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Glucose Modulation of Ischemic Brain Injury: Review and Clinical Recommendations

      Ischemic brain injury is the third-leading cause of death among Americans and the leading cause of serious disability. Based on studies of animal models, a substantial amount of experimental evidence shows that hyperglycemia at the onset of brain ischemia worsens postischemic neurologic outcome. Consistent with these observations, hyperglycemia also is associated with a worsening of postischemic brain injury in humans. In humans, however, data are often difficult to interpret because of problems in determining the timing of hyperglycemia relative to a critical ischemic event and in elucidating the effect of coexisting patho-physiologic processes (for example, a stress response) on outcome. Glucose modulation of neurologic injury is observed when ischemia is either global (for example, that accompanying cardiac arrest or severe systemic hypotension) or focal (for example, that accompanying thrombotic or embolic stroke). Toxicity is probably the result of an intracellular lactic acidosis. Specifically, the associated hydrogen ions are injurious to neurons and glia. On the basis of these factors, we recommend diligent monitoring of blood glucose concentrations in patients who are at increased risk for new-onset, ongoing, or recurring cerebral ischemia. In such patients, the use of fluid infusions, corticosteroid drugs, and insulin, as well as stress management, should be tailored to treat preexisting hyperglycemia and prevent new-onset hyperglycemia. Maintenance of normoglycemia is recommended. When one attempts to treat preexisting hyperglycemia, care should be taken to avoid rapid fluid shifts, electrolyte abnormalities, and hypoglycemia, all of which can be detrimental to the brain.
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      References

      1. Heart and Stroke Facts: 1995 Statistical Supplement. American Heart Association,, Dallas1994: 12
      2. Centers for Disease Control and Prevention.
        HIV/AIDS Surveillance Rep. 1994; 6: 14
        • Lanier WL
        Glucose management during cardiopulmonary bypass: cardiovascular and neurologic implications [editorial].
        Anesth Analg. 1991; 72: 423-427
        • Nedergaard M
        • Goldman SA
        • Desai S
        • Pulsinelli WA
        Acid-induced death in neurons and glia.
        J Neurosci. 1991; 11: 2489-2497
        • Smith ML
        • von Hanwehr R
        • Siesjo BK
        Changes in extra-and intracellular pH in the brain during and following ischemia in hyperglycemic and in moderately hypoglycemic rats.
        J Cereb Blood Flow Metab. 1986; 6: 574-583
        • Rehncrona S
        • Rosen I
        • Siesjo BK
        Brain lactic acidosis and ischemic cell damage. 1. Biochemistry and neurophysiol-ogy.
        J Cereb Blood Flow Metab. 1981; 1: 297-311
        • Marsh WR
        • Anderson RE
        • Sundt Jr, TM
        Effect of hyperglycemia on brain pH levels in areas of focal incomplete cerebral ischemia in monkeys.
        J Neurosurg. 1986; 65: 693-696
        • Hochachka PW
        • Mommsen TP
        Protons and anaerobiosis.
        Science. 1983; 219: 1391-1397
        • Siesjo BK
        Mechanisms of ischemic brain damage.
        Crit Care Med. 1988; 16: 954-963
        • Wass CT
        • Lanier WL
        Improving neurologic outcome following cardiac arrest.
        Anesthesiol Clin North Am. 1995 Dec; 13: 869-903
        • Pulsinelli WA
        • Waldman S
        • Rawlinson D
        • Plum F
        Moderate hyperglycemia augments ischemic brain damage: a neuropathologic study in the rat.
        Neurology. 1982; 32: 1239-1246
        • Busa WB
        • Nuccitelli R
        Metabolic regulation via intracellular pH.
        Am J Physiol. 1984; 246: R409-R438
        • Milde LM
        Cerebral protection.
        in: Cucchiara RF Mich-enfelder JD Clinical Neuroanesthesia. Churchill Livingstone, New York1990: 207-209
        • Lanier WL
        • Hofer RE
        • Gallagher WJ
        Metabolism of glucose, glycogen, and high-energy phosphates during transient forebrain ischemia in diabetic rats: effect of insulin treatment.
        Anesthesiology. 1996; 84: 917-925
        • Low JA
        Cerebral perfusion, metabolism, and outcome.
