Hyperglycemia and Hypoglycemia in Stroke

Updated: Oct 12, 2015
  • Author: Pitchaiah Mandava, MD, PhD; Chief Editor: Helmi L Lutsep, MD  more...
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Overview

Practice Essentials

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, 5]

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). [6] 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 [7]
  • 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. [8]

Ntaios et al designed an intravenous insulin protocol that controls acute poststroke hyperglycemia but frequently leads to hypokalemia. Further study is therefore required. [9]

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), [10] 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.

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Overview

Preexisting hyperglycemia is found commonly in patients presenting with acute stroke, and is reported to be present in 20 to 50% of patients. In many trials of thrombolytic agents, hyperglycemia occurred in about 20-30% of subjects.

Although confounded by other factors, such as severity of the infarct, hyperglycemia in the face of acute stroke worsens clinical outcome. Nondiabetic hyperglycemic ischemic stroke patients have a 3-fold higher 30-day mortality and diabetic patients have a 2-fold 30-day mortality. [1] In several trials involving thrombolytic and anticoagulation therapy in patients with stroke, hyperglycemia appears to be an independent risk factor for worsened outcome. [11] In addition, hyperglycemia has been suggested as an independent risk factor in hemorrhagic conversion of the stroke after administration of thrombolytic therapy.

Several case reports describe hypoglycemia mimicking acute stroke or symptoms of transient ischemic attack (TIA). [2, 3, 4, 12] Berkovic et al reported that hypoglycemia was the cause of symptoms mimicking acute stroke in 3 of 1460 patients admitted to their stroke unit over a 5-year period. [2]

For patient education information, see eMedicineHealth's Brain and Nervous System Center, as well as Stroke.

Go to Acute Management of Stroke, Diabetes Mellitius, Type 2, and Hypoglycemia for more complete information on these topics.

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Hyperglycemia in Stroke

Diabetes mellitus

Diabetes mellitus is an independent risk factor for stroke and may be one of the factors causing strokes at younger ages in groups such as Hispanic Americans that have a relatively high incidence of diabetes. [13, 14, 15] The mechanism is believed to be accelerated atherosclerosis, which can affect vessels in many distributions, including small and large vessels. Cardiac involvement may predispose to embolic strokes as well.

In addition, patients with diabetes may have any of several lipid abnormalities. Elevated levels of triglycerides, low-density lipoproteins (LDL), and very low-density lipoproteins (VLDL), along with lower than normal levels of high-density lipoprotein (HDL), are common findings in the lipid profiles of patients with diabetes. The combined effect of these factors results in promotion of atherosclerosis and thrombosis.

Proposed mechanisms for hyperglycemia and worsened outcomes

The specific mechanism(s) by which hyperglycemia leads to poorer clinical outcome in patients receiving anticoagulants or thrombolytics is not known, although several have been proposed. In some vascular beds, hyperglycemia causes glycosylation and thereby interferes with protein and enzyme function, including those functions that regulate production of substances that cause vasodilation and cellular adhesion within the vasculature. Hyperglycemia results in the formation of advanced glycation end products that are toxic to endothelial cells, and production of free radicals from various sources may result in further vascular injury.

Hyperglycemia worsens outcome and increases rate of mortality from stroke. Two mechanisms have been postulated to explain the negative influence of hyperglycemia on outcome following stroke: (1) poorer reperfusion due to vascular injury and a loss of vascular tone through oxidation of nitric oxide dependent mechanisms; and (2) increased acidosis, perhaps from lactic acid/acid sensing channels, leading to further tissue injury. Both mechanisms have been supported by experimental data.

Martini and Kent suggest that, even if an occluded vessel causing stroke is recanalized, effective reperfusion may not be established in patients with hyperglycemia. [16] By setting up a “pro-constrictive, pro-thrombotic and pro-inflammatory” state, hyperglycemia may be harmful to the endothelial cells and the vascular tree.

Parsons et al used magnetic resonance imaging (MRI) and magnetic resonance spectroscopy in patients with hyperglycemic stroke and reported that the detrimental effect of hyperglycemia may be due to metabolic acidosis in the infracted brain parenchyma. [17] However, earlier animal studies suggested that hyperglycemia has a detrimental effect on the cerebral vascular tree. [18, 19]

Possible protective effects of hyperglycemia in lacunar stroke subtype

Although hyperglycemia worsens clinical outcome in ischemic strokes, this does not appear to be the case in lacunar strokes. In reporting data from the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) database, Bruno et al found that, despite higher baseline glucose levels being associated with worse functional outcomes in nonlacunar stroke patients, there was a complex relationship between baseline glucose values and excellent functional outcomes in lacunar strokes. [20]

In another study, Uyttenboogaart et al reported that, in lacunar stroke subjects, moderate hyperglycemia, defined as glucose levels between 8 and 12 mmol/L, was associated with better clinical outcome (modified Rankin Score of 0-2) compared with normoglycemic patients. [21] However, clinical outcome was worsened for subjects with baseline glucose values greater than 12 mmol/L.

