Spontaneous cortical spreading depression and intracranial pressure following acute subdural hematoma in a rat.

Acute subdural hemorrhage (ASDH) is a frequent and devastating consequence of traumatic brain injury. Tissue damage develops rapidly and makes treatment even more difficult. Management of increased intracranial pressure (ICP) due to extravasated blood volume and brain swelling is often insufficient to control all adverse effects of ASDH. In addition to sheer volume, spontaneously triggered cortical spreading depression (CSD) that leads to cell death following ischemia or trauma may contribute to injury development after ASDH. Therefore, we explored the occurrence of CSD by tissue impedance (IMP) measurement in a rat model subjected to ASDH. IMP and intraventricular and mean arterial pressure were monitored before (baseline), during (blood infusion), and after ASDH for 3 h.Tissue impedance increased by around 203% of baseline during subdural infusion of 300 µl of autologous, venous blood and dropped back to baseline within 22 min. Fifty-six minutes after the start of ASDH a cluster of four short-lasting (3-3.5 min; 140-160% of baseline) IMP increases started that reflected spontaneous CSDs. This pattern presumes that CSD occurs early after ASDH and therefore may contribute to the rapid lesion development in this disease.

Effects of a small acute subdural hematoma following traumatic brain injury on neuromonitoring, brain swelling and histology in pigs.

An acute subdural hematoma (ASDH) induces pathomechanisms which worsen outcome after traumatic brain injury, even after a small hemorrhage. Synergistic effects of a small ASDH on brain damage are poorly understood, and were studied here using neuromonitoring for 10 h in an injury model of controlled cortical impact (CCI) and ASDH. Pigs (n = 32) were assigned to 4 groups: sham, CCI (2.5 m/s), ASDH (2 ml) and CCI + ASDH. Intracranial pressure was significantly increased above sham levels by all injuries with no difference between groups. CCI and ASDH reduced ptiO(2) by a maximum of 36 ± 9 and 26 ± 11%, respectively. The combination caused a 31 ± 11% drop. ASDH alone and in combination with CCI caused a significant elevation in extracellular glutamate, which remained increased longer for CCI + ASDH. The same two groups had significantly higher peak lactate levels compared to sham. Somatosensory evoked potential (SSEP) amplitude was persistently reduced by combined injury. These effects translated into significantly elevated brain water content and histological damage in all injury groups. Thus, combined injury had stronger effects on glutamate and SSEP when compared to CCI and ASDH, but no clear-cut synergistic effects of 2 ml ASDH on trauma were observed. We speculate that this was partially due to the CCI injury severity.

Caspase-dependent cell death involved in brain damage after acute subdural hematoma in rats.

Traumatic brain injury is associated with acute subdural hematoma (ASDH) that worsens outcome. Although early removal of blood can reduce mortality, patients still die or remain disabled after surgery and additional treatments are needed. The blood mass and extravasated blood induce pathomechanisms such as high intracranial pressure (ICP), ischemia, apoptosis and inflammation which lead to acute as well as delayed cell death. Only little is known about the basis of delayed cell death in this type of injury. Thus, the purpose of the study was to investigate to which extent caspase-dependent intracellular processes are involved in the lesion development after ASDH in rats. A volume of 300microL blood was infused into the subdural space under monitoring of ICP and tissue oxygen concentration. To asses delayed cell death mechanisms, DNA fragmentation was measured 1, 2, 4 and 7 days after ASDH by TUNEL staining, and the effect of the pan-caspase inhibitor zVADfmk on lesion volume was assessed 7 days post-ASDH. A peak of TUNEL-positive cells was found in the injured cortex at day 2 after blood infusion (53.4+/-11.6 cells/mm(2)). zVADfmk (160ng), applied by intracerebroventricular injection before ASDH, reduced lesion volume significantly by more than 50% (vehicle: 23.79+/-7.62mm(3); zVADfmk: 9.06+/-4.08). The data show for the first time that apoptotic processes are evident following ASDH and that caspase-dependent mechanisms play a crucial role in the lesion development caused by the blood effect on brain tissue.

Brain oxygen monitoring: in-vitro accuracy, long-term drift and response-time of Licox- and Neurotrend sensors.

