Correlation of end-tidal CO2 with transcranial Doppler flow velocity is decreased during chemoregulation in delayed cerebral vasospasm after subarachnoid haemorrhage--results of a pilot study.

BACKGROUND: Cerebrovascular responses to variations in blood pressure and CO2 are attenuated during delayed vasospasm after subarachnoid hemorrhage (SAH). Transcranial Doppler sonography (TCD) is routinely used to assess the presence of vasospasm, but cerebral blood flow velocities (CBF-V) measured by TCD do not necessarily reflect cerebral blood flow (CBF) or the severity of vasospasm. We hypothesized that the correlation of end-tidal pCO2 levels with CBF-V and CBF is equally decreased in subjects with cerebral vasospasm during variations in pCO2. METHODS: Four cynomolgus monkeys were assigned to the vasospasm group and eight animals to the control group. The animals in the vasospasm group underwent placement of an autologous subarachnoid blood clot and vasospasm was confirmed by angiography on day 7. In both groups, CBF and CBF-V were measured simultaneously while end-tidal pCO2 was altered. CBF was measured using a thermal probe placed on the cortical surface and CBF-V was measured using a commercial TCD device. RESULTS: Pearson's correlation coefficient between CBF-V values and pCO2 levels in the control group was strong (r = 0.94, p < 0.001) while it was moderate in the vasospasm group (r = 0.54, p = 0.04). The correlation of CBF values with pCO2 in healthy controls was equally strong (r = 0.87, p = 0.005), while there was no correlation in the vasospasm group (r = -0.09, p = 0.83). CONCLUSION: In this pilot study, correlations of CBF-V with pCO2 values during chemoregulation testing were lower in animals with vasospasm than in healthy ones. This correlation coefficient based on modifications in pCO2 may potentially facilitate the non-invasive assessment of vasospasm.

Measurement of nitric oxide and brain tissue oxygen tension in patients after severe subarachnoid hemorrhage.

OBJECTIVE: Nitric oxide (NO), one of the most powerful endogenous vasodilators, is thought to play a major role in the development of delayed vasospasm in patients with subarachnoid hemorrhage (SAH). However, the role of the production of cerebral NO in patients with SAH is not known. In other SAH studies, NO metabolites such as nitrite and nitrate have been demonstrated to be decreased in cerebrospinal fluid and in plasma. METHODS: In this study, a microdialysis probe was used, along with a multiparameter sensor, to measure NO metabolites, brain tissue oxygen tension, brain tissue carbon dioxide tension, and pH in the cortex of patients with severe SAH who were at risk for developing secondary brain damage and vasospasm. NO metabolites, glucose, and lactate were analyzed in the dialysates to determine the time course of NO metabolite changes and to test the interrelationship between the analytes and clinical variables. RESULTS: Brain tissue oxygen tension was strongly correlated to dialysate nitrate and nitrite (r2 = 0.326; P < 0.001); however, no correlation was noted between brain tissue oxygen tension and NO metabolites in cerebrospinal fluid (r2 = 0.018; P = 0.734). No significant correlation between NO production, brain tissue carbon dioxide tension, and dialysate glucose and lactate was observed. CONCLUSION: Cerebral ischemia and compromised substrate delivery are often responsible for high morbidity rates and poor outcomes after SAH. The relationship between brain tissue oxygen and cerebral NO metabolites that we demonstrate suggests that substrate delivery and NO are linked in the pathophysiology of vasospasm after SAH.

Induced mitochondrial failure in the feline brain: implications for understanding acute post-traumatic metabolic events.

