombin time (PT)

Activated partial thromboplastin time (aPTT)

Imaging studies

Because hyperglycemia may accelerate the ischemic process in stroke, it is possible that characteristic features of acute stroke will appear on computed tomography (CT) or magnetic resonance imaging (MRI) scans sooner than they would in patients without hyperglycemia.

If strokelike symptoms are a result of hypoglycemia, a CT scan of the head may initially be normal. Later, in patients with severe hypoglycemia that is prolonged and complicated by anoxic brain injury and coma, CT scanning of the brain may show cortical atrophy (reflecting laminar necrosis).[7] If the hypoglycemia is transitory and the clinical status of the patient returns to normal, follow-up CT-scan findings may again be normal.

Management

Hyperglycemia

In terms of primary prevention, treatment of diabetes appears to reduce the incidence of atherosclerotic complications.

Intensive approaches to multiple risk factors in stroke have been suggested, including the following:

Reduction of low-density lipoprotein (LDL) - To below 100 mg/dL in diabetic patients Increase of high-density lipoprotein (HDL) - With fibrates if tolerated, an effect that

is especially beneficial in patients with insulin resistance [8]

Tight glucose control

Hypertensive management

Patients with acute stroke and hyperglycemia are often kept NPO (nothing by mouth), because of the complicating effects of feeding on the blood glucose level.

Typically, hyperglycemia in the setting of acute stroke is treated with subcutaneous insulin on a sliding scale. Refractory hyperglycemia may require the use of intravenous (IV) insulin; however, IV insulin increases the risk of hypoglycemia. The safety and efficacy of IV insulin in the treatment of hyperglycemia in patients with acute stroke are being determined by ongoing/planned clinical trials.

Bellolio et al analyzed the results of 7 trials involving 1296 participants (639 in the intervention group and 657 in the control group) and concluded that the administration of intravenous insulin to maintain serum glucose levels in the first hours after an acute ischemic stroke did not provide any benefit in terms of function, death, or improvement in final outcome.[9]

Ntaios et al designed an intravenous insulin protocol that controls acute poststroke hyperglycemia but frequently leads to hypokalemia. Further study is therefore required.[10]

Transition from acute therapy to the initiation of chronic therapy in hyperglycemia depends on the condition’s persistence or whether evidence of diabetes exists.

Hypoglycemia

When hypoglycemia is discovered, the glucose level must be brought expeditiously to a normal level. IV fluids, such as dextrose 25% in water (D25W) or dextrose 50% in water (D50W),[11] may be necessary. Treatment of hypoglycemia beyond the initial therapy depends on the condition’s underlying cause.

Neurologists typically do not treat patients with glucose-containing fluids without coadministration of thiamine in order to avoid the possibility of precipitating acute Wernicke encephalopathy or chronic Korsakoff psychosis.