BACKGROUND: Oxygen tension sensors have been used to monitor tissue oxygenation in human brain for several years. The working principals of the most frequently used sensors, the Licox (LX) and Neurotrend (NT), are different, and they have never been validated independently for correct measurement in vitro. Therefore, we tried to clarify if the two currently available sensors provide sufficient accuracy and stability. METHOD: 12 LX oxygen tension sensors and NT sensors were placed into a liquid-filled tonometer chamber. The solution was kept at 37 +/- 0.2 degrees C and equilibrated with five calibration gases containing different O(2)- and CO(2)-concentrations. After equilibration, readings were taken for each gas concentration (accuracy test). Afterwards, the sensors were left in 3% O(2) and 9% CO(2) and readings were taken after 24, 48, 72, 96 and 120 hours (drift test). Thereafter, a 90% response time test was performed transferring sensors from 1% to 5% oxygen concentration and back, using pre-equilibrated tonometers. FINDINGS: All Licox oxygen probes [12] were used for this study. Two of 14 Neurotrend sensors did not calibrate, revealing a failure rate of 14% for NT. Oxygen tension during the accuracy test was measured as follows: 1% O(2) (7.1 mmHg): LX 6.5 +/- 0.4, NT 5.3 +/- 2.3 mmHg, 2% O(2) (14.2 mmHg): LX 12.9 +/- 0.6, NT 12.1 +/- 2.2 mmHg, 3% O(2) (21.4 mmHg): LX 19.8 +/- 0.7, NT 19.4 +/- 2.4 mmHg, 5% O(2) (35.8 mmHg): LX 33.4 +/- 1.0 mmHg, NT 33.5 +/- 2.9 mmHg, 8% O(2) (57.0 mmHg): 53.8 +/- 1.5, NT 53.6 +/- 3.3 mmHg. After 120 hours in 3% O(2) (21 mmHg), LX measured 19.8 +/- 1.9 mmHg, NT 17.9 +/- 4.7 mmHg. 90% response time from 1% to 5%/5% to 1% oxygen concentration was 129 +/- 27/174 +/- 26 sec for LX, 55 +/- 19/98 +/- 39 sec for NT. CONCLUSIONS: Both systems are measuring oxygen tension sufficiently, but more accurately with LX probes. NT sensors read significantly lower pO(2) in 1% O(2) and show an increasing deviation with higher oxygen concentrations which was due to two of twelve probes. A slight drift towards lower oxygen tension readings for both sensors but more pronounced for the NT does not impair long-term use. NT measures pCO(2) and pH very accurately.

Extracellular N-acetyl-aspartate as a biochemical marker of the severity of neuronal damage following experimental acute traumatic brain injury.

We evaluated the acute changes in interstitial and whole brain N-acetyl-aspartate (NAA) measured by high-performance liquid chromatography in animal models of isolated traumatic brain injury (TBI) and TBI combined with secondary insult (hypotension-hypoxia [HH]). The Marmarou impact-acceleration model was used. Four groups were studied: (1) sham-operated control, (2) TBI alone (TBI 500 gm, 2 m), (3) TBI plus 30 min of hypoxia (PaO2, approximately 40 mm Hg) and hypotension (mean arterial blood pressure, approximately 40 mm Hg) (THH), and (4) HH alone. The baseline value for dialysate NAA (NAAd) in the rats was 8.17+/-1 microM. No significant difference between groups was found for this baseline value. The TBI group had a modest (100%) transient increase in NAAd after isolated TBI. The HH group had a transient (500%) increase in NAAd at 1 h, sustained for 2 h. In the THH group, there was a persistent increase in NAAd (800%) that peaked at 2.5 h. The whole brain NAA (NAAw) concentration in controls was 8.5+/-0.5 mmol/kg wet weight. There was no significant difference between TBI and controls; however, there was a significant decrease in NAAw in the THH and HH group compared to controls. Thus, in this animal model of TBI and TBI with secondary insult, we found that persistent, marked elevation in NAA is associated with TBI and secondary ischemic/hypoxic insult, but not with isolated TBI alone.

Detection of ultra-early brain damage after acute subdural hematoma in the rat by magnetic resonance imaging.

We measured serial changes in diffusion-weighted magnetic resonance imaging (DW) and in apparent diffusion coefficient (ADC) 1 to 3 hours after induction of acute subdural hematoma (ASDH) in rats, to assess the rate of development of cytotoxic edema and ischemic brain damage observed in this model. Cortical ADC values underneath the hematoma in ASDH rats (n = 12) were significantly lower than those in sham-operated rats (n = 5) at 1 hour. By 3 hours, the area of ADC abnormality had further increased. The lesion areas, as percentage of hemispheric areas on 1- and 3-hour ADC maps, correlated significantly with those on the histologic sections stained with hematoxylin and eosin. The results indicate that DWI with ADC mapping may provide a valuable diagnostic tool for monitoring of early pathologic changes following subdural hematoma in head-injured patients.