        CUIT Opin Pediatr. 1995; 7: 132-139
        • Callahan DJ
        • Engle MJ
        • Volpe JJ
        Hypoxic injury to developing glial cells: protective effect of high glucose.
        Pediatr Res. 1990; 27: 186-190
        • McGowan IE
        • Marro PJ
        • Mishra OP
        • Delivoria-Papadopoulos M
        Brain cell membrane function during hypoxia in hyperglycemic newborn piglets.
        Pediatr Res. 1995; 37: 133-139
        • Vannucci RC
        • Yager JY
        Glucose, lactic acid, and perinatal hypoxic-ischemic brain damage.
        Pediatr Neurol. 1992; 8: 3-12
        • Vannucci RC
        • Mujsce DJ
        Effect of glucose on perinatal hypoxic-ischemic brain damage.
        Biol Neonate. 1992; 62: 215-224
        • Myers RE
        • Yamaguchi S
        Nervous system effects of cardiac arrest in monkeys: preservation of vision.
        Arch Neurol. 1977; 34: 65-74
        • Longstreth Jr, WT
        • Diehr P
        • Inui TS
        Prediction of awakening after out-of-hospital cardiac arrest.
        N Engl J Med. 1983; 308: 1378-1382
        • Longstreth Jr, WT
        • Inui TS
        High blood glucose level on hospital admission and poor neurological recovery after cardiac arrest.
        Ann Neurol. 1984; 15: 59-63
        • D'Alecy LG
        • Lundy EF
        • Barton KJ
        • Zelenock GB
        Dextrose containing intravenous fluid impairs outcome and increases death after eight minutes of cardiac arrest and resuscitation in dogs.
        Surgery. 1986; 100: 505-511
        • Lanier WL
        • Stangland KJ
        • Scheithauer BW
        • Milde JH
        • Michenfelder JD
        The effects of dextrose infusion and head position on neurologic outcome after complete cerebral ischemia in primates: examination of a model.
        Anesthesiology. 1987; 66: 39-48
        • Nakakimura K
        • Fleischer IE
        • Drummond JC
        • Scheller MS
        • Zornow MH
        • Grafe MR
        • et al.
        Glucose administration before cardiac arrest worsens neurologic outcome in cats.
        Anesthesiology. 1990; 72: 1005-1011
        • Natale IE
        • Stante SM
        • D'Alecy LG
        Elevated brain lactate accumulation and increased neurologic deficit are associated with modest hyperglycemia in global brain ischemia.
        Resuscitation. 1990; 19: 271-289
        • Warner DS
        • Todd MM
        • Dexter F
        • Ludwig P
        • McAllister AM
        Temporal thresholds for hyperglycemia-augmented ischemic brain damage in rats.
        Stroke. 1995; 26: 655-660
        • Sieber FE
        • Palmon SC
        • Traystman RJ
        • Martin LM
        Brain ischemia and diabetes.
        J Neurosurg Anesthesiol. 1995; 7: A307
        • Longstreth Jr, WT
        • Diehr P
        • Cobb LA
        • Hanson RW
        • Blair AD
        Neurologic outcome and blood glucose levels during out-of-hospital cardiopulmonary resuscitation.
        Neurology. 1986; 36: 1186-1191
        • Garcia MJ
        • McNamara PM
        • Gordon T
        • Kannell WB
        Morbidity and mortality in diabetics in the Framingham population: sixteen year follow-up study.
        Diabetes. 1974; 23: 105-111
        • Melamed E
        Reactive hyperglycaemia in patients with acute stroke.
        J Neurol Sci. 1976; 29: 267-275
        • Asplund K
        • Hagg E
        • Helmers C
        • Lithner F
        • Strand T
        • Wester PO
        The natural history of stroke in diabetic patients.
        Acta Med Scand. 1980; 207: 417-424
        • Pulsinelli WA
        • Levy DE
        • Sigsbee B
        • Scherer P
        • Plum F
        Increased damage after ischemic stroke in patients with hyperglycemia with or without established diabetes mellitus.
        Am J Med. 1983; 74: 540-544
        • Roehmholdt ME
        • Palumbo PJ
        • Whisnant JP
        • Elveback LR
        Transient ischemic attack and stroke in a community-based diabetes cohort.
