eMedicine Specialties > Neurology > Neuro-vascular Diseases
Metabolic Disease & Stroke: Hyperglycemia/Hypoglycemia
Updated: Apr 4, 2006
Introduction
Background
This article primarily addresses effects of hyperglycemia and hypoglycemia in the setting of acute stroke. Preexisting hyperglycemia is found commonly in patients presenting with acute stroke, and hypoglycemia may present with focal symptoms mimicking acute stroke. The reader is referred to more definitive discourses about the general management of diabetes and other manifestations of hyperglycemia and hypoglycemia in the general neurologic and endocrinologic literature.
Hyperglycemia: 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 (Capes, 2001). In several trials involving thrombolytic and anticoagulation therapy in patients with stroke, hyperglycemia appears to be an independent risk factor for worsened outcome. Hyperglycemia has been suggested as an independent risk factor in hemorrhagic conversion of the stroke after administration of thrombolytic therapy.
Hypoglycemia: Several case reports describe hypoglycemia mimicking acute stroke or symptoms of transient ischemic attack (TIA). Misdiagnosis and improper treatment could worsen the outcomes. Therefore, evaluation of glucose levels is recommended in patients presenting with symptoms suggestive of acute stroke, particularly prior to administration of recombinant tissue-type plasminogen activator (rtPA). Symptoms caused by hypoglycemia can occur suddenly and fluctuate, suggesting a vascular etiology.
Pathophysiology
Hyperglycemia
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. 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.
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, including the following:
- 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:
- Poorer reperfusion due to vascular injury
- Increased acidosis, perhaps from lactic acid, leading to further tissue injury
Both mechanisms have been supported by experimental data. Parsons et al (2002) used MRI and MR spectroscopy in patients with hyperglycemic stroke and report that the detrimental effect of hyperglycemia may be due to metabolic acidosis in the infracted brain parenchyma. However, earlier animal studies suggested that hyperglycemia has a detrimental effect on cerebral vascular tree (Kawai, 1997; Quast, 1997).
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 rtPA administration in patients with diabetes. 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.
Hypoglycemia
Low levels of glucose can result from the following:
- Overuse of oral hypoglycemic agents or insulin
- Overproduction of endogenous insulin, which may be a result of an insulinoma
- Medical illnesses such as sepsis, renal failure, and hepatic failure
Two different mechanisms have been suggested as the causes of hypoglycemia-related strokelike episodes, as follows:
- 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.
- Gold and Marshall suggest that coagulation defects may be the cause of strokelike episodes.
Frequency
International
Hyperglycemia: Hyperglycemia is reported to be present in 20-50% of patients incurring acute stroke. In many trials of thrombolytic agents, hyperglycemia occurred in about 20-30% of subjects.
Hypoglycemia: The Diabetes Control and Complications Trial (DCCT) 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. Berkovic et al reported that hypoglycemia was the cause of symptoms mimicking acute stroke in 3 of a total of 1460 patients admitted to their stroke unit over a 5-year period.
Clinical
History
- Hyperglycemia and acute stroke
- Patients may come to the attention of physicians because of preexisting diabetes mellitus.
- Diabetes may be seen with other risk factors for stroke such as hypertension and hypercholesterolemia.
- Hyperglycemia also may be seen in the setting of an acute stroke without a history of diabetes, presumably due to a sympathetic response to the infarct.
- Hypoglycemia 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.
- Aggressively tight control, either patient driven or physician directed, may give rise to chronic hypoglycemia or recurrent episodes of hypoglycemia.
- If factitious hypoglycemia is suspected, such behavior may have manifested earlier by similar episodes or other factitious behaviors.
Physical
- Signs and symptoms of acute stroke are covered in other articles (Stroke, Hemorrhagic; Stroke, Ischemic).
- Retinopathy, neuropathy, and peripheral vascular disease may be found in patients with long-standing diabetes.
- In the literature, signs of an acute stroke, such as hemiplegia, aphasia, and cortical blindness, have been reported with hypoglycemia.
Workup
Laboratory Studies
- 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.
Imaging Studies
- Obtain CT scan of the head when stroke is suspected. More recently, MRI with diffusion/perfusion sequences has been used for assessment of acute stroke.