Fluid percussion injury transiently increases then decreases brain oxygen consumption in the rat.

The oxygen consumption (VO2 microL/h/mg) of sham and of traumatized rat brains within 30 min and 6 h after a lateral fluid percussion injury (FPI) was measured with the Cartesian microrespirometer. Brain slices were cut at the plain of injury and site-specific 20-60-microg cores of tissue were transferred to the microrespirometer. In sham brains, the cortical VO2 (CVO2) was 13.78+/-0.64 and the hippocampal VO2 (HPVO2) was 11.20+/-0.58 microL/h/mg (p<0.05). Within 30 min of the injury, the respective values of 16.89+/-0.55 and 14.91+/-0.06 were significantly increased (p<0.05). The combined VO2 (CVO2, HPVO2) of 12.49+/-0.06 microL/h/mg in shams was significantly less than the combined VO2 of 15.90+/-0.59 microL/h/mg at 30 min post FPI (p<0.001). The maximal CVO2 of 19.49+/-1.10 microL/h/mg and the maximal HPVO2 of 15.98+/-0.99 microL/h/mg were both obtained from the ipsilateral side of the injury. Whereas the contralateral cortical value for injured brains was not significantly different from that of the shams, both ipsilateral and contralateral hippocampal values were significantly greater than that of the shams in response to injury (p<0.05). By 6 h postinjury, the combined VO2 had dropped to 10.01+/-0.84 microL/h/mg but was not significantly lower than the sham values. The data indicate that normal CVO2 is greater than normal HPVO2. The FPI produces significant increases in both CVO2 and HPVO2. Also, while the immediate increase in CVO2 appears to be injury-site dependent, that is, regional, the increase in HPVO2 appears to be global.

Reducing hemoglobin oxygen affinity does not increase hydroxyl radicals after acute subdural hematoma in the rat.

Extensive evidence is available to show the importance of ischemia after severe human head injury. We have previously shown that pharmacologically increasing the release of oxygen in brain tissue where the local oxygen pressure is low reduces infarct size in animal models. To study the possible negative effects of this strategy, we tested the effect of an allosteric modifier of hemoglobin (RSR13) on free radical production in the rat acute subdural hematoma (ASDH) model, both under normoxic as well as under hyperoxic, normobaric conditions. When compared to baseline, induction of ASDH resulted in a significant increase (p < 0.05) in 2,3-DHBA (2,3 dihydroxybenzoic acid, produced from salicylate after attack by hydroxyl radicals) at 30 and 60 min postinduction, both for the control group (39% and 91%) as well as the RSR13-treated group (41% and 62%). The 2,5-DHBA also increased significantly (p < 0.05) in the drug-treated animals at the 30- and 60-min time points when compared to baseline (49% and 77%). At all time points, except the 30-min, the increase in 2,3-DHBA was less marked in the RSR13 animals than in the control group. Similarly, the 2,5-DHBA increase after ASDH was lower at all time points except for the 30-min time point in the RSR13-treated group. These results indicate that enhanced tissue oxygen release by the allosteric modifier of hemoglobin RSR13 does not increase hydroxyl radical production after ASDH. Clinical trials are needed to test this compound in humans after severe head injury.

The effects of long-term nicotine treatment on locomotion, exploration and memory in young and old rats.

To assess the effects of long-term treatment with nicotine on several behavioral measures (locomotor activity, exploratory efficiency, habituation, short-term and long-term memory) of young (5 months) and old (22 months) rats in a hexagonal tunnel maze, nicotine was added to the drinking water (0, 20 or 50 mg/l) for up to 131 experimental days. With the exception of effects on exploratory efficiency, young and old rats did not differ in their response to the drug. Nicotine decreased body weight throughout the experiment. Nicotine treatment reduced water intake during the first 30 min of the daily 4.5 h access to drinking water. Nicotine increased locomotor activity throughout the experiment. When nicotine treatment was discontinued during a 7-day withdrawal period, locomotor activity immediately dropped to control values. Intertrial habituation was not affected by nicotine. Long-term nicotine treatment had an attenuating effect on exploratory efficiency in young rats; however, the drug did not influence performance in tasks measuring spatial memory. Finally, age increased weight, decreased locomotor activity and impaired exploratory efficiency and short-term memory. Age, however, did not affect the performance of the long-term memory task.

