Object. Recent animal studies demonstrate that excitatory amino acids (EAAs) play a major role in neuronal damage after brain trauma and ischemia. However, the role of EAAs in patients who have suffered severe head injury is not understood. Excess quantities of glutamate in the extracellular space may lead to uncontrolled shifts of sodium, potassium, and calcium, disrupting ionic homeostasis, which may lead to severe cell swelling and cell death. The authors evaluated the role of EEAs in human traumatic brain injury.
Methods. In 80 consecutive severely head injured patients, a microdialysis probe was placed into the gray matter along with a ventriculostomy catheter or an intracranial pressure (ICP) monitor for 4 days. Levels of EAAs and structural amino acids were analyzed using high-performance liquid chromatography. Multifactorial analysis of the amino acid pattern was performed and its correlations with clinical parameters and outcome were tested. The levels of EAAs were increased up to 50 times normal in 30% of the patients and were significantly correlated to levels of structural amino acids both in each patient and across the whole group (p < 0.01). Secondary ischemic brain injury and focal contusions were most strongly associated with high EAA levels (27 ± 22 µmol/L). Sustained high ICP and poor outcome were significantly correlated to high levels of EAAs (glutamate > 20 µmol/L; p < 0.01).
Conclusions. The release of EAAs is closely linked to the release of structural amino acids and may thus reflect nonspecific development of membrane micropores, rather than presynaptic neuronal vesicular exocytosis. The magnitude of EAA release in patients with focal contusions and ischemic events may be sufficient to exacerbate neuronal damage, and these patients may be the best candidates for treatment with glutamate antagonists in the future.
Adams JH, , Graham DI, & Gennarelli TA: Head injury in man and experimental animals: neuropathology. Acta Neurochir (Suppl 32):15–30, 1983 Adams JH, Graham DI, Gennarelli TA: Head injury in man and experimental animals: neuropathology. Acta Neurochir (Suppl 32):15–30, 1983
Becker DP, , Katayama Y, & Tamura T, et al: Excitotoxic ion fluxes and neuronal dysfunction following traumatic brain injury. J Cereb Blood Flow Metab 9 (Suppl 1):S302, 1989 (Abstract) Becker DP, Katayama Y, Tamura T, et al: Excitotoxic ion fluxes and neuronal dysfunction following traumatic brain injury. J Cereb Blood Flow Metab 9 (Suppl 1):S302, 1989 (Abstract)
Benveniste H, , Drejer J, & Schousboe A, et al: Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem 43:1369–1374, 1984 Benveniste H, Drejer J, Schousboe A, et al: Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem 43:1369–1374, 1984
Bouma GJ, , Muizelaar JP, & Stringer WA, et al: Ultra-early evaluation of regional cerebral blood flow in severely head-injured patients using xenon-enhanced computerized tomography. J Neurosurg 77:360–368, 1992 Bouma GJ, Muizelaar JP, Stringer WA, et al: Ultra-early evaluation of regional cerebral blood flow in severely head-injured patients using xenon-enhanced computerized tomography. J Neurosurg 77:360–368, 1992
Bullock R: Opportunities for neuroprotective drugs in clinical management of head injury. J Emerg Med 11 (Suppl 1):23–30, 1993 Bullock R: Opportunities for neuroprotective drugs in clinical management of head injury. J Emerg Med 11 (Suppl 1):23–30, 1993
Bullock R, , Butcher SP, & Chen MH, et al: Correlation of extracellular glutamate concentration with extent of blood flow reduction after subdural hematoma in the rat. J Neurosurg 74:794–801, 1991 Bullock R, Butcher SP, Chen MH, et al: Correlation of extracellular glutamate concentration with extent of blood flow reduction after subdural hematoma in the rat. J Neurosurg 74:794–801, 1991