- The mechanism by which these tests 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 scan, 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 scan of the brain may show cortical atrophy reflecting laminar necrosis. 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.
Treatment
Medical Care
- 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 LDL (to below 100 mg/dL in diabetics), increase of HDL (with fibrates if tolerated, an effect especially beneficial in patients with insulin resistance [Robins, 2001]), tight glucose control, and hypertensive management.
- Intensive insulin treatment for hyperglycemia has been studied in the surgical intensive care unit setting and has been proven to reduce incidence of critical care neuropathy (Van den Berghe, 2001). A subgroup analysis of patients with traumatic brain injury suggested that long-term clinical outcome was better in the group that was treated with intensive insulin (Van den Berghe, 2005).
- Morbidity was reduced in patients treated with intensive insulin who were admitted to the medical intensive care unit, but overall mortality was unchanged (Van den Berghe, 2006). Mortality was reduced in the subset of patients who had ICU stays of at least 3 days.
- Studies indicate that treatment of hypertension in diabetic patients reduces stroke risk by over 40%. Guidelines published by Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommend lower, more strict hypertension targets in diabetics of 130/80 (Chobanian, 2003).
- The benefit of treatment of hyperglycemia with insulin in the setting of acute stroke has not been confirmed in randomized controlled clinical trials, and there is not yet sufficient evidence to recommend changing current recommendations to maintain glucose levels below 180 mg/dL. The risk of inducing hypoglycemia as part of an aggressive correction of serum glucose is as yet unknown in the acute stroke setting.
- 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, also may 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), 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.
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.
Diet
Advise patients with new-onset diabetes to consult a dietitian for dietary advice.
Medication
Regarding the general management of diabetes, refer to appropriate sections of articles that deal with treatment of diabetes (Diabetes Mellitus, Type 1 - A Review; Diabetes Mellitus, Type 2 - A Review; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2).
Typically, hyperglycemia in the setting of acute stroke is treated with subcutaneous insulin in a sliding scale. Refractory hyperglycemia may require the use of intravenous (IV) insulin; however, IV insulin increases the risk of hypoglycemia.
Safety and efficacy of IV insulin in treatment of hyperglycemia in patients with acute stroke are being determined by ongoing/planned clinical trials.
Antihyperglycemic agents
These agents increase glucose metabolism.
Insulin (Humulin, Novolin, Lente)
Stimulates proper utilization of glucose by cells and reduces blood sugar levels. Use sliding scale.
Dosing
Adult
Sliding scales for insulin vary widely and must be tailored to individual needs of patient; an example using regular insulin is given below but local practices may mandate a tighter glucose control:
Blood glucose 150-200 mg/dL: 2 units SC
Blood glucose 201-250 mg/dL: 4 units SC
Blood glucose 251-300 mg/dL: 6 units SC
Blood glucose 301-350 mg/dL: 8 units SC
Blood glucose 351-400 mg/dL: 10 units SC
Pediatric
Administer as in adults
Interactions
Acetazolamide, AIDS antivirals, asparaginase, phenytoin, nicotine, isoniazid, diltiazem, diuretics, corticosteroids, thiazide diuretics, thyroid hormone, estrogens, ethacrynic acid, calcitonin, oral contraceptives, diazoxide, dobutamine, phenothiazines, cyclophosphamide, dextrothyroxine, lithium carbonate, epinephrine, morphine sulfate, and niacin may decrease hypoglycemia effects
Calcium, ACE inhibitors, alcohol, tetracyclines, beta blockers, lithium carbonate, anabolic steroids, pyridoxine, salicylates, MAOIs, mebendazole, sulfonamides, phenylbutazone, chloroquine, clofibrate, fenfluramine, guanethidine, octreotide, pentamidine, and sulfinpyrazone may increase hypoglycemic effects
Contraindications
Documented hypersensitivity; hypoglycemia
Precautions
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Closely monitor blood glucose levels when using sliding scale insulin in order to avoid hypoglycemia, especially when used in combination with oral hypoglycemic agents, because they may not reach maximum efficacy until several hours after administration and may have prolonged duration of action
Vitamins
These are essential for normal DNA synthesis.
Thiamine; vitamin B-1 (Thiamilate)
For thiamine deficiency including Wernicke encephalopathy syndrome.