The neuroprotective effect of a new serotonin receptor agonist, BAY X3702, upon focal ischemic brain damage caused by acute subdural hematoma in the rat.

We tested the neuroprotective effect of a novel, high affinity serotonin (5-HT1A) agonist, BAY X3702, in a rat model of acute subdural hematoma (ASDH). Animals were treated with 0.01 mg/kg (n=8), 0.003 mg/kg (n=8) BAY X3702 or vehicle (n=4) 15 min before (i.v.) and after (continuous infusion) injection of 400 microl of autologous blood into the subdural space. The ischemic brain damage at 4 h after ASDH was 59.01+/-39 and 60.8+/-49 mm(3) for the low- and high-dose BAY X3702 group, respectively, which was significantly smaller compared to the vehicle-treated ASDH group (106.2+/-33 mm(3)). The result indicates that this novel, high affinity 5-HT(1A) agonist, BAY X3702, is neuroprotective in this model.

Lactate administration attenuates cognitive deficits following traumatic brain injury.

Moderately head injured patients often suffer long term neurological sequelae. There is no therapy for brain trauma and current treatments aim only to minimize secondary damage. These secondary effects are often triggered by the inability to re-establish ionic homeostasis after injury, due to large energy demands. Recent reports have demonstrated that neurons are capable of utilizing lactate as an energy source, thus this report examines the usefulness of lactate administration in the attenuation of behavioural deficits following a moderate brain injury. Lactate infusion (i.v.) was started 30 min after lateral fluid percussion injury and continued for 3 h. Cognitive deficits were determined using the Morris water maze. Lactate infused injured animals demonstrated significantly less cognitive deficits than saline infused injured animals. Thus, lactate infusion attenuated the cognitive deficits normally observed in this model, and therefore may provide moderately head injured patients with a treatment to help ameliorate the sequelae.

The use of an unbaited radial maze in neurotoxicology: II. Sensory inputs, general malaise and locomotor activity.

An unbaited 6-arm radial tunnel maze (6-arm RTM) is used in our laboratory to screen for working- and reference memory deficits in rats in the course of neurotoxicological studies. In the 6-arm RTM animals are minimally stressed, and do not need food reward as a reinforcer. Maze behavior is assessed using mean error score of arm repetitions as a measure of 'working memory', left-right discrimination within each arm (expressed as percent "blind-alley" visits) as a measure of 'reference memory' and trial time (time to complete 12 arm entries) as a measure of locomotor activity. As shown for other mazes sensory deficits may affect spatial orientation. Sensory dysfunction are likely to be induced by neurotoxic compounds, while at toxic doses reduced locomotor activity is a common finding. When using the 6-arm RTM in the course of neurotoxicity studies to assess cognitive functions such potentially confounding effects have to be excluded to allow the conclusion of a cognitive impairment. The aim of the following experiments was to assess if visual, vibrissal or olfactory dysfunction, or hypoactivity may affect memory parameters in the 6-arm RTM. Loss of visual, olfactory or vibrissal input alone did not affect any of the maze parameters. Combined loss of visual and vibrissal or olfactory inputs increased mean error score. Loss of olfaction prolonged trial time under both lighting conditions. Acrylamide- and vitamin B6-induced sensorymotor dysfunctions and hypoactivity did not affect mean error score or percent blind-alley visits in the 6-arm RTM. Similarly, gastrointestinal distress and hypoactivity induced by lithium chloride injections did not affect parameters of working or reference memory. Results indicate that in the 6-arm RTM (1) olfactory, visual and, to a minor extent, vibrissal input contribute to the sensory information necessary for spatial orientation and (2) reduced locomotor activity secondary to impaired sensorymotor abilities or drug-induced illness do not influence working or reference memory parameter.

The use of an unbaited tunnel maze in neurotoxicology: I. Trimethyltin-induced brain lesions.