Bullock R, & Fujisawa H: The role of glutamate antagonists for the treatment of CNS injury. J Neurotrauma 9 (Suppl 2):5443–5462, 1992 Bullock R, Fujisawa H: The role of glutamate antagonists for the treatment of CNS injury. J Neurotrauma 9 (Suppl 2):5443–5462, 1992
Bullock R, , Inglis FM, & Kuroda Y, et al: Transient hippocampal hypermetabolism associated with glutamate release after acute subdural haematoma in the rat: a potentially neurotoxic mechanism. J Cereb Blood Flow Metab 11 (Suppl 2):S109, 1991 (Abstract) Bullock R, Inglis FM, Kuroda Y, et al: Transient hippocampal hypermetabolism associated with glutamate release after acute subdural haematoma in the rat: a potentially neurotoxic mechanism. J Cereb Blood Flow Metab 11 (Suppl 2):S109, 1991 (Abstract)
Bullock R, , Zauner A, & Tsuji O, et al: Excitatory amino acid release after severe human head trauma: effect of intracranial pressure and cerebral perfusion pressure changes, in Nagai H, , Kamiya K, & Ishii S (eds): Intracranial Pressure IX. Tokyo: Springer-Verlag, 1994, pp 264–267 Bullock R, Zauner A, Tsuji O, et al: Excitatory amino acid release after severe human head trauma: effect of intracranial pressure and cerebral perfusion pressure changes, in Nagai H, Kamiya K, Ishii S (eds): Intracranial Pressure IX. Tokyo: Springer-Verlag, 1994, pp 264–267
Bullock R, , Zauner A, & Tsuji O, et al: Patterns of excitatory amino acid release and ionic flux after severe head trauma, in Tsubokawa T, , Marmarou A, & Robertson C, et al (eds): Neurochemical Monitoring in the Intensive Care Unit. Tokyo: Springer-Verlag, 1995, pp 64–67 Bullock R, Zauner A, Tsuji O, et al: Patterns of excitatory amino acid release and ionic flux after severe head trauma, in Tsubokawa T, Marmarou A, Robertson C, et al (eds): Neurochemical Monitoring in the Intensive Care Unit. Tokyo: Springer-Verlag, 1995, pp 64–67
Butcher SP, , Bullock R, & Graham DL, et al: Correlation between amino acid release and neuropathologic outcome in rat brain following middle cerebral artery occlusion. Stroke 21:1727–1733, 1990 Butcher SP, Bullock R, Graham DL, et al: Correlation between amino acid release and neuropathologic outcome in rat brain following middle cerebral artery occlusion. Stroke 21:1727–1733, 1990
Chen MH, , Bullock R, & Graham DI, et al: Ischemic neuronal damage after acute subdural hematoma in the rat: effects of pretreatment with a glutamate antagonist. J Neurosurg 74:944–950, 1991 Chen MH, Bullock R, Graham DI, et al: Ischemic neuronal damage after acute subdural hematoma in the rat: effects of pretreatment with a glutamate antagonist. J Neurosurg 74:944–950, 1991
Choi DW, , Maulucci-Gedde M, & Kriegstein AR: Glutamate neurotoxicity in cortical cell culture. J Neurosci 7:357–368, 1987 Choi DW, Maulucci-Gedde M, Kriegstein AR: Glutamate neurotoxicity in cortical cell culture. J Neurosci 7:357–368, 1987
Choi SC, & Chinchilli VM: Analysis of within- and across-subject correlations, in Bozdogan H, & Gupta AK (eds): Multivariate Statistical Modeling and Data Analysis. Dordrecht: Reidel, 1989, pp 77–94 Choi SC, Chinchilli VM: Analysis of within- and across-subject correlations, in Bozdogan H, Gupta AK (eds): Multivariate Statistical Modeling and Data Analysis. Dordrecht: Reidel, 1989, pp 77–94
During MJ, & Spencer DD: Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain. Lancet 341:1607–1610, 1993 During MJ, Spencer DD: Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain. Lancet 341:1607–1610, 1993
Erb DE, & Povlishock JT: Axonal damage in severe traumatic brain injury: an experimental study in the cat. Acta Neuropathol 76:347–358, 1988 Erb DE, Povlishock JT: Axonal damage in severe traumatic brain injury: an experimental study in the cat. Acta Neuropathol 76:347–358, 1988