        Mayo Clin Proc. 1983; 58: 56-58
        • Candelise L
        • Landi G
        • Orazio EN
        • Boccardi E
        Prognostic significance of hyperglycemia in acute stroke.
        Arch Neurol. 1985; 42: 661-663
        • Brint S
        • Kraig R
        • Kiessling M
        • Pulsinelli W
        Hyperglycemia augments infarct size in focal experimental brain ischemia [abstract].
        Ann Neurol. 1985; 18: 127
        • Berger L
        • Hakim AM
        The association of hyperglycemia with cerebral edema in stroke.
        Stroke. 1986; 17: 865-871
        • Cox NH
        • Lorains JW
        The prognostic value of blood glucose and glycosylated haemoglobin estimation in patients with stroke.
        Postgrad Med J. 1986; 62: 7-10
        • Abbott RD
        • Donahue RP
        • MacMahon SW
        • Reed DM
        • Yano K
        Diabetes and the risk of stroke: the Honolulu Heart Program.
        JAMA. 1987; 257: 949-952
        • Ginsberg MD
        • Prado R
        • Dietrich WD
        • Busto R
        • Watson BD
        Hyperglycemia reduces the extent of cerebral infarction in rats.
        Stroke. 1987; 18: 570-574
        • Nedergaard M
        Transient focal ischemia in hyperglycemic rats is associated with increased cerebral infarction.
        Brain Res. 1987; 408: 79-85
        • Nedergaard M
        • Diemer NH
        Focal ischemia of the rat brain, with special reference to the influence of plasma glucose concentration.
        Acta Neuropathol. 1987; 73: 131-137
        • Woo E
        • Chan YW
        • Yu YL
        • Huang CY
        Admission glucose level in relation to mortality and morbidity outcome in 252 stroke patients.
        Stroke. 1988; 19: 185-191
        • Adams Jr, HP
        • Olinger CP
        • Marler JR
        • Biller J
        • Brott TG
        • Barsan WG
        • et al.
        Comparisons of admission serum glucose concentration with neurologic outcome in acute cerebral infarction: a study in patients given naloxone.
        Stroke. 1988; 19: 455-458
        • de Courten-Myers G
        • Myers RE
        • Schoolfield L
        Hyperglycemia enlarges infarct size in cerebrovascular occlusion in cats.
        Stroke. 1988; 19: 623-630
        • Prado R
        • Ginsberg MD
        • Dietrich WD
        • Watson BD
        • Busto R
        Hyperglycemia increases infarct size in collaterally perfused but not end-arterial vascular territories.
        J Cereb Blood Flow Metab. 1988; 8: 186-192
        • de Courten-Myers GM
        • Kleinholz M
        • Wagner KR
        • Myers RE
        Fatal strokes in hyperglycemic cats.
        Stroke. 1989; 20: 1707-1715
        • Zasslow MA
        • Pearl RG
        • Shuer LM
        • Steinberg GK
        • Lieberson RE
        • Larson Jr, CP
        Hyperglycemia decreases acute neuronal ischemic changes after middle cerebral artery occlusion in cats.
        Stroke. 1989; 20: 519-523
        • Woo J
        • Lam CW
        • Kay R
        • Wong AH
        • Teoh R
        • Nicholls MG
        The influence of hyperglycemia and diabetes mellitus on immediate and 3-month morbidity and mortality after acute stroke.
        Arch Neurol. 1990; 47: 1174-1177
        • Hoffman WE
        • Braucher E
        • Pelligrino DA
        • Thomas C
        • Albrecht RF
        • Miletich DJ
        Brain lactate and neurologic outcome following incomplete ischemia in fasted, nonfasted, and glucose-loaded rats.
        Anesthesiology. 1990; 72: 1045-1050
        • Kraft SA
        • Larson Jr, CP
        • Shuer LM
        • Steinberg GK
        • Benson GV
        • Pearl RG
        Effect of hyperglycemia on neuronal changes in a rabbit model of focal cerebral ischemia.
        Stroke. 1990; 21: 447-450
        • O'Neill PA
        • Davies I
        • Fullerton KJ
        • Bennett D
        Stress hormone and blood glucose response following acute stroke in the elderly.