In our laboratory we use an unbaited 6-arm radial tunnel maze (6-arm RTM) to assess working and reference memory in the course of neurotoxicity studies. The 6-arm RTM is believed to measure parameters comparable to those assessed in radial-arm mazes, but without the need of food deprivation and rewarding of animals. This is especially useful in the course of neurotoxicity studies as interferences of e.g. food deprivation with drug pharmacokinetics can be avoided. Since the 6-arm RTM is less evaluated than conventional mazes the aim of this study was to further confirm mean error score as measure of 'working memory', left-right discrimination within each radial arm (expressed as percent "blind-alley" visits) as measure of 'reference memory', and number of arm entries/min as a measure of motor activity. Therefore, hippocampal lesions were induced by injecting animals with the neurotoxicant trimethyltin (TMT). TMT at a dose of 5 mg/kg slightly lesioned hippocampal CA3 pyramidal cells in 3 of 8 animals, but did not affect behavioral measures in the 6-arm RTM. In all surviving animals treated with 7 or 9 mg/kg TMT moderate to marked loss of CA3 pyramidal cells was observed, while in 4 of these 7 rats CA4 pyramidal cells were also affected. Other brain lesions were not observed. TMT-induced brain lesions led to increased mean error score and number of arm visits during the retention phase and after changing maze configuration, whereas percent "blind-alley" visits were not affected.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute and late changes in N-acetyl-aspartate following diffuse axonal injury in rats: an MRI spectroscopy and microdialysis study.

N-acetyl-aspartate (NAA) measured by proton nuclear magnetic resonance spectroscopy (1H-NMR) has been used as a marker of neuronal injury in many cerebral pathologies. Therefore, we evaluate the roles of microdialysis vs. 1H-NMR as techniques to assess NAA (NAAd; NAA/Creatine ratio) in the living brain, and compare the results with whole brain NAA (NAAw), analyzed by HPLC after diffuse traumatic brain injury (TBI). Acute (4 h post-injury survival) and late (48 h survival) changes were studied in a sham-operated group (Sham, n = 4), and two injured groups (TBI/4 h, n = 8; TBI/48 h, n = 7). Baseline NAAd was 8.17 +/- 1 microM, and there was no significant difference between groups. There was only a small (twice of control), but transient increase in NAAd in the TBI/4 h group after trauma. Baseline NAA/Cr ratio was 1.35 +/- 0.2, which did not change significantly between baseline, 1, 2, 3, 4 and 48 h or between groups after TBI. Whole brain NAAw (baseline 8.5 +/- 0.5 mmol kg-1 wet weight) did not differ significantly between groups before and after TBI. Diffuse TBI did not produce long-term changes in NAA, assessed by three different methods. These results may indicate that NAA is not a sensitive marker of the severity of diffuse axonal damage. However, further studies are needed to evaluate whether confounding factors such as microdialysis probe, voxel position and non-regional tissue homogenization might have influenced our data.

Microdialytic monitoring during cerebrovascular surgery.

Using microdialysis, levels of metabolites in the extracellular fluid of the cerebral cortex were monitored during neurovascular surgery (9 aneurysm and 5 extra-intracranial bypass operations). Our aim was to use microdialysis to detect any local ischemia which might be caused by brain retraction or temporary clipping. Parameters were therefore quantified whose levels in the dialysate are known to be influenced by ischemia (on-line pH, ascorbic acid, uric acid, glutathione, cysteine, glucose, lactate, glucose:lactate ratio). In the aneurysm series, on-line pH fell after introduction of the retractor, and in the majority of cases the other parameters also showed changes in accordance with ischemic conditions in the region of the probe. These changes disappeared at the end of retraction, or sometimes even before. During the bypass operations, there were no marked changes in on-line pH or in any of the measured parameters. However, in some of these patients values for the glucose:lactate ratio, ascorbic acid and uric acid lay outside the suggested basal levels for minimally disturbed cortex, indicating possible changes in metabolism caused by inadequate perfusion (carotid artery occlusion). We conclude that microdialysis is a sensitive method of detecting intraoperative changes in cerebral metabolism.

Extracellular levels of glucose and lactate measured by quantitative microdialysis in the human brain.

The aim of this study was to use quantitative microdialysis to estimate the true extracellular concentrations of glucose and lactate in minimally disturbed human brain. These values are important as criteria for microdialytical monitoring in critical care patients and for determining therapy. Microdialysis procedures were carried out during tumor operations, the probe being inserted distant from the site of manipulation in minimally disturbed tissue. Two methods were used: 1. The zero net flux method of Lönnroth. 2. The low flow method (10 mm membrane length, flow rate 0.3 microliter min-1, high in vivo recovery). Both methods gave similar values of about 2000 microM for lactate and slightly less for glucose (1700 microM). Glucose levels correspond with those measured by other methods in humans, allowing for the fact that our patients were anesthetised. Extracellular glucose levels were positively correlated with blood glucose values measured before the operation, and with extracellular lactate. Results confirm that extracellular glucose is zero when blood glucose is about 2 mM.