Faden AI, , Demediuk P, & Panter SS, et al: The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 244:798–800, 1989 Faden AI, Demediuk P, Panter SS, et al: The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 244:798–800, 1989
Gentleman D, & Jennett B: Hazards of inter-hospital transfer of comatose head injured patients. Lancet 2:853–855, 1981 Gentleman D, Jennett B: Hazards of inter-hospital transfer of comatose head injured patients. Lancet 2:853–855, 1981
Graham DI, , Lawrence AE, & Adams JH, et al: Brain damage in fatal non-missile head injury without high intracranial pressure. J Clin Pathol 41:34–37, 1988 Graham DI, Lawrence AE, Adams JH, et al: Brain damage in fatal non-missile head injury without high intracranial pressure. J Clin Pathol 41:34–37, 1988
Hayes RL, , Jenkins LW, & Lyeth BG, et al: Pretreatment with phencyclidine, an N-methyl-D-aspartate antagonist, attenuates long-term behavioral deficits in the rat produced by traumatic brain injury. J Neurotrauma 5:259–274, 1988 Hayes RL, Jenkins LW, Lyeth BG, et al: Pretreatment with phencyclidine, an N-methyl-D-aspartate antagonist, attenuates long-term behavioral deficits in the rat produced by traumatic brain injury. J Neurotrauma 5:259–274, 1988
Heiss WD, , Hayakawa T, & Waltz AG: Cortical neuronal function during ischemia. Effects of occlusion of one middle cerebral artery on single-unit activity in cats. Arch Neurol 33:813–820, 1976 Heiss WD, Hayakawa T, Waltz AG: Cortical neuronal function during ischemia. Effects of occlusion of one middle cerebral artery on single-unit activity in cats. Arch Neurol 33:813–820, 1976
Hillered L, , Hallström A, & Segersvärd S, et al: Dynamics of extracellular metabolites in the striatum after middle cerebral artery occlusion in the rat monitored by intracerebral microdialysis. J Cereb Blood Flow Metab 9:607–616, 1989 Hillered L, Hallström A, Segersvärd S, et al: Dynamics of extracellular metabolites in the striatum after middle cerebral artery occlusion in the rat monitored by intracerebral microdialysis. J Cereb Blood Flow Metab 9:607–616, 1989
Hillered L, , Persson L, & Carlson H, et al: Studies on excitatory amino acid receptor-linked brain disorders in rat and man using in vivo microdialysis. Clin Neuropharmacol 15 (Suppl 1, Part A):695A–696A, 1992 Hillered L, Persson L, Carlson H, et al: Studies on excitatory amino acid receptor-linked brain disorders in rat and man using in vivo microdialysis. Clin Neuropharmacol 15 (Suppl 1, Part A):695A–696A, 1992
Inglis F, , Kuroda Y, & Bullock R: Glucose hypermetabolism after acute subdural hematoma is ameliorated by a competitive NMDA antagonist. J Neurotrauma 9:75–84, 1992 Inglis F, Kuroda Y, Bullock R: Glucose hypermetabolism after acute subdural hematoma is ameliorated by a competitive NMDA antagonist. J Neurotrauma 9:75–84, 1992
Jenkins LW, , Lyeth BG, & Lewelt W, et al: Combined pretrauma scopolamine and phencyclidine attenuates posttraumatic increased sensitivity to delayed secondary ischemia. J Neurotrauma 5:275–287, 1988 Jenkins LW, Lyeth BG, Lewelt W, et al: Combined pretrauma scopolamine and phencyclidine attenuates posttraumatic increased sensitivity to delayed secondary ischemia. J Neurotrauma 5:275–287, 1988
Jenkins LW, , Moszynski K, & Lyeth BG, et al: Increased vulnerability of the mildly traumatized rat brain to cerebral ischemia: the use of controlled secondary ischemia as a research tool to identify common or different mechanisms contributing to mechanical and ischemic brain injury. Brain Res 477:211–224, 1989 Jenkins LW, Moszynski K, Lyeth BG, et al: Increased vulnerability of the mildly traumatized rat brain to cerebral ischemia: the use of controlled secondary ischemia as a research tool to identify common or different mechanisms contributing to mechanical and ischemic brain injury. Brain Res 477:211–224, 1989