OBJECTIVE: Recently, evidence has become available implicating mitochondrial failure as a crucial factor in the pathogenesis of acute brain damage following severe traumatic brain injury (TBI). However, it remains unclear how mitochondrial dysfunction affects cerebral metabolism. Therefore the aim of the study was to evaluate the impact of 'isolated' mitochondrial failure on local cerebral metabolism. METHODS: Cerebral mitochondrial metabolism was blocked by local microdialysis perfusion with cyanide in seven cats. Local brain tissue oxygen tension (p(tiO(2))), carbon dioxide tension (p(tiCO(2))) and pH, as well as extracellular cerebral fluid, glucose, lactate, pyruvate and glutamate were monitored, using a Neurotrend sensor and microdialysis, respectively. Tissue oxygen consumption was measured in a microrespirometric system, and ultrastructural changes evaluated via electron microscopy. RESULTS: Brain tissue oxygen tension increased from a baseline of 31+/-9 mmHg to 84+/-30 mmHg after 60 min of cyanide perfusion (P<0.05), concomitant a decrease in oxygen consumption from 14.45+/-3.91 microl/h/mg to 10.83+/-1.74 microl/h/mg (P<0.05). Brain tissue pH was decreased after 60 min of cyanide perfusion (6.83+/-0.16) compared to baseline (7.07+/-0.39) (P<0.05), whereas p(tiCO(2)) did not show significant changes. Lactate massively increased from a baseline of 599+/-270 micromol/l to 2609+/-1188 micromol/l immediately after cyanide perfusion (P<0.05). The lactate:glucose ratio increased from 0.79+/-0.15 before cyanide perfusion to 6.40+/-1.44 at 40 min after cyanide perfusion (P<0.05), while no significant changes in the lactate:pyruvate ratio could be observed. Glutamate increased from a baseline of 11.6+/-7.2 micromol/l to 61.4+/-44.7 micromol/l after cyanide perfusion (P<0.05). CONCLUSION: The results of this study show that 'isolated' cerebral mitochondrial failure initiates changes in cerebral substrates and biochemistry, which are very similar to most of the changes seen after severe human head injury, except for the early fall in p(tiO(2)), further indicating a crucial involvement of mitochondrial impairment in the development of brain damage after TBI.

High level of extracellular potassium and its correlates after severe head injury: relationship to high intracranial pressure.

OBJECT: Disturbed ionic and neurotransmitter homeostasis are now recognized as probably the most important mechanisms contributing to the development of secondary brain swelling after traumatic brain injury (TBI). Evidence obtained in animal models indicates that posttraumatic neuronal excitation by excitatory amino acids leads to an increase in extracellular potassium, probably due to ion channel activation. The purpose of this study was therefore to measure dialysate potassium in severely head injured patients and to correlate these results with measurements of intracranial pressure (ICP), patient outcome, and levels of dialysate glutamate and lactate, and cerebral blood flow (CBF) to determine the role of ischemia in this posttraumatic ion dysfunction. METHODS: Eighty-five patients with severe TBI (Glasgow Coma Scale Score < 8) were treated according to an intensive ICP management-focused protocol. All patients underwent intracerebral microdialyis. Dialysate potassium levels were analyzed using flame photometry, and dialysate glutamate and dialysate lactate levels were measured using high-performance liquid chromatography and an enzyme-linked amperometric method in 72 and 84 patients, respectively. Cerebral blood flow studies (stable xenon computerized tomography scanning) were performed in 59 patients. In approximately 20% of the patients, dialysate potassium values were increased (dialysate potassium > 1.8 mM) for 3 hours or more. A mean amount of dialysate potassium greater than 2 mM throughout the entire monitoring period was associated with ICP above 30 mm Hg and fatal outcome, as were progressively rising levels of dialysate potassium. The presence of dialysate potassium correlated positively with dialysate glutamate (p < 0.0001) and lactate (p < 0.0001) levels. Dialysate potassium was significantly inversely correlated with reduced CBF (p = 0.019). CONCLUSIONS: Dialysate potassium was increased after TBI in 20% of measurements. High levels of dialysate potassium were associated with increased ICP and poor outcome. The simultaneous increase in dialysate potassium, together with dialysate glutamate and lactate, supports the concept that glutamate induces ionic flux and consequently increases ICP, which the authors speculate may be due to astrocytic swelling. Reduced CBF was also significantly correlated with increased levels of dialysate potassium. This may be due to either cell swelling or altered vasoreactivity in cerebral blood vessels caused by higher levels of potassium after trauma. Additional studies in which potassium-sensitive microelectrodes are used are needed to validate these ionic events more clearly.