        Stroke. 1991; 22: 842-847
        • Kiers L
        • Davis SM
        • Larkins R
        • Hopper J
        • Tress B
        • Rossiter SC
        • et al.
        Stroke topography and outcome in relation to hyperglycaemia and diabetes.
        J Neurol Neurosurg Psychiatry. 1992; 55: 263-270
        • Murros K
        • Fogelholm R
        • Kettunen S
        • Vuorela AL
        • Valve J
        Blood glucose, glycosylated haemoglobin, and outcome of ischemic brain infarction.
        J Neurol Sci. 1992; 111: 59-64
        • Matchar DB
        • Divine GW
        • Heyman A
        • Feussner JR
        The influence of hyperglycemia on outcome of cerebral infarction.
        Ann Intern Med. 1992; 117: 449-456
        • Wagner KR
        • Kleinholz M
        • de Courten-Myers GM
        • Myers RE
        Hyperglycemic versus normoglycemic stroke: topography of brain metabolites, intracellular pH, and infarct size.
        J Cereb Blood Flow Metab. 1992; 12: 213-222
        • Jorgensen H
        • Nakayama H
        • Raaschou HO
        • Olsen TS
        Stroke in patients with diabetes: the Copenhagen Stroke Study.
        Stroke. 1994; 25: 1977-1984
        • de Courten-Myers GM
        • Kleinholz M
        • Wagner KR
        • Myers RE
        Normoglycemia (not hypoglycemia) optimizes out come from middle cerebral artery occlusion.
        J Cereb Blood Flow Metab. 1994; 14: 227-236
        • Metz S
        • Keats AS
        Benefits of a glucose-containing priming solution for cardiopulmonary bypass.
        Anesth Analg. 1991; 72: 428-434
        • Feibel JH
        • Hardy PM
        • Campbell RG
        • Goldstein MN
        • Joynt RJ
        Prognostic value of the stress response following stroke.
        JAMA. 1977; 238: 1374-1376
        • Wexler BC
        • Saroff J
        Metabolic changes in response to acute cerebral ischemia following unilateral carotid artery ligation in arteriosclerotic versus nonarteriosclerotic rats.
        Stroke. 1970; 1: 38-51
        • Samanta A
        • Blandford RL
        • Burden AC
        • Castleden CM
        Glucose tolerance following strokes in the elderly.
        Age Ageing. 1986; 15: 111-113
        • Bell DS
        Stroke in the diabetic patient.
        Diabetes Care. 1994; 17: 213-219
        • Shu CC
        • Hoffman WE
        • Thomas C
        • Albrecht RF
        Sympathetic activity enhances glucose-related ischemic injury in the rat.
        Anesthesiology. 1993; 78: 1120-1125
        • Werner C
        • Hoffman WE
        • Thomas C
        • Miletich DJ
        • Albrecht RF
        Ganglionic blockade improves neurologic outcome from incomplete ischemia in rats: partial reversal by exogenous catecholamines.
        Anesthesiology. 1990; 73: 923-929
        • Hoffman WE
        • Baughman VL
        • Albrecht RF
        Interaction of catecholamines and nitrous oxide ventilation during incomplete brain ischemia in rats.
        Anesth Analg. 1993; 77: 908-912
        • Braughler JM
        • Pregenzer JF
        • Chase RL
        • Duncan LA
        • Jacobsen EJ
        • McCall JM
        Novel 21-amino steroids as potent inhibitors of iron-dependent lipid peroxidation.
        J Bio I Chem. 1987; 262: 10438-10440
        • Sapolsky RM
        • Pulsinelli WA
        Glucocorticoids potentiate ischemic injury to neurons: therapeutic implications.
        Science. 1985; 229: 1397-1400
        • Munck A
        Glucocorticoid inhibition of glucose uptake by peripheral tissues: old and new evidence, molecular mechanisms, and physiological significance.
        Perspect Bio I Med. 1971; 14: 265-269
        • Wass CT
        • Scheithauer BW
        • Bronk JT
        • Wilson RM
        • Lanier WL
        Insulin treatment of corticosteroid-associated hyperglycemia and its effect on outcome after forebrain ischemia in rats.
