Increases in GABA concentrations during cerebral ischaemia: a microdialysis study of extracellular amino acids.

OBJECTIVES: Increases in the extracellular concentration of the excitatory amino acids glutamate and aspartate during cerebral ischaemia in patients are well recognised. Less emphasis has been placed on the concentrations of the inhibitory amino acid neurotransmitters, notably gamma-amino-butyric acid (GABA), despite evidence from animal studies that GABA may act as a neuroprotectant in models of ischaemia. The objective of this study was to investigate the concentrations of various excitatory, inhibitory and non-transmitter amino acids under basal conditions and during periods of cerebral ischaemia in patients with head injury or a subarachnoid haemorrhage. METHODS: Cerebral microdialysis was established in 12 patients with head injury (n=7) or subarachnoid haemorrhage (n=5). Analysis was performed using high performance liquid chromatography for a total of 19 (excitatory, inhibitory and non-transmitter) amino acids. Patients were monitored in neurointensive care or during aneurysm clipping. RESULTS: During stable periods of monitoring the concentrations of amino acids were relatively constant enabling basal values to be established. In six patients, cerebral ischaemia was associated with increases (up to 1350 fold) in the concentration of GABA, in addition to the glutamate and aspartate. Parallel increases in the concentration of glutamate and GABA were found (r=0.71, p<0.005). CONCLUSIONS: The results suggest that, in the human brain, acute cerebral ischaemia is not accompanied by an imbalance between excitatory and inhibitory amino acids, but by an increase in all neurotransmitter amino acids. These findings concur with the animal models of ischaemia and raise the possibility of an endogenous GABA mediated neuroprotective mechanism in humans.

Head injury monitoring using cerebral microdialysis and Paratrend multiparameter sensors.

INTRODUCTION: Following head injury complex pathophysiological changes occur in brain metabolism. The objective of the study was to monitor brain metabolism using the Paratrend multiparameter sensor and microdialysis catheters. PATIENTS, MATERIAL AND METHODS: Following approval by the Local Ethics Committee and consent from the relatives, patients with severe head injury were studied using a triple bolt inserted into the frontal region, transmitting an intracranial pressure monitor, microdialysis (10 mm or 30 mm membrane; glucose, lactate, pyruvate, glutamate) catheter and Paratrend multiparameter (oxygen, carbon dioxide, pH and temperature) sensor. A Paratrend sensor was also inserted into the femoral artery for continuous blood gas analysis. RESULTS: 21 patients were studied with cerebral microdialysis for a total of 91 monitoring days (range 19 hours to 12 days). Of these, 14 patients were also studied with cerebral and arterial Paratrend sensors. The mean (+/- 95% confidence intervals) arterial and cerebral oxygen levels were 123 +/- 10.9 mmHg and 27.9 +/- 5.71 mmHg respectively. The arterial and cerebral carbon dioxide levels were 34.3 +/- 2.35 mmHg and 45.3 +/- 3.07 mmHg respectively. Episodes of systemic hypoxia and hypotension resulting in falls in cerebral oxygen and rises in cerebral carbon dioxide were rapidly detected by the arterial and cerebral Paratrend sensors. Systemic pyrexia was reflected in the brain with the cerebral Paratrend sensor reading 0.17 degree C (mean) higher than the arterial sensor. Elevations of cerebral glucose were detected, but the overall cerebral glucose was low (mean 1.57 +/- 0.53 mM 10 mm membrane; mean 1.95 +/- 0.68 mM 30 mm membrane) with periods of undetectable glucose in 6 patients. Lactate concentrations (mean 5.08 +/- 0.73 mM 10 mm membrane; mean 8.27 +/- 1.31 mM 30 mm membrane) were higher than glucose concentrations in all patients. The lactate/pyruvate ratio was 32.1 +/- 5.16 for the 10 mm membrane and 30.6 +/- 2.17 for the 30 mm membrane. Glutamate concentrations varied between patients (mean 15.0 +/- 10.5 microM 10 mm membrane; mean 28.8 +/- 17.8 microM 30 mm membrane). CONCLUSION: The combination of microdialysis catheters and Paratrend sensors enabling the monitoring of substrate delivery and brain metabolism, and the detection of secondary metabolic insults has the potential to assist in the management of head-injured patients.

Clinical cerebral microdialysis: a methodological study.

OBJECT: Clinical microdialysis enables monitoring of the cerebral extracellular chemistry of neurosurgical patients. Introduction of the technique into different hospitals' neurosurgical units has resulted in variations in the method of application. There are several variables to be considered, including length of the catheter membrane, type of perfusion fluid, flow rate of perfusion fluid, and on-line compared with delayed analysis of samples. The objects of this study were as follows: 1) to determine the effects of varying catheter characteristics on substance concentration; 2) to determine the relative recovery and true extracellular concentration by varying the flow rate and extrapolating to zero flow; and 3) to compare substance concentration obtained using a bedside enzyme analyzer with that of off-line high-performance liquid chromatography (HPLC). METHODS: A specially designed bolt was used to conduct two adjacent microdialysis catheters into the frontal cortex of patients with head injury or poor-grade subarachnoid hemorrhage who were receiving ventilation. One reference catheter (10-mm membrane, perfused with Ringer's solution at 0.3 microl/minute) was constant for all studies. The other catheter was varied in terms of membrane length (10 mm or 30 mm), perfusion fluid (Ringer's solution or normal saline), and flow rate (0.1-1.5 microl/minute). The effect of freezing the samples on substance concentration was established by on-line analysis and then repeated analysis after storage at -70 degrees C for 3 months. Samples assayed with the bedside enzyme analyzer were reassessed using HPLC for the determination of glutamate concentrations. CONCLUSIONS: Two adjacent microdialysis catheters that were identical in membrane length, perfusion fluid, and flow rate showed equivalent results. Variations in perfusion fluid and freezing and thawing of samples did not result in differences in substance concentration. Catheter length had a significant impact on substance recovery. Variations in flow rate enabled the relative recovery to be calculated using a modification of the extrapolation-to-zero-flow method. The recovery was approximately 70% at 0.3 microl/minute and 30% at 1 microl/minute (10-mm membrane) for all analytes. Glutamate results obtained with the enzyme analyzer showed good correlation with those from HPLC.