Substrate delivery and ionic balance disturbance after severe human head injury.

The most important early pathomechanism in traumatic brain injury (TBI) is alteration of the resting membrane potential. This may be mediated via voltage, or agonist-dependent ion channels (e.g. glutamate-dependent channels). This may result in a consequent increase in metabolism with increased oxygen consumption, in order to try to restore ionic balance via the ATP-dependent pumps. We hypothesize that glutamate is an important agonist in this process and may induce an increase in lactate, potassium and brain tissue CO2, and hence a decrease in brain pH. Further we propose that an increase in lactate is thus not an indicator of anaerobic metabolic conditions as has been thought for many years. We therefore analyzed a total of 85 patients with TBI, Glasgow Coma Scale (GCS) < 8 using microdialysis, brain tissue oxygen, CO2 and pH monitoring. Cerebral blood flow studies (CBF) were performed to test the relationship between regional cerebral blood flow (rCBF) and the metabolic determinants. Glutamate was significantly correlated with lactate (p < 0.0001), potassium (p < 0.0001), brain tissue pH (p = 0.0005), and brain tissue CO2 (p = 0.006). rCBF was inversely correlated with glutamate, lactate and potassium. 44% of high lactate values were observed in brain with tissue oxygen values, above the threshold level for cell damage. These results support the hypothesis of a glutamate driven increase in metabolism, with secondary traumatic depolarization and possibly hyperglycolysis. Further, we demonstrate evidence for lactate production in aerobic conditions in humans after TBI. Finally, when reduced regional cerebral blood flow (rCBF) is observed, high dialysate glutamate, lactate and potassium values are usually seen, suggesting ischemia worsens these TBI-induced changes.

High extracellular potassium and its correlates after severe head injury: relationship to high intracranial pressure.

Disturbed ionic and neurotransmitter homeostasis are now recognized to be probably the most important mechanisms contributing to the development of secondary brain swelling after traumatic brian injury (TBI). Evidence obtained from animal models indicates that posttraumatic neuronal excitation via excitatory amino acids leads to an increase in extracellular potassium, probably due to ion channel activation. The purpose of this study was therefore to measure dialysate potassium in severely head injured patients and to correlate these results with intracranial pressure (ICP), outcome, and also with the levels of dialysate glutamate, lactate, and cerebral blood flow (CBF) so as to determine the role of ischemia in this posttraumatic ionic dysfunction. Eighty-five patients with severe TBI (Glasgow Coma Scale score < 8) were treated according to an intensive ICP management-focused protocol. All patients underwent intracerebral microdialyis. Dialysate potassium levels were analyzed by flame photometry, as were dialysate glutamate and dialysate lactate levels, which were measured using high-performance liquid chromatography and an enzyme-linked amperometric method in 72 and 84 patients respectively. Cerebral blood flow studies (stable Xenon--computerized tomography scanning) were performed in 59 patients. In approximately 20% of the patients, potassium values were increased (dialysate potassium > 1.8 mmol). Mean dialysate potassium (> 2 mmol) was associated with ICP above 30 mm Hg and fatal outcome. Dialysate potassium correlated positively with dialysate glutamate (p < 0.0001) and lactate levels (p < 0.0001). Dialysate potassium was significantly inversely correlated with reduced CBF (p = 0.019). Dialysate potassium was increased after TBI in 20% of measurements. High levels of dialysate potassium were associated with increased ICP and poor outcome. The simultaneous increase of potassium, together with dialysate glutamate and lactate, supports the hypothesis that glutamate induces ionic flux and consequently increases ICP due to astrocytic swelling. Reduced CBF was also significantly correlated with increased levels of dialysate potassium. This may be due to either cell swelling or altered potassium reactivity in cerebral blood vessels after trauma.