        Anesthesiology. 1996; 84: 644-651
        • Koide T
        • Wieloch TW
        • Siesjo BK
        Chronic dexamethasone pretreatment aggravates ischemic neuronal necrosis.
        J Cereb Blood Flow Metab. 1986; 6: 395-404
        • Norris JW
        • Hachinski VC
        High dose steroid treatment in cerebral infarction.
        BMJ. 1986; 292: 21-23
        • Mulley G
        • Wilcox RG
        • Mitchell JR
        Dexamethasone in acute stroke.
        BMJ. 1978; 2: 994-996
        • Santambrogio S
        • Martinotti R
        • Sardella F
        • Porro F
        • Randazzo A
        Is there a real treatment for stroke? Clinical and statistical comparison of different treatments in 300 patients.
        Stroke. 1978; 9: 130-132
        • Bauer RB
        • Tellez H
        Dexamethasone as treatment in cere-brovascular disease. 2. A controlled study in acute cerebral infarction.
        Stroke. 1973; 4: 547-555
        • Norris JW
        Steroid therapy in acute cerebral infarction.
        Arch Neurol. 1976; 33: 69-71
        • Hall ED
        • McCall JM
        • Means ED
        Therapeutic potential of the lazaroids (21-aminosteroids) in acute central nervous system trauma, ischemia and subarachnoid hemorrhage.
        Adv Pharmacol. 1994; 28: 221-268
        • Hall ED
        • Pazara KE
        • Braughler JM
        21-Aminosteroid lipid peroxidation inhibitor U74006F protects against cerebral ischemia in gerbils.
        Stroke. 1988; 19: 997-1002
        • Kannel WB
        • McGee DI
        Diabetes and cardiovascular disease: the Framingham study.
        JAMA. 1979; 241: 2035-2038
        • Palumbo PJ
        • Elveback LR
        • Whisnant JP
        Neurologic complications of diabetes mellitus: transient ischemic attack, stroke, and peripheral neuropathy.
        Adv Neurol. 1978; 19: 593-601
        • Alex M
        • Baron EK
        • Goldenberg S
        • Blumenthal HT
        An autopsy study of cerebrovascular accident in diabetes mellitus.
        Circulation. 1962; 25: 663-673
        • McMillan DE
        • Utterback NG
        • La Puma J
        Reduced erythro-cyte deformability in diabetes.
        Diabetes. 1978; 27: 895-901
        • Sagel J
        • Colwell JA
        • Crook L
        • Laimins M
        Increased platelet aggregation in early diabetes mellitus.
        Ann Intern Med. 1975; 82: 733-738
        • Colwell JA
        • Nair RM
        • Halushka PV
        • Rogers C
        • Whetsell A
        • Sagel J
        Platelet adhesion and aggregation in diabetes mellitus.
        Metabolism. 1979; 28: 394-400
        • Chakrabarti R
        • Meade TW
        • WHO Multinational Group
        Clotting factors, platelet function and fibrinolytic activity in diabetics and in a comparison group [abstract].
        Diabetologia. 1976; 12: 383
        • Barnes AJ
        • Locke P
        • Scudder PR
        • Dormandy TL
        • Dormandy JA
        • Slack J
        Is hyperviscosity a treatable component of diabetic microcirculatory disease?.
        Lancet. 1977; 2: 789-791
        • Pelligrino DA
        • LaManna JC
        • Duckrow RB
        • Bryan Jr, RM
        • Harik SI
        Hyperglycemia and blood-brain barrier glucose transport.
        J Cereb Blood Flow Metab. 1992; 12: 887-899
        • Hofer RE
        • Lanier WL
        Effects of insulin on blood, plasma, and brain glucose in hyperglycemic diabetic rats.
        Stroke. 1991; 22: 505-509
        • Hofer RE
        • Lanier WL
        The effects of insulin infusion on plasma and brain glucose in hyperglycemic diabetic rats: a comparison with placebo-treated diabetic and nondiabetic rats.
        Anesthesiology. 1991; 75: 673-678
        • Weglinski MR
        • Hofer RE
        • Lanier WL
        The effects of a continuous glucose infusion on blood, plasma, and brain glucose in anesthetized rats.