The mechanism by which hyperglycemia may be protective in lacunar stroke is not known, although it could involve particular sensitivity of white matter to glucose levels in the face of ischemia.

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Hypoglycemia in Stroke

Low levels of glucose can result from overuse of oral hypoglycemic agents or insulin, overproduction of endogenous insulin (which may be a result of an insulinoma), or medical illnesses such as sepsis, renal failure, and hepatic failure.

Two different mechanisms have been suggested as the causes of hypoglycemia-related strokelike episodes. First, the brain uses glucose predominantly for oxidative metabolism. Different brain regions have different metabolic demands. The need for glucose is highest in the cerebral cortex and basal ganglia. The cerebellum and the subcortical white matter have less demand for this substrate. Focal deficits may be a result of asymmetric distribution of glucose transporters. Second, Gold and Marshall suggest that coagulation defects may be the cause of strokelike episodes. [22]

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Evaluation of Glycemic Levels and Stroke

Presentation of patients with hyperglycemia and acute 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. However, 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.

Presentation of patients with hypoglycemia and strokelike symptoms

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 diagnosed earlier, and recent changes in the doses of hypoglycemic agents and insulin may have been instituted. In particular, aggressively tight control, either patient driven or clinician directed, may give rise to chronic hypoglycemia or recurrent episodes of hypoglycemia. However, if factitious hypoglycemia is suspected, such behavior may have manifested earlier by similar episodes or other factitious behaviors.

Misdiagnosis and improper treatment of hypoglycemia could worsen the outcomes. Thus, evaluation of glucose levels is recommended in patients presenting with symptoms suggestive of acute stroke, particularly before administration of recombinant tissue-type plasminogen activator (rtPA). Symptoms caused by hypoglycemia can occur suddenly and fluctuate, suggesting a vascular etiology.

See Stroke, Hemorrhagic and Stroke, Ischemic.

Rundel et al suggest that measuring insulin resistance using the homeostasis model assessment index may help improve estimation of future risk of stroke in nondiabetic individuals. [23]

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Diagnosis

Hyperglycemic hyperosmolar state (HHS) can cause focal symptoms including visual loss, focal seizures, and movement disorders. Stroke can precipitate the hyperglycemic state and must be distinguished from primary HHS. In addition, hyperglycemia has been associated with onset of focal neurologic symptoms in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome. Infection may also be associated with both acute stroke and hyperglycemia.

Hypoglycemia is a stroke mimic, and its underlying cause needs to be investigated.

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Routine Tests

In the setting of acute stroke, obtaining serum glucose levels along with a broader panel of complete blood count, electrolyte values, prothrombin time (PT), and activated partial thromboplastin time (aPTT) is routine practice.

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CT Scanning of the Head

Obtain a computed tomography (CT) scan of the head when stroke is suspected. More recently, magnetic resonance imaging (MRI) with diffusion/perfusion sequences has been used for assessment of acute stroke.

The mechanism by which CT scanning and MRI specifically affect the diagnosis or treatment of patients with stroke and hyperglycemia is not clear. However, that hyperglycemia may accelerate the ischemic process has been postulated, so that features characteristic of acute stroke, such as hypodensity on CT scans, may be seen earlier than in patients without hyperglycemia.

If strokelike symptoms are a result of hypoglycemia, abnormal findings on imaging studies are dependent on the degree and duration of insult to the brain. Initially, results on CT scan of the head may 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. [6] The regions that are most prone to injury are cortical gray matter, followed by basal ganglia and cerebellar cortex. If hypoglycemia is transitory and the clinical status of the patient returns to normal, follow-up CT scan findings also may be normal.

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Management of 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 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 especially beneficial in patients with insulin resistance, [7] ) tight glucose control, and hypertensive management.

Studies indicate that treatment of hypertension in patients with diabetes reduces stroke risk by more than 40%. Guidelines published by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommend lower, more strict hypertension targets of 130/80 mm Hg in persons with diabetes. [24]

Patients with acute stroke and hyperglycemia are often kept NPO because of complicating effects of feeding on blood sugar level. Transition from acute therapy to initiation of chronic therapy depends on persistence of hyperglycemia or evidence that the patient has diabetes.

Consultations

Diabetes is managed in a primary care setting. However, certain patients whose diabetes is difficult to control or patients who may be experiencing the myriad of complications of diabetes may benefit from consultation with an endocrinologist.

Acute hyperglycemic therapy

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 treatment of hyperglycemia in patients with acute stroke are being determined by ongoing/planned clinical trials.