[Cerebral oxygen reactivity determination--a simple test with potential prognostic relevance]. / Zerebrale Sauerstoffreaktivitätsbestimmung--ein einfacher Test mit potentiell prognostischer Relevanz.

UNLABELLED: Brain tissue oximetry (ptiO2) using flexible micro-polarographic electrodes is a loco-regional approach to monitor oxygen supply to the injured brain, after neuronal damage. In patients after severe head injury (SHI), disturbances of CBF and CO2 related vasoconstriction have been demonstrated. CO2 reactivity testing may assist to determine outcome in these patients. Not much information is available on the preservation of vasoreactivity to arterial hyperoxia after neuronal damage. Therefore, we studied the response of ptiO2 in 7 piglets and in 14 patients on day one after trauma to 100% FiO2 ventilation (O2rea) and analyzed the 3 month outcome using the Glasgow-Outcome-Score (GOS). In the animal study, we placed a Paratrend 7 (P7) sensor for ptiO2 measurements in the non injured frontal white matter. The animals were anesthetized and mechanically ventilated. FiO2 was increased from 30 (+/- 5)% to 100% over a period of 5 minutes. In patients, we placed the P7 probe in the frontal lobe. FiO2 was increased from 35 (+/- 5)% to 100% over a period of 6 hours. O2rea was tested by calculating the percentage change of ptiO2 during 100% FiO2 ventilation, compared to the baseline value of 35% FiO2. By analyzing the patient outcome, we were able to define two patient populations according to the GOS at three month (Group I: favorable outcome [GOS 0-2]; Group II: poor outcome [GOS 3-4]). For the non-injured brain tissue in animals were revealed an O2rea = 0.21 (+/- 0.12). PATIENTS: Group I: O2rea = 0.4 (+/- 0.16); Group II: 0.9 (+/- 0.6). Group I and II were statistical significant different (p < 0.05; unpaired t-test). Oxygen reactivity in severely head patients is a simple test with prognostic value using ptiO2 measurement. These results may be explained by the close relationship of CBF disturbances to oxygen vasoreactivity after traumatic brain injury. The O2rea in animals without neuronal damage is smaller than in patients after SHI. We speculate, the animal data could be considered as normal value of O2rea in non injured brain tissue.

rCBF in hemorrhagic, non-hemorrhagic and mixed contusions after severe head injury and its effect on perilesional cerebral blood flow.

Intracerebral contusions can lead to regional ischemia caused by extensive release of excitotoxic aminoacids leading to increased cytotoxic brain edema and raised intracranial pressure. rCBF measurements might provide further information about the risk of ischemia within and around contusions. Therefore, the aim of the presented study was to compare the intra- and perilesional rCBF of hemorrhagic, non-hemorrhagic and mixed intracerebral contusions. In 44 patients, 60 stable Xenon-enhanced CT CBF-studies were performed (EtCO2 30 +/- 4 mmHg SD), initially 29 hours (39 studies) and subsequent 95 hours after injury (21 studies). All lesions were classified according to localization and lesion type using CT/MRI scans. The rCBF was calculated within and 1-cm adjacent to each lesion in CT-isodens brain. The rCBF within all contusions (n = 100) of 29 +/- 11 ml/100 g/min was significantly lower (p < 0.0001, Mann-Whitney U) compared to perilesional rCBF of 44 +/- 12 ml/100 g/min and intra/perilesional correlation was 0.4 (p < 0.0005). Hemorrhagic contusions showed an intra/perilesional rCBF of 31 +/- 11/44 +/- 13 ml/100 g/min (p < 0.005), non-hemorrhagic contusions 35 +/- 13/46 +/- 10 ml/100 g/min (p < 0.01). rCBF in mixed contusions (25 +/- 9/44 +/- 12 ml/100 g/min, p < 0.0001) was significantly lower compared to hemorrhagic and non-hemorrhagic contusions (p < 0.02). Intracontusional rCBF is significantly reduced to 29 +/- 11 ml/100 g/min but reduced below ischemic levels of 18 ml/100 g/min in only 16% of all contusions. Perilesional CBF in CT normal appearing brain closed to contusions is not critically reduced. Further differentiation of contusions demonstrates significantly lower rCBF in mixed contusions (defined by both hyper- and hypodense areas in the CT-scan) compared to hemorrhagic and non-hemorrhagic contusions. Mixed contusions may evolve from hemorrhagic contusions with secondary increased perilesional cytotoxic brain edema leading to reduced cerebral blood flow and altered brain metabolism. Therefore, the treatment of ICP might be individually modified by the measurement of intra- and pericontusional cerebral blood.