Jones TH, , Morawetz RB, & Crowell RM, et al: Thresholds of focal cerebral ischemia in awake monkeys. J Neurosurg 54:773–782, 1981 Jones TH, Morawetz RB, Crowell RM, et al: Thresholds of focal cerebral ischemia in awake monkeys. J Neurosurg 54:773–782, 1981
Katayama Y, , Becker DP, & Tamura T, et al: Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury. J Neurosurg 73:889–900, 1990 Katayama Y, Becker DP, Tamura T, et al: Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury. J Neurosurg 73:889–900, 1990
Kawamata T, , Katayama Y, & Hovda D, et al: Administration of excitatory amino acid antagonists via microdialysis attenuates the increase in glucose utilization seen following concussive brain injury. J Cereb Blood Flow Metab 12:12–24, 1992 Kawamata T, Katayama Y, Hovda D, et al: Administration of excitatory amino acid antagonists via microdialysis attenuates the increase in glucose utilization seen following concussive brain injury. J Cereb Blood Flow Metab 12:12–24, 1992
Kirino T, , Tamura A, & Sano K: Delayed neuronal death in the rat hippocampus following transient forebrain ischemia. Acta Neuropathol 64:139–147, 1984 Kirino T, Tamura A, Sano K: Delayed neuronal death in the rat hippocampus following transient forebrain ischemia. Acta Neuropathol 64:139–147, 1984
Kotapka MJ, , Graham DI, & Adams JH, et al: Hippocampal pathology in fatal non-missile human head injury. Acta Neuropathol 83:530–534, 1992 Kotapka MJ, Graham DI, Adams JH, et al: Hippocampal pathology in fatal non-missile human head injury. Acta Neuropathol 83:530–534, 1992
Kuroda Y, , Fujisawa H, & Strebel S, et al: Effect of neuroprotective N-methyl-D-aspartate antagonists on increased intracranial pressure: studies in the rat acute subdural hematoma model. Neurosurgery 35:106–112, 1994 Kuroda Y, Fujisawa H, Strebel S, et al: Effect of neuroprotective N-methyl-D-aspartate antagonists on increased intracranial pressure: studies in the rat acute subdural hematoma model. Neurosurgery 35:106–112, 1994
Lindroth P, & Mopper K: High performance liquid chromatographic determination of sub-picomole amounts of amino acids by precolumn fluorescence derivatization with o-pthaldialdehyde. Anal Chem 51:1667–1674, 1979 Lindroth P, Mopper K: High performance liquid chromatographic determination of sub-picomole amounts of amino acids by precolumn fluorescence derivatization with o-pthaldialdehyde. Anal Chem 51:1667–1674, 1979
Lyeth BG, , Jenkins LW, & Hamm RJ, et al: Pretreatment with MK-801 reduces behavioral deficits following traumatic brain injury in rats. Soc Neurosci 15:1113, 1989 (Abstract) Lyeth BG, Jenkins LW, Hamm RJ, et al: Pretreatment with MK-801 reduces behavioral deficits following traumatic brain injury in rats. Soc Neurosci 15:1113, 1989 (Abstract)
McIntosh TK, , Vink R, & Soares H, et al: Effect of noncompetitive blockade of N-methyl-D-aspartate receptors on the neurochemical sequelae of experimental brain injury. J Neurochem 55:1170–1179, 1990 McIntosh TK, Vink R, Soares H, et al: Effect of noncompetitive blockade of N-methyl-D-aspartate receptors on the neurochemical sequelae of experimental brain injury. J Neurochem 55:1170–1179, 1990
McIntosh TK, , Vink R, & Soares H, et al: Effects of the N-methyl-D-aspartate receptor blocker MK-801 on neurologic function after experimental brain injury. J Neurotrauma 6:247–259, 1989 McIntosh TK, Vink R, Soares H, et al: Effects of the N-methyl-D-aspartate receptor blocker MK-801 on neurologic function after experimental brain injury. J Neurotrauma 6:247–259, 1989