Dosing
Adult
Initial: 100 mg IV/IM qd; can be given PO, but for initial treatment parenteral routes preferable owing to poor oral absorption; occasionally, higher doses (eg, 300 mg) have been given as initial treatment
Pediatric
Not established
Interactions
None reported
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
A - Safe in pregnancy
Precautions
Sensitivity reactions can occur (intradermal test-dose recommended in suspected sensitivity); deaths have resulted from IV use; sudden onset or worsening of Wernicke encephalopathy, following glucose, may occur in thiamine-deficient patients; administer before or together with dextrose-containing fluids in suspected thiamine deficiency
Follow-up
Patient Education
- For excellent patient education resources, visit eMedicine's Stroke Center. Also, see eMedicine's patient education article Stroke.
Miscellaneous
Medicolegal Pitfalls
- The usual medicolegal risks of delayed diagnosis or misdiagnosis of stroke as well as medication adverse effects are pertinent to this chapter.
- Hypoglycemia also is associated with complications, especially in the setting of stroke and possible ongoing cerebral ischemia. These complications were defined earlier in this article.
References
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Keywords
hyperglycemia, hypoglycemia, acute stroke, diabetes, diabetes mellitus, thrombolytic therapy, anticoagulation therapy, transient ischemic attack, TIA, recombinant tissue-type plasminogen activator, rtPA, metabolic disease and stroke
Contributor Information and Disclosures
Author
Pitchaiah Mandava, MD, PhD, Assistant Professor, Department of Neurology, Baylor College of Medicine; Consulting Staff, Department of Neurology, Michael E DeBakey Veterans Affairs Medical Center
Pitchaiah Mandava, MD, PhD is a member of the following medical societies: American Academy of Neurology, Sigma Xi, and Stroke Council of the American Heart Association
Disclosure: Nothing to disclose.
Coauthor(s)
Thomas A Kent, MD, Professor, Department of Neurology, Baylor College of Medicine; Neurology Care Line Executive, Michael E DeBakey Veterans Affairs Medical Center
Thomas A Kent, MD is a member of the following medical societies: American Academy of Neurology, American Neurological Association, New York Academy of Sciences, Royal Society of Medicine, Sigma Xi, and Stroke Council of the American Heart Association
Disclosure: Nothing to disclose.
Medical Editor
Richard M Zweifler, MD, Professor, Director of Stroke Center, Director of Neurosonology Lab, Director of Vascular Neurology Fellowship, Director of Medical Student Education, Department of Neurology, University of South Alabama
Richard M Zweifler, MD is a member of the following medical societies: American Academy of Neurology, American Heart Association, American Medical Association, American Society of Neuroimaging, American Stroke Association, Medical Association of the State of Alabama, National Stroke Association, Royal Society of Medicine, Society of Neurosurgical Anesthesia and Critical Care, and Stroke Council of the American Heart Association
Disclosure: Nothing to disclose.
Pharmacy Editor
Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.
Managing Editor
Howard S Kirshner, MD, Professor of Neurology, Psychiatry and Hearing and Speech Sciences, Vice Chairman, Department of Neurology, Vanderbilt University School of Medicine; Director, Vanderbilt Stroke Center; Program Director, Stroke Service, Vanderbilt Stallworth Rehabilitation Hospital; Consulting Staff, Department of Neurology, Nashville Veterans Affairs Medical Center
Howard S Kirshner, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Heart Association, American Medical Association, American Neurological Association, American Society of Neurorehabilitation, National Stroke Association, Phi Beta Kappa, and Tennessee Medical Association
Disclosure: Boehringer Ingelheim Honoraria Speaking and teaching; BMS/Sanofi Honoraria Speaking and teaching; Pfizer Honoraria Speaking and teaching; Novartis Consulting fee Review panel membership
CME Editor
Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.
Chief Editor
Helmi L Lutsep, MD, Associate Professor, Department of Neurology, Oregon Health and Science University; Associate Director, Oregon Stroke Center
Helmi L Lutsep, MD is a member of the following medical societies: American Academy of Neurology and American Stroke Association
Disclosure: Co-Axia Consulting fee Review panel membership; Talecris Consulting fee Review panel membership; AGA Medical Consulting fee Review panel membership; Boehringer Ingelheim Honoraria Speaking and teaching; Boston Scientific Honoraria Speaking and teaching