Cerebral oxygenation in patients after severe head injury: monitoring and effects of arterial hyperoxia on cerebral blood flow, metabolism and intracranial pressure.

Early impaired cerebral blood flow (CBF) after severe head injury (SHI) leads to poor brain tissue oxygen delivery and lactate accumulation. The purpose of this investigation was to elucidate the relationship between CBF, local dialysate lactate (lact(md)) and dialysate glucose (gluc(md)), and brain tissue oxygen levels (PtiO2) under arterial normoxia. The effect of increased brain tissue oxygenation due to high fractions of inspired oxygen (FiO2) on lact(md) and CBF was explored. A total of 47 patients with SHI were enrolled in this studies (Glasgow Coma Score [GCS] < 8). CBF was first assessed in 40 patients at one time point in the first 96 hours (27 +/- 28 hours) after SHI using stable xenon computed tomography (Xe-CT) (30% inspired xenon [FiXe] and 35% FiO2). In a second study, sequential double CBF measurements were performed in 7 patients with 35% FiO2 and 60% FiO2, respectively, with an interval of 30 minutes. In a subsequent study, 14 patients underwent normobaric hyperoxia by increasing FiO2 from 35 +/- 5% to 60% and then 100% over a period of 6 hours. This was done to test the effect of normobaric hyperoxia on lact(md) and brain gluc(md), as measured by local microdialysis. Changes in PtiO2 in response to changes in FiO2 were analyzed by calculating the oxygen reactivity. Oxygen reactivity was then related to the 3-month outcome data. The levels of lact(md) and gluc(md) under hyperoxia were compared with the baseline levels, measured at 35% FiO2. Under normoxic conditions, there was a significant correlation between CBF and PtiO2 (R = 0.7; P < .001). In the sequential double CBF study, however, FiO2 was inversely correlated with CBF (P < .05). In the 14 patients undergoing the 6-hour 100% FiO2 challenge, the mean PtiO2 levels increased to 353 (87% compared with baseline), although the mean lact(md) levels decreased by 38 +/- 16% (P < .05). The PtiO2 response to 100% FiO2 (oxygen reactivity) was inversely correlated with outcome (P < .01). Monitoring PtiO2 after SHI provides valuable information about cerebral oxygenation and substrate delivery. Increasing arterial oxygen tension (PaO2) effectively increased PtiO2, and brain lact(md) was reduced by the same maneuver.

Increased inspired oxygen concentration as a factor in improved brain tissue oxygenation and tissue lactate levels after severe human head injury.

OBJECT: Early impairment of cerebral blood flow in patients with severe head injury correlates with poor brain tissue O2 delivery and may be an important cause of ischemic brain damage. The purpose of this study was to measure cerebral tissue PO2, lactate, and glucose in patients after severe head injury to determine the effect of increased tissue O2 achieved by increasing the fraction of inspired oxygen (FiO2). METHODS: In addition to standard monitoring of intracranial pressure and cerebral perfusion pressure, the authors continuously measured brain tissue PO2, PCO2, pH, and temperature in 22 patients with severe head injury. Microdialysis was performed to analyze lactate and glucose levels. In one cohort of 12 patients, the PaO2 was increased to 441+/-88 mm Hg over a period of 6 hours by raising the FiO2 from 35+/-5% to 100% in two stages. The results were analyzed and compared with the findings in a control cohort of 12 patients who received standard respiratory therapy (mean PaO2 136.4+/-22.1 mm Hg). The mean brain PO2 levels increased in the O2-treated patients up to 359+/-39% of the baseline level during the 6-hour FiO2 enhancement period, whereas the mean dialysate lactate levels decreased by 40% (p < 0.05). During this O2 enhancement period, glucose levels in brain tissue demonstrated a heterogeneous course. None of the monitored parameters in the control cohort showed significant variations during the entire observation period. CONCLUSIONS: Markedly elevated lactate levels in brain tissue are common after severe head injury. Increasing PaO2 to higher levels than necessary to saturate hemoglobin, as performed in the O2-treated cohort, appears to improve the O2 supply in brain tissue. During the early period after severe head injury, increased lactate levels in brain tissue were reduced by increasing FiO2. This may imply a shift to aerobic metabolism.