Meldrum B: Protection against ischaemic neuronal damage by drugs acting on excitatory neurotransmission. Cerebrovasc Brain Metabol Rev 2:27–57, 1990 Meldrum B: Protection against ischaemic neuronal damage by drugs acting on excitatory neurotransmission. Cerebrovasc Brain Metabol Rev 2:27–57, 1990
Meyer JS, , Hayman LA, & Yamamoto M, et al: Local cerebral blood flow measured by CT after stable xenon inhalation. AJR 135:239–251, 1980 Meyer JS, Hayman LA, Yamamoto M, et al: Local cerebral blood flow measured by CT after stable xenon inhalation. AJR 135:239–251, 1980
Muizelaar JP, & Schröder ML: Overview of monitoring of cerebral blood flow and metabolism after severe head injury. Can J Neurol Sci 21 (Suppl):1–6, 1994 Muizelaar JP, Schröder ML: Overview of monitoring of cerebral blood flow and metabolism after severe head injury. Can J Neurol Sci 21 (Suppl):1–6, 1994
Nehls DG, , Park CK, & MacCormack AG, et al: The effects of N-methyl-D-aspartate receptor blockade with MK-801 upon the relationship between cerebral blood flow and glucose utilization. Brain Res 511:271–279, 1990 Nehls DG, Park CK, MacCormack AG, et al: The effects of N-methyl-D-aspartate receptor blockade with MK-801 upon the relationship between cerebral blood flow and glucose utilization. Brain Res 511:271–279, 1990
Nicholls D, & Attwell D: The release and uptake of excitatory amino acids. Trends Pharmacol Sci 11:462–468, 1990 Nicholls D, Attwell D: The release and uptake of excitatory amino acids. Trends Pharmacol Sci 11:462–468, 1990
Nilsson P, , Hillered L, & Olsson Y, et al: Regional changes in interstitial K+ and Ca2+ levels following cortical compression contusion trauma in rats. J Cereb Blood Flow Metab 13:183–192, 1993 Nilsson P, Hillered L, Olsson Y, et al: Regional changes in interstitial K+ and Ca2+ levels following cortical compression contusion trauma in rats. J Cereb Blood Flow Metab 13:183–192, 1993
Nilsson P, , Hillered L, & Pontén U, et al: Changes in cortical extracellular levels of energy-related metabolites and amino acids following concussive brain injury in rats. J Cereb Blood Flow Metab 10:631–637, 1990 Nilsson P, Hillered L, Pontén U, et al: Changes in cortical extracellular levels of energy-related metabolites and amino acids following concussive brain injury in rats. J Cereb Blood Flow Metab 10:631–637, 1990
Persson L, & Hillered L: Chemical monitoring of neurosurgical intensive care patients using intracerebral microdialysis. J Neurosurg 76:72–80, 1992 Persson L, Hillered L: Chemical monitoring of neurosurgical intensive care patients using intracerebral microdialysis. J Neurosurg 76:72–80, 1992
Ronne-Engström E, , Hillered L, & Flink R, et al: Intracerebral microdialysis of extracellular amino acids in the human epileptic focus. J Cereb Blood Flow Metab 12:873–876, 1992 Ronne-Engström E, Hillered L, Flink R, et al: Intracerebral microdialysis of extracellular amino acids in the human epileptic focus. J Cereb Blood Flow Metab 12:873–876, 1992
Rothman SM, & Olney JW: Excitotoxicity and the NMDA receptor. Trends Neurosci 10:299–302, 1987 Rothman SM, Olney JW: Excitotoxicity and the NMDA receptor. Trends Neurosci 10:299–302, 1987
Schröder ML, , Muizelaar JP, & Kuta AJ: Documented reversal of global ischemia immediately after removal of acute subdural hematoma. Report of two cases. J Neurosurg 80:324–327, 1994 Schröder ML, Muizelaar JP, Kuta AJ: Documented reversal of global ischemia immediately after removal of acute subdural hematoma. Report of two cases. J Neurosurg 80:324–327, 1994
Shapira Y, , Yadid G, & Cotev S, et al: Protective effect of MK801 in experimental brain injury. J Neurotrauma 7:131–139, 1990 Shapira Y, Yadid G, Cotev S, et al: Protective effect of MK801 in experimental brain injury. J Neurotrauma 7:131–139, 1990