        Resuscitation. 1991; 22: 65-74
        • Weglinski MR
        • Lanier WL
        The effects of transient hyperglycemia on brain glucose in rats anesthetized with halothane.
        Anesthesiology. 1990; 73: 291-296
        • Pulsinelli W
        • Waldman S
        • Sigsbee B
        • Rawlinson D
        • Scherer P
        • Plum F
        Experimental hyperglycemia and diabetes mellitus worsen stroke outcome.
        Trans Am Neurol Assoc. 1980; 105: 21-24
        • Liberthson RR
        • Nagel EL
        • Hirschman JC
        • Nussenfeld SR
        Prehospital ventricular defibrillation: prognosis and follow-up course.
        NEngl JMed. 1974; 291: 317-321
        • Kassell NF
        • Tomer JC
        • Haley Jr, EC
        • Jane JA
        • Adams HP
        • Kongable GL
        The International Cooperative Study on the Timing of Aneurysm Surgery. Part I. Overall management results.
        J Neurosurg. 1990; 73: 18-36
        • Voll CL
        • Auer RN
        Insulin attenuates ischemic brain damage independent of its hypoglycemic effect.
        J Cereb Blood Flow Metab. 1991; 11: 1006-1014
        • Warner DS
        • Gionet TX
        • Todd MM
        • McAllister AM
        Insulin-induced normoglycemia improves ischemic outcome in hyperglycemic rats.
        Stroke. 1992; 23: 1775-1780
        • LeMay DR
        • Gehua L
        • Zelenock GB
        • D'Alecy LG
        Insulin administration protects neurologic function in cerebral ischemia in rats.
        Stroke. 1988; 19: 1411-1419
        • Agardh CD
        • Kalimo H
        • Olsson Y
        • Siesjo BK
        Hypoglycemic brain injury. I. Metabolic and light microscopic findings in rat cerebral cortex during profound insulin-induced hypoglycemia and in the recovery period following glucose administration.
        Acta Neuropathol. 1980; 50: 31-41
        • Auer RN
        • Olsson Y
        • Siesjo BK
        Hypoglycemic brain injury in the rat: correlation of density of brain damage with the EEG isoelectric time; a quantitative study.
        Diabetes. 1984; 33: 1090-1098
        • Siemkowicz E
        • Hansen AJ
        Clinical restitution following cerebral ischemia in hypo-, normo- and hyperglycemic rats.
        Acta Neurol Scand. 1978; 58: 1-8
        • Sieber F
        • Smith DS
        • Kupferberg J
        • Crosby L
        • Uzzell B
        • Buzby G
        • et al.
        Effects of intraoperative glucose on protein catabolism and plasma glucose levels in patients with supratentorial tumors.
        Anesthesiology. 1986; 64: 453-459
        • Atchison SR
        • Rettke SR
        • Fromme GA
        • Janossy TA
        • Kunkel SE
        • Williamson KR
        • et al.
        Plasma glucose concentrations during liver transplantation.
        Mayo Clin Proc. 1989; 64: 241-245
        • Skeie B
        • Manner T
        • Askanazi J
        • Khambatta H
        Parenteral nutrition.
        in: Barash PG Cullen BF Stoelting RK Clinical Anesthesia. 2nd ed. Lippincott,, Philadelphia1992: 265-287
        • Doyon S
        • Roberts JR
        Reappraisal of the “coma cocktail”: dextrose, flumazenil, naloxone, and thiamine.
        Emerg Med Clin North Am. 1994; 12: 301-316
        • American Heart Association
        Standards and guidelines for cardiopulmonary resuscitation and emergency cardiac care. Part IV. Adult advanced cardiac life support.
        JAMA. 1980; 244: 479-494
        • American Heart Association
        Guidelines for cardiopulmonary resuscitation and emergency cardiac care. Part III. Adult advanced cardiac life support.
        JAMA. 1992; 268: 2199-2241
        • Duck SC
        • Wyatt DT
        Factors associated with brain herniation in the treatment of diabetic ketoacidosis.
        J Pediatr. 1988; 113: 10-14
        • Rosenbloom AL
        • Riley WJ
        • Weber FT
        • Malone N
        Donnelly WHo Cerebral edema complicating diabetic ketoacidosis in childhood.
        J Pediatr. 1980; 96: 357-361