Contrast echocardiography and transcranial Doppler sonography for detection of a patent foramen ovale.

We report the case of a patient, in whom a patent foramen ovale was detected. For the detection of a patent foramen ovale simulation of Valsalva's manoeuvre with a positive airway pressure of 20 cm H2O was applied. Change of ventilation manoeuvre by ventilation with positive airway pressure of 35/30/15 cm H2O at a tidal volume of 1200 ml make a distinct increase in passage of contrast medium from the right to the left atrium. These findings were detected by contrast transesophageal echocardiography and indirectly by transcranial Doppler sonography and were reproducible. This may stress the importance of preoperative screening of patent foramen ovale in patients to be operated on in the sitting position. Contrast echocardiography and the ventilatory manoeuvre with high airway pressure and PEEP might increase the detection rate of patent foramen ovale with a right to left shunt during general anaesthesia.

CSF and ECF glutamate concentrations in head injured patients.

Excitatory Amino Acids (EAAs) release has been considered to be neurotoxic in traumatic brain injury patients. Microdialysis samples of extracellular space (ECS) and high glutamate concentrations in cerebrospinal fluid (CSF) following Traumatic Brain Injury (TBI) have been documented. The objective of this study was to determine the correlation between EAA release in ECS and CSF in focal and diffuse injury. Head injury patients (GCS < or = 8, n = 16) admitted to Medical College of Virginia Hospital were instrumented for microdialysis collection of ECS samples. CSF samples were collected through the external ventricular drainage catheter at four hour intervals for the first four days following injury. As a control group, CSF was collected from normal pressure hydrocephalus patients (n = 6). Elevated glutamate levels were observed in both CSF and ECS following head injury. The average glutamate concentration in CSF (3.20 +/- 3.62 mumol/l) was significantly increased from control levels (1.13 +/- 0.49 mumol/l, p < 0.05). Comparison of CSF and extracellular fluid (ECF) samples showed that the glutamate concentrations were maximal on the first and second days and gradually decreased on days 3 and 4. On days 4, the level of the glutamate had remained elevated above the normal level.

Evidence for time-dependent glutamate-mediated glycolysis in head-injured patients: a microdialysis study.

In the brain, lactate is not only a marker of anaerobic glycolysis due to hypoxia/ischemia, but also a neuronal energy source which is provided by glutamate-induced astrocytic glycolysis. In the present study we wanted to investigate the relationship between glutamate release and lactate production during the entire time-course and during three time periods of microdialytic monitoring in 54 severely head injured patients. Within-subject Spearman rank correlations were calculated in each period for glutamate and lactate, for each patient and the mean of all correlation coefficients were analyzed for difference from zero by a one-sample t-test. The results show a strong overall positive relationship between glutamate and lactate. However, during the first 12 hours after injury, there was no significant correlation. Thereafter, good correlation was seen. The splitting of patients into groups with good (Glasgow Outcome Scale; GOS 0-2) and poor outcome (GOS 3-4) showed a similar strong correlation for patients with good outcome, but this was lost for patients with poor outcome. The results clearly indicate that glutamate "drives" astrocytic lactate production in head-injured patients. The contribution of glutamate to overall lactate release is thus time-dependent. During the first 12 hours after injury, factors such as hypoxia, ischemia or edema overshadowed glutamate-induced glycolysis in astrocytes. In addition, the effect of glutamate is more pronounced in patients with good outcome.