Shimada N, , Graf R, & Rosner G, et al: Differences in ischemia-induced accumulation of amino acids in the cat cortex. Stroke 21:1445–1451, 1990 Shimada N, Graf R, Rosner G, et al: Differences in ischemia-induced accumulation of amino acids in the cat cortex. Stroke 21:1445–1451, 1990
Shimada N, , Graf R, & Rosner G, et al: Ischemia-induced accumulation of extracellular amino acids in cerebral cortex, white matter, and cerebrospinal fluid. J Neurochem 60:66–71, 1993 Shimada N, Graf R, Rosner G, et al: Ischemia-induced accumulation of extracellular amino acids in cerebral cortex, white matter, and cerebrospinal fluid. J Neurochem 60:66–71, 1993
Shiraishi K, , Sharp FR, & Simon RP: Sequential metabolic changes in rat brain following middle cerebral artery occlusion: a 2-deoxyglucose study. J Cereb Blood Flow Metab 9:765–773, 1989 Shiraishi K, Sharp FR, Simon RP: Sequential metabolic changes in rat brain following middle cerebral artery occlusion: a 2-deoxyglucose study. J Cereb Blood Flow Metab 9:765–773, 1989
Smith DH, , Okiyama K, & McIntosh T: Ketamine and magnesium attenuates memory loss after experimental brain injury. Soc Neurosci 17:167, 1991 (Abstract) Smith DH, Okiyama K, McIntosh T: Ketamine and magnesium attenuates memory loss after experimental brain injury. Soc Neurosci 17:167, 1991 (Abstract)
Smith DH, , Okiyama K, & Thomas M, et al: The effects of two novel NMDA antagonists on regional cation concentration and edema formation following experimental brain injury. J Cereb Blood Flow Metab 11 (Suppl 2):S300, 1991 (Abstract) Smith DH, Okiyama K, Thomas M, et al: The effects of two novel NMDA antagonists on regional cation concentration and edema formation following experimental brain injury. J Cereb Blood Flow Metab 11 (Suppl 2):S300, 1991 (Abstract)
Smith DH, , Okiyama K, & Thomas M, et al: An NMDA receptor-associated glycine site antagonist attenuates memory loss after experimental brain injury. Soc Neurosci 2:779, 1990 (Abstract) Smith DH, Okiyama K, Thomas M, et al: An NMDA receptor-associated glycine site antagonist attenuates memory loss after experimental brain injury. Soc Neurosci 2:779, 1990 (Abstract)
Smith DH, , Thomas M, & Soares H, et al: Differential effects of competitive and non-competitive N-methyl-D-aspartate (NMDA) antagonists following experimental brain injury. J FASEB 4:400, 1990 (Abstract) Smith DH, Thomas M, Soares H, et al: Differential effects of competitive and non-competitive N-methyl-D-aspartate (NMDA) antagonists following experimental brain injury. J FASEB 4:400, 1990 (Abstract)
Takizawa S, , Hogan M, & Hakim AM: The effects of a competitive NMDA receptor antagonist (CGS-19755) on cerebral blood flow and pH in focal ischemia. J Cereb Blood Flow Metab 11:786–793, 1991 Takizawa S, Hogan M, Hakim AM: The effects of a competitive NMDA receptor antagonist (CGS-19755) on cerebral blood flow and pH in focal ischemia. J Cereb Blood Flow Metab 11:786–793, 1991
Zauner A, , Bullock R, & Kuta AJ, et al: Glutamate release and cerebral blood flow after severe human head injury. Acta Neurochir Suppl 67:40–44, 1996 Zauner A, Bullock R, Kuta AJ, et al: Glutamate release and cerebral blood flow after severe human head injury. Acta Neurochir Suppl 67:40–44, 1996
Zauner A, , Doppenberg EMR, & Woodward JJ, et al: Continuous monitoring of cerebral substrate delivery and clearance: initial experience in 24 patients with severe acute brain injuries. Neurosurgery 41:1082–1093, 1997 Zauner A, Doppenberg EMR, Woodward JJ, et al: Continuous monitoring of cerebral substrate delivery and clearance: initial experience in 24 patients with severe acute brain injuries. Neurosurgery 41:1082–1093, 1997
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