Increase in extracellular glutamate caused by reduced cerebral perfusion pressure and seizures after human traumatic brain injury: a microdialysis study

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Object. To determine the extent and duration of change in extracellular glutamate levels after human traumatic brain injury (TBI), 17 severely brain injured adults underwent implantation of a cerebral microdialysis probe and systematic sampling was conducted for 1 to 9 days postinjury.

Methods. A total of 772 hourly microdialysis samples were obtained in 17 patients (median Glasgow Coma Scale score 5 ± 2.5, mean age 39.4 ± 20.4 years). The mean (± standard deviation) glutamate levels in the dialysate were evaluated for 9 days, during which the mean peak concentration reached 25.4 ± 13.7 (µM on postinjury Day 3. In each patient transient elevations in glutamate were seen each day. However, these elevations were most commonly seen on Day 3. In all patients there was a mean of 4.5 ± 2.5 transient elevations in glutamate lasting a mean duration of 4.4 ± 4.9 hours. These increases were seen in conjunction with seizure activity. However, in many seizure-free patients the increase in extracellular glutamate occurred when cerebral perfusion pressure was less than 70 mm Hg (p < 0.001). Given the potential injury-induced uncoupling of cerebral blood flow and metabolism after TBI, these increases in extracellular glutamate may reflect a degree of enhanced cellular crisis, which in severe head injury in humans appears to last up to 9 days.

Conclusions. Extracellular neurochemical measurements of excitatory amino acids may provide a marker for secondary insults that can compound human TBI.

Article Information

Address for Dr. Ronne-Engstrom: Uppsala University, Uppsala, Sweden.Address for Dr. Caron: Silver Cross Hospital, Joliet, Illinois.Address for Dr. Shalmon: University of Miami, Miami, Florida.Address reprint requests to: Paul M. Vespa, M.D., Department of Surgery (Division of Neurosurgery), University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, California 90024. email: vespa@ucla.edu.

© AANS, except where prohibited by US copyright law.

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    Upper: Graph showing the trend of consecutive hourly microdialysate glutamate levels (circles) along with the simultaneous lowest CPP value (diamonds) during each corresponding hour in a 33-year-old man with multiple bilateral contusions and a GCS score of 4. At Hour 45, the CPP is greater than 90 mm Hg (torr) and there is a decrease in glutamate levels to less than 20 µM, but this is followed by a second glutamate increase at Hour 50. Between Hours 60 to 70, 74 to 77 and 80 to 94, CPP values are less than 70 mm Hg, with a fluctuating yet sustained increase in glutamate in the 50- to 90-µM range. The double dotted lines represent the CPP threshold of 70 mm Hg. Lower: Graph showing another example of the trend of consecutive hourly microdialysate glutamate levels with corresponding CPP values in a 30-year-old woman with a right frontal contusion and a GCS score of 3. Transient elevations in glutamate occur with sustained decreases in CPP to less than 70 mm Hg at 26, 32, 46, 59, 67, and 74 hours. At Hours 30 to 40 and Hours 48 to 58 there is a decrease in glutamate with sustained CPP greater than 70 mm Hg. Note that the duration and extent of the glutamate increases match those of decreases in CPP.

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    Graph showing the trend of mean glutamate levels (± standard deviation) of all patients by postinjury day. There are different numbers of patients on each postinjury day, and the mean values represent different numbers of individual samples per patient per day. See Time Course of Glutamate Increases for full description.

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    Bar graph showing the means of isolated glutamate transient elevations for individual patients segregated by postinjury day. Each bar type represents one patient, and each plotted value is a mean of all transient increases on that postinjury day for each patient. Transient elevations continued to occur on each of the days sampled, with variations in the mean amplitudes of the transient readings between patients, but no decrease in transient events across time.

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    Upper: Scatterplot of matched hourly samples of glutamate level and lowest CPP during the sampling hour. An increase in glutamate values is seen at CPP values lower than 70 mm Hg (p < 0.001). Note that most values of CPP are greater than 70 mm Hg. Two patients with evidence of glutamate increases related to seizure activity were excluded. Lower: Scatterplot of matched hourly samples of glutamate and CPP for two patients in whom seizure activity occurred intermittently during microdialysis. An increase in glutamate levels is seen as CPP increases. Note that in this group of patients CPP levels of less than 70 mm Hg are rare.

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    Bar graph comparing grouped hourly amino acid levels and the matching hourly CPP values, stratified by CPPs of less than and greater than 70 mm Hg. There were no differences in mean levels of serine (p < 0.27) or aspartate (p < 0.07) between the two CPP strata. There was a higher mean level of glutamate at a CPP of less than 70 and a higher mean level of glycine at a CPP of greater than 70. The increase in glutamate at a CPP of less than 70 mm Hg is specific for that EAA. *p < 0.01; **p < 0.001.

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    Bar graph showing matched hourly samples of glutamate, glycine, and CPP in a 27-year-old man with diffuse axonal injury and a GCS of 3. Transient increases in glycine occur during which glutamate levels are relatively low (10 µM, solid arrow). At other times there are transient increases in glutamate associated with a reduction in CPP at 96 hours (open arrow), with less prominent increases in glycine.

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