Determinants of cerebral extracellular potassium after severe human head injury.

The key role players of brain swelling seen after severe human head injury have only been partly determined. We used our human head injury data base to determine relationships between potassium, glutamate, lactate and cerebral blood flow (CBF). A total of 70 severely head injured patients (GCS < or = 8) were studied using intracerebral microdialysis to measure extracellular glutamate, potassium and lactate. Xenon CT was used to determine regional cerebral blood flow (rCBF). The mean +/- SEM of the r value of all patients, between potassium and glutamate, and potassium and lactate was 0.25 +/- 0.04 (p < 0.0001) and 0.17 +/- 0.06 (p = 0.006), respectively, demonstrating in both cases a positive relationship. rCBF was negatively correlated with potassium with marginal significance (r = -0.35, p = 0.08). When separated into two groups, patients with contusion had higher potassium levels than patients without contusion (1.55 +/- 0.03 mmol/l versus 1.26 +/- 0.02 mmol/l, respectively). These results in severely head injured patients confirm previous in vitro and animal studies in which relationships between potassium, glutamate, lactate and CBF were found. Potassium efflux is a major determinant of cell swelling leading to clinically significant cytotoxic edema due to increased glutamate release during reduced cerebral blood flow.

Factors affecting excitatory amino acid release following severe human head injury.

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 micromol/L). Sustained high ICP and poor outcome were significantly correlated to high levels of EAAs (glutamate > 20 micromol/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.

Determination of the ischemic threshold for brain oxygen tension.

Measuring brain tissue oxygenation is now possible due to major advances in the technical development of Clark-electrodes and fiberoptic systems. However, to make this technique clinically useful for both nurses and medical staff, the ischemic threshold for brain tissue oxygen tension (brain pO2) must be determined. Three end points were used for determination of the critical brain pO2 value. 1) Infarct determination after permanent middle cerebral artery occlusion in a feline model. 2) Threshold analysis using the schemic threshold for cerebral blood flow (CBF) as a "gold standard" in severely head injury patients. 3) Outcome analysis in severely head injured patients. Brain pO2 dropped to 19 +/- 6 mm Hg and 23 +/- 6, 4 to 5 hours after MCA occlusion in the cat (n = 12). In severely head injured patients, a brain pO2 < or = 19 mm Hg was correlated with poor outcome (n = 24). The ischemic threshold for (r)CBF of 18 ml/100 g/min corresponded to a brain pO2 of 22 mm Hg, in the same patients. By using the above mentioned end points as a reference, we found the critical value for brain pO2 to be in between 19 and 23 mm Hg. Clearly, the difference between our threshold value and the lower critical brain pO2 level found by other groups using the Licox system, needs to be clarified in a comparison study before a uniform threshold for brain pO2 can be determined.

Cortical extracellular sodium transients after human head injury: an indicator of secondary brain damage?

Animal studies indicate that elevated extracellular sodium can increase glutamate-induced excitotoxicity. Therefore, we investigated the relationship between sodium and glutamate and the effect of changes in sodium concentrations on the outcome of head-injured patients. Thirty-four (34) patients were selected for this study and divided into a group of patients having episodes (> or = 30-min) of high sodium in dialysates (> or = 200 mM; HIGH, n = 11) and a group of patients having no such episodes (NORMAL, n = 23). Levels for sodium (226 +/- 5.7 mM), glutamate (12.53 +/- 2.2 microM) and ICP (32.2 +/- 4.0 mm Hg,) were relatively high during the high sodium episodes. Overall, mean values for glutamate, ICP and outcome did not differ amono both groups. The mean dialysate sodium concentration, however, was significantly higher in the HIGH (178 +/- 6 mM) compared to the NORMAL group (158 +/- 3 mM; p < 0.01). Spearman rank correlation between sodium and glutamate or ICP were not significant. The HIGH sodium group did not have significantly more patients with poor outcome than the NORMAL group. The results indicated sodium concentrations did not affect the outcome of head-injured patients. However, other sodium monitoring techniques are desirable to elucidate these apparent potentially major sodium transients, which we have observed in the human cortex, after severe head injury.