On-line monitoring of substrate delivery and brain metabolism in head injury.

Head injury is associated with complex pathophysiological changes in metabolism. The objective of the study was to investigate these changes by applying on-line bedside monitoring of cerebral metabolism using microdialysis. Following approval by the Local Ethics Committee and consent from the next of kin, a microdialysis catheter was inserted into the frontal cortex of patients with severe head injury. Twenty-one patients were studied for 102.3 +/- 26.9 hours (mean +/- 95% confidence interval; total 89.4 patient monitoring days). The overall cerebral glucose (mean of means) was 1.63 +/- 0.31 mM with periods of undetectable glucose recorded. The cerebral lactate and lactate/pyruvate ratio were 4.69 +/- 0.61 mM and 29.9 +/- 3.73 respectively. Patients who died (n = 4) or who were severely disabled (not proceeding to rehabilitation, n = 5) had a tendency towards lower glucose (1.39 +/- 0.35 mM), higher lactate (5.10 +/- 1.02 mM) and higher lactate/pyruvate ratios (35.5 +/- 7.67) compared to patients with good outcome (home or proceeding to rehabilitation, n = 12, glucose 1.80 +/- 0.49 mM, lactate 4.38 +/- 0.85 mM, lactate/pyruvate ratio 27.9 +/- 4.33). Trends in these metabolic parameters relating to outcome were identifiable. In the majority of patients, cerebral glutamate levels (overall mean of means 9.47 +/- 4.59 microM) were initially high and then declined to stable levels. Patients in whom the glutamate level remained elevated or in whom secondary rises in glutamate were seen had a poor outcome. The application of bedside analysis of microdialysis enables the progress of the patient to be monitored on-line. In addition to establishing trends of improving and deteriorating metabolism, the technique has the potential to monitor the effects of therapeutic manoeuvres on the biochemistry.

Monitoring of brain metabolism during aneurysm surgery using microdialysis and brain multiparameter sensors.

The aim of the study was to monitor brain metabolism during aneurysm clipping using microdialysis and multiparameter sensors, particularly to investigate the effects of temporary clipping of vessels. Microdialysis catheters (n = 10) and Paratrend brain multiparameter (O2, CO2, pH and temperature) sensors (n = 15) were inserted into the cerebral cortex via a specially designed triple bolt prior to craniotomy. Baseline brain O2 levels ranging from 15-45 mmHg (2.0-6.0 kPa) and glucose levels from 0.5-3 mmol l-1 were stable during uneventful periods. The mean lactate/pyruvate (L/P) ratio ranged from 32 to 65 (normal < 30), indicating a tendency towards anerobic metabolism in all patients. Overall, short periods of temporary clipping (< 3 min; n = 6) were well tolerated producing no significant reduction in brain O2 (pre-clip mean 23 mmHg (3.0 kPa) vs. post-clip mean 20 mmHg (2.6 kPa)) or elevation of the L/P ratio (pre-clip mean 42 vs. post-clip mean 43). Two patients with prolonged temporary clipping showed derangements in the Paratrend parameters associated with increases in the L/P ratio. The results demonstrated that the monitored variables remained stable during uneventful procedures, including transient temporary clipping, but adverse events such as prolonged temporary clipping resulted in pronounced changes in brain metabolism. Monitoring of metabolism during aneurysm surgery may be of benefit in selected patients.

Monitoring by subcutaneous microdialysis in neurosurgical intensive care.

Microdialysis is an in vivo sampling technique which provides a powerful approach to monitoring metabolic events. We have performed a study to determine the feasibility and effectiveness of subcutaneous microdialysis in monitoring patients on the Neurosurgical Intensive Care Unit (NICU). A microdialysis probe was placed in the subcutaneous fat of the anterior abdominal wall and perfused with Ringer's solution. Collecting vials were changed every 30 minutes and monitoring continued for 2-6 days. Biochemical analysis of glucose, lactate, and glutamate was correlated with clinical events. The normal ranges of glucose, lactate and glutamate were 3-6 mM. 1-2.5 mM and 5-20 microM, respectively. Periods of low tissue glucose were detected by microdialysis which were not detected by routine plasma sampling. In one patient, following an apparently brief period of hypoxia, there was a prolonged disturbance of tissue chemistry. Another patient with obesity had significantly higher concentrations of dialysate glucose, lactate and glutamate. Monitoring by subcutaneous microdialysis on intensive care units is feasible, reveals unexpected changes in tissue metabolism and might be an important adjunct for the interpretation of intracerebral data.