Experimental and clinical monitoring of glucose by microdialysis.

The aim of this investigation was to assess the use of cerebral extracellular glucose as a parameter for microdialytic monitoring in neurosurgical critical care patients. Samples were collected from four patients with severe head injury and one with subarachnoid haemorrhage for periods of 4.5-67 h. Glucose and lactate were analysed in the dialysates. The ratios of glucose to lactate were calculated to partially allow for changes in microdialytic conditions over time. On-line pH was measured for up to 3 days in three patients. In experiments with spontaneous hypertensive rats we found that extracellular glucose became unmeasurable in the ischemic zone after middle cerebral artery occlusion. Similarly, in 3 patients glucose became undetectable for several hours, and glucose/lactate tended to decrease during measurement. This was accompanied by high ICP in one patient, and by a hypoxic episode in another. In the two other patients glucose/lactate ratios showed a rising trend. Findings indicate that glucose, and the glucose/lactate ratio show some correlations with clinical course and are promising parameters for cerebral monitoring and therapeutic decision making.

A concept for the introduction of cerebral microdialysis in neurointensive care.

Before microdialysis (MD) can be introduced into the clinic as an improved method of cerebral monitoring, certain ethical, methodological and clinical factors must be considered. Access to the brain for probe insertion is offered by craniotomy or by routine intracranial pressure (ICP) monitoring and the additional lesion is minimal. Care must be taken that the two devices do not interfere with each other. In contrast to ICP monitoring, MD provides information about multiple aspects of brain metabolism. We can monitor either still intact tissue to prevent additional damage, or injured brain to decide on and control therapies. The parameters used must reflect pathological changes an early stage, and the analysis should be available on-line or immediately after sample collection. The effects off factors such as tube length and flow rate on the behaviour of the chosen parameters (in our case on-line pH, radical scavengers and uric acid) in the MD set-up must be investigated in vitro and in animal models before use in the clinic. The range of non-pathological values of parameters of interest in human brain should be known For this purpose we took measurements during an extracranial-intracranial bypass operation, and were able to compare values with those in a severely damaged brain. The mutual chronology of parameter changes and clinical events must be clear. Future aspects include the use of low-flow methods offering nearly 100% recovery, improved analytical methods, and combination of MD with other monitoring methods to obtain more exact information.

A new screwing device for fixing a microdialysis probe in critical care patients.

We describe a new, easy method which extends the use of clinical microdialysis to neurotrauma patients who primarily do not need a decompressing surgical intervention. In all head trauma patients in whom a Camino ICP-monitor is indicated a second hole (2 mm in diameter) is made, and the MD probe is fixed using the new screwing device. Before clinical use the system was tested during postmortem, confirming correct cortical placement of the probe in almost all cases. Two case reports are presented including their metabolic values. An extension to patients with non-traumatic brain disorders might be a future aspect.

Low extracellular (ECF) glucose affects the neurochemical profile in severe head-injured patients.

Glucose (Gluc) is the main energy source for the brain. After severe head-injury energy demand is massively increased and supply is often decreased. In pilot microdialysis studies, many patients with severe head-injury had undetectable glucose concentrations, probably reflecting changes in metabolism and/or reduced supply. We therefore investigated whether patients with low ECF glucose (criterion: < 50 microM for > or = 5 hrs), LOWgluc, differ from patients with higher glucose levels (NORMALgluc) We also tested the interrelationships between other parameters such as lactate, glutamate, K+, brain O2 and CO2, ICP, CPP, and CBF in these two groups. We found that patients with low ECF glucose, LOWgluc, have significantly lower lactate concentrations than patients with "normal" glucose, NORMALgluc, levels do. Spearman correlations between glucose and most other parameters were similar in both patient groups. However, glutamate correlated positively with glucose, lactate, brain CO2 and negatively with brain O2 in the NORMALgluc patient group, whereas glutamate did not significantly correlate with any of these parameters in the LOWgluc group. There was also no correlation between outcome and the dialysate glucose. The results indicate that low ECF glucose is almost always present in severe head-injury. Moreover, the lack of correlation between low glucose and outcome, however, suggests that other energy substrates, such as lactate, are important after TBI.