Correlations between brain tissue oxygen tension, carbon dioxide tension, pH, and cerebral blood flow--a better way of monitoring the severely injured brain?

BACKGROUND: The ideal method for monitoring the acutely injured brain would measure substrate delivery and brain function continuously, quantitatively, and sensitively. We have tested the hypothesis that brain PO2, pCO2, and pH, which can now be measured continuously using a single sensor, are valid indicators of regional cerebral blood flow (CBF) and oxidative metabolism, by measuring its product, brain pCO2. METHODS: Twenty-five patients (Glasgow Coma Score < or = 8) were studied. A Clark electrode, combined with a fiber optic system (Paratrend 7, Biomedical Sensors, Malvern, PA) was used to measure intraparenchymal brain PO2, pCO2, and pH. Data were averaged over a 1-h period before and after CBF studies. Regional CBF was measured around the probe, using stable xenon computed tomography. Regression analyses and Spearman Rank tests were used for data analysis. RESULTS: Regional CBF and mean brain PO2 were strongly correlated (r=0.74, p=0.0001). CBF values < 18 mL/100 g/min were all accompanied by brain PO2 < or = 26 mm Hg. The four patients with a brain PO2 < 18 mm Hg died. Brain pCO2 and pH, however, were not correlated with CBF (r=0.36, p=0.24 and r=0.30, p=0.43, respectively). CONCLUSIONS: Until recently, substrate supply to the severely injured brain could only be intermittently estimated by measuring CBF. The excellent intra-regional correlation between CBF and brain pO2, suggests that this method does allow continuous monitoring of true substrate delivery, and offers the prospect that measures to increase O2 delivery (e.g., increasing CBF, CPP, perfluorocarbons etc.) can be reliably tested by brain PO2 monitoring.

Extended neuromonitoring: new therapeutic opportunities?

In order to optimize therapy for the injured brain it is desirable to continuously monitor substrate delivery in the critically ill patient. Interruption of substrate delivery is a major factor of the great vulnerability to ischemic damage, which affects a majority of patients after severe head injury, stroke or subarachnoid hemorrhage. An approach to protecting the brain during ischemia is to increase the delivery of oxygen via residual blood flow through ischemic tissue. Hypothermia is also an important means of protecting brain cells from the deleterious effects of ischemia, after severe head injury, because it reduces metabolic demands. In this study we continuously measured brain oxygen, brain CO2, brain pH and brain temperature, as well as hourly brain glucose and lactate. A multiparameter sensor was inserted into brain tissue, via a three lumen bolt, along with a ventriculostomy catheter and a microdialysis probe in 60 severely head injured patients. Brain oxygen delivery was increased by stepwise increase of inspired oxygen (FiO2) from 30% to 60% to 100% over a period of 6 h, in order to test the effect of enhanced oxygen tension, on tissue oxygen. In most patients brain oxygen was initially low, and progressively increased, over the monitoring period, to a steady state level, around 30-40 mmHg. In those who died or remained vegetative, brain oxygen fell to anerobic levels. Episodes of increased ICP (n = 25), hypotension (n = 15), and respiratory difficulties (n = 9) caused an immediate increase in brain CO2. Multiple logistic regression analysis showed brain oxygen to be the strongest predictor for outcome in these patients. By increasing FiO2, an increase in oxygen delivery of more than 100%, and a simultaneous decline in lactate production was seen (p < 0.01). Brain temperature was closely related to rectal temperature, brain oxygen, and cerebral blood flow. Patients who were spontaneously hypothermic had a poor outcome (p < 0.01). A fuller understanding of dynamic factors affecting brain metabolism and substrate delivery may be obtained with extended neuromonitoring.