Vigilance is recommended regarding blood glucose levels, as sliding scale insulin may be ineffective for those patients who had diabetes and were hyperglycemic in the acute stroke setting. Those patients who were hyperglycemic but did not have a history of diabetes (eg, "stress hyperglycemia") did respond well to a sliding scale. [25]

Transition from acute therapy to initiation of chronic therapy depends on persistence of hyperglycemia or evidence that the patient has diabetes.

Intensive insulin therapy

The Diabetes Control and Complications Trial (DCCT) reported that intensive insulin therapy delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with insulin-dependent diabetes. [26] However, the investigators also found a 3-fold higher rate of severe hypoglycemia in the group that received intensive treatment for diabetes than in those who received conventional therapy. Patients in the group receiving intensive therapy required medical attention for hypoglycemia at an incidence of 62 episodes per 100 patient-years. [26] A study by Lawson et al also found that intensive insulin therapy decreases the extent of early macrovascular disease in young individuals with type 1 diabetes, but there were no effects on the numbers of affected patients or on macrovascular mortality. [27]

Van den Berghe et al studied intensive insulin therapy for hyperglycemia in the surgical intensive care unit setting and demonstrated a reduction in the incidence of critical care neuropathy. [28] The investigators performed a subgroup analysis of patients with traumatic brain injury that suggested long-term clinical outcome was better in the group that was treated with intensive insulin, [29] but patients with stroke were not widely represented in this study. Although morbidity was reduced in patients treated with intensive insulin who were admitted to the medical intensive care unit (ICU), overall mortality was unchanged. [29] However, in the subset of patients who had ICU stays of at least 3 days, mortality was reduced.

Results of a large single-blinded multicenter randomized study [30] disagreed with the findings of the Van den Berghe reports [29, 31] . Mortality was increased in the group of patients with glucose targets of 81-108 mg/dL compared with the group with glucose target less than 180 mg/dL. Severe hypoglycemia that was defined as glucose less than 40 mg/dL was also increased in the group receiving intensive therapy. [30]

In addition, 2 small randomized studies failed to show clear clinical efficacy of intensive glucose control. [25, 32] In both trials, the intensive treatment groups had an increased incidence of hypoglycemia. In addition, mortality was increased in the groups receiving intensive treatment, but the values did not reach statistical significance in either study.

Larger trials are planned to determine definitive safety and efficacy of intensive glucose control. For the time being, it appears reasonable to use a sliding scale in order to maintain reasonable levels of blood glucose (eg, 140 mg/dL), as more aggressive targets may worsen outcome.

The Stroke Hyperglycemia Insulin Network Effort (SHINE) has been set up to study the safety and efficacy of standard versus intensive insulin glucose control with insulin in patients with acute ischemic stroke and hyperglycemia. [33]

Sulfonylurea agents

Animal studies and retrospective analyses suggest that the sulfonylurea agent glibenclamide improves outcome after large artery stroke. [34, 35] The mechanism does not appear to involve reduction in blood glucose as the benefit was seen in rats even if blood glucose was maintained at higher levels, and the dose is lower than needed for glucose reduction. Whether these findings will be confirmed in prospective human trials remains to be seen.

Complications

In some studies, hyperglycemia appears to be associated with a reduced incidence of primary intracerebral hemorrhage. However, risk of hemorrhagic conversion of strokes appears to increase after recombinant tissue-type plasminogen activator (rtPA; see alteplase) administration in patients with diabetes. [36, 37] This risk may be present even at moderate elevations of serum glucose level. Notably, moderate hyperglycemia is presently not an exclusion criterion for administration of rtPA in patients with acute stroke; the range of blood glucose for which rtPA treatment of patients with acute stroke is acceptable is 50-400 mg/dL.

See Stroke Anticoagulation and Prophylaxis and Thrombolytic Therapy in Stroke.

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Management of Hypoglycemia

Frequent monitoring of glucose levels may be necessary to prevent hypoglycemia, especially when changes in doses of medications have been made. Other metabolic abnormalities, such as hepatic or renal failure, may also carry a risk of hypoglycemia.

When hypoglycemia is discovered, the glucose level must be brought expeditiously to a normal level. Intravenous fluids, such as dextrose 25% in water (D25W) or dextrose 50% in water (D50W), [10] may be necessary. Note that dextrose 5% in water (D5W) is not an appropriate fluid, because excess of free water may exacerbate cerebral edema, and because hyperglycemia may be induced, with harmful effects as above. Also, serum glucose levels should be monitored at frequent intervals.

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. A patient who is hypoglycemic because of systemic illness or malnutrition may be particularly vulnerable to vitamin deficiency.

Treatment of hypoglycemia beyond the initial therapy depends on the underlying cause.

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