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Multipotent neural stem/progenitor cells (NS/NPCs) that are capable of generating neurons and glia offer enormous potential for treating neurological diseases. Adult NS/NPCs that reside in the mature mammalian brain can be isolated and expanded in vitro, and could be a potential source for autologous transplantation to replace cells lost to brain injury or disease. When these cells are transplanted into the normal brain, they can survive and become region-specific cells. However, it has not been reported whether these cells can survive for an extended period and become functional cells in an injured heterotypic environment. In this study, we tested survival, maturation fate, and electrophysiological properties of adult NS/NPCs after transplantation into the injured rat brain. NS/NPCs were isolated from the subventricular zone of adult Fisher 344 rats and cultured as a monolayer. Recipient adult Fisher 344 rats were first subjected to a moderate fluid percussive injury. Two days later, cultured NS/NPCs were injected into the injured brain in an area between the white matter tracts and peri-cortical region directly underneath the injury impact. The animals were sacrificed 2 or 4 weeks after transplantation for immunohistochemical staining or patch-clamp recording. We found that transplanted cells survived well at 2 and 4 weeks. Many cells migrated out of the injection site into surrounding areas expressing astrocyte or oligodendrocyte markers. Whole cell patch-clamp recording at 4 weeks showed that transplanted cells possessed typical mature glial cell properties. These data demonstrate that adult NS/NPCs can survive in an injured heterotypic environment for an extended period and become functional cells.

Object Few therapies have consistently demonstrated effectiveness in preserving O2 delivery after spinal cord injury (SCI). Perfluorocarbons (PFCs) offer great promise to carry and deliver O2 more efficiently than conventional measures. The authors investigated the use of Clark-type microelectrodes to monitor spinal cord oxygenation directly (intraparenchymal [IP] recording) and indirectly (cerebrospinal fluid [CSF] recording) in the context of SCI, O2 therapy, and PFC treatment. Methods After placement of a subdural/CSF Licox probe in rats, incremental increases in the fraction of inspired O2 (FiO2) up to 100% were administered to establish a dose-response curve. The probe was then placed in the parenchyma of the same animals for a second dose-response curve. In a second study, rats with CSF or IP probes underwent SCI with the NYU Impactor and treatment with O2, followed by administration of PFC, or saline in the control group. Results All animals in the first experiment responded to the FiO2 dose increase, with changes in PO2 evident in both CSF and IP levels. The SCI in the second experiment caused a marked drop in PO2 from a mean of 21.4 to 10.4 mm Hg, with most animals dropping to less than half their preinjury value. All animals responded to 100% O2 treatment. Every animal that received PFCs showed significant improvement, with a mean increase in PO2 of 23.3 mm Hg. Only 1 saline-treated animal showed any benefit. Oxygen values in the PFC treatment group reached up to 6 times the normal level. Conclusions Oxygen levels in SCI show a profound drop almost immediately postinjury. Administration of PFCs combined with 100% O2 therapy can reverse tissue hypoxia and holds promise for reducing ischemic injury.

Object The primary objective of this study was to estimate the prevalence of idiopathic normal-pressure hydrocephalus (NPH), both diagnosed and undiagnosed, among residents of assisted-living and extended-care facilities, by using a practical screening tool. A secondary objective was to evaluate prospectively the diagnosis and outcome of surgical treatment in a subset of patients residing in healthcare facilities who were at risk for idiopathic NPH. Methods A retrospective chart analysis was performed using the medical records from four nursing homes. The final analysis included 147 patient records. Symptomatology and comorbidity were evaluated, as was the ability to perform activities of daily living. In a subset of 17 patients residing in healthcare facilities, the authors applied a standard idiopathic NPH diagnostic and management protocol and followed up the patients 1 year after treatment. The estimated incidence of suspected idiopathic NPH among all patients in the retrospective survey ranged from 9 to 14%, depending on the diagnostic criteria used. Among the cohort of 17 patients available for an in-hospital study and 1-year follow up, 11 received shunts and seven of these showed either transient or sustained improvement. Conclusions A valid and practical diagnostic method is needed to identify idiopathic NPH accurately before admitting patients to a healthcare facility. Data from a prospective study of 17 patients residing in healthcare facilities indicated that supplementary tests remain predictive of a positive response to shunt insertion but cannot predict whether a favorable outcome will be sustained in a population of patients who have been confined to a wheelchair for a prolonged period of time. This finding supports the notion of a finite window of opportunity for successful treatment of idiopathic NPH and the imperativeness of an early diagnosis.

Object. The diagnosis and management of idiopathic normal-pressure hydrocephalus (NPH) remains controversial, particularly in selecting patients for shunt insertion. The use of clinical criteria coupled with imaging studies has limited effectiveness in predicting shunt success. The goal of this prospective study was to assess the usefulness of clinical criteria together with brain imaging studies, resistance testing, and external lumbar drainage (ELD) of cerebrospinal fluid (CSF) in determining which patients would most likely benefit from shunt surgery. Methods. One hundred fifty-one patients considered at risk for idiopathic NPH were prospectively studied according to a fixed management protocol. The clinical criterion for idiopathic NPH included ventriculomegaly demonstrated on computerized tomography or magnetic resonance imaging studies combined with gait disturbance, incontinence, and dementia. Subsequently, all patients with a clinical diagnosis of idiopathic NPH underwent a lumbar tap for the measurement of CSF resistance. Following this procedure, patients were admitted to the hospital neurosurgical service for a 3-day ELD of CSF. Video assessment of gait and neuropsychological testing was conducted before and after drainage. A shunt procedure was then offered to patients who had experienced clinical improvement from ELD. Shunt outcome was assessed at 1 year postsurgery. Conclusions. Data in this report affirm that gait improvement immediately following ELD is the best prognostic indicator of a positive shunt outcome, with an accuracy of prediction greater than 90%. Furthermore, bolus resistance testing is useful as a prognostic tool, does not require hospitalization, can be performed in an outpatient setting, and has an overall accuracy of 72% in predicting successful ELD outcome. Equally important is the finding that improvement with shunt surgery is independent of age up to the ninth decade of life in patients who improved on ELD.

Brain temperature was continuously measured in 58 patients after severe head injury and compared to rectal temperature, intracranial pressure, cerebral blood flow, and outcome after 3 months. The temperature difference between brain and rectal temperature was also calculated. Mild hypothermia (34-36 degrees C) was also used to treat uncontrollable intracranial pressure (ICP) above 20 mm Hg when other methods failed. Brain and rectal temperature were strongly correlated (r = 0.866; p0.001). Four groups were identified. The mean brain temperature ranged from 36.9 +/- 0.4 degrees C in the normothermic group to 38.2 +/- 0.5 degrees C in the hyperthermic group, 35.3 +/- 0.5 degrees C in the mild therapeutic hypothermia group, and 34.3 +/- 1.5 degrees C in the hypothermia group without active cooling. The mean DeltaT(br-rect) was positive for patients with a T(br) above 36.0 degrees C (0.0 +/- 0.5 degrees C) and negative for patients during mild therapeutic hypothermia (-0.2 +/- 0.6 degrees C) and also in those with a brain temperature below 36 degrees C without active cooling (0.8 +/- -1.4 degrees C) - the spontaneous hypothermic group. The cerebral perfusion pressure (CPP) was increased significantly by active cooling compared to the normothermic and hyperthermic groups. The mean cerebral blood flow (CBF) in patients with a brain temperature between 36.0 degrees C and 37.5 degrees C was 37.8 +/- 14.0 mL/100 g/min. The lowest CBF was measured in patients with a brain temperature36.0 degrees C and a negative brain-rectal temperature difference (17.1 +/- 14.0 mL/100 g/min). A positive trend for improved outcome was seen in patients with mild hypothermia. Simultaneous monitoring of brain and rectal temperature provides important diagnostic and prognostic information to guide the treatment of patients after severe head injury (SHI) and the wide differentials that can develop between the brain and core temperature, especially during rapid cooling, strongly supports the use of brain temperature measurement if therapeutic hypothermia is considered for head injury care.

The present studies determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with a clinically relevant NSAID, celecoxib, to kill tumor cells. Celecoxib and PDE5 inhibitors interacted in a greater than additive fashion to kill multiple tumor cell types. Celecoxib and sildenafil killed ex vivo primary human glioma cells as well as their associated activated microglia. Knock down of PDE5 recapitulated the effects of PDE5 inhibitor treatment; the nitric oxide synthase inhibitor L-NAME suppressed drug combination toxicity. The effects of celecoxib were COX2 independent. Over-expression of c-FLIP-s or knock down of CD95/FADD significantly reduced killing by the drug combination. CD95 activation was dependent on nitric oxide and ceramide signaling. CD95 signaling activated the JNK pathway and inhibition of JNK suppressed cell killing. The drug combination inactivated mTOR and increased the levels of autophagy and knock down of Beclin1 or ATG5 strongly suppressed killing by the drug combination. The drug combination caused an ER stress response; knock down of IRE1α/XBP1 enhanced killing whereas knock down of eIF2α/ATF4/CHOP suppressed killing. Sildenafil and celecoxib treatment suppressed the growth of mammary tumors in vivo. Collectively our data demonstrate that clinically achievable concentrations of celecoxib and sildenafil have the potential to be a new therapeutic approach for cancer.

A secondary and often lethal consequence of traumatic brain injury is cellular edema that we posit is due to astrocytic swelling caused by transmembrane water fluxes augmented by vasopressin-regulated aquaporin-4 (AQP4). We therefore tested whether vasopressin 1a receptor (V1aR) inhibition would suppress astrocyte AQP4, reduce astrocytic edema, and thereby diminish TBI-induced edematous changes. V1aR inhibition by SR49059 significantly reduced brain edema after cortical contusion injury (CCI) in rat 5h post-injury. Injured-hemisphere brain water content (n=6 animals/group) and astrocytic area (n=3/group) were significantly higher in CCI-vehicle (80.5±0.3%; 18.0±1.4 µm(2)) versus sham groups (78.3±0.1%; 9.5±0.9 µm(2)), and SR49059 blunted CCI-induced increases in brain edema (79.0±0.2%; 9.4±0.8µm(2)). CCI significantly up-regulated GFAP, V1aR and AQP4 protein levels and SR49059 suppressed injury induced up regulation (n=6/group). In CCI-vehicle, sham and CCI-SR49059 groups, GFAP was 1.58±0.04, 0.47±0.02, and 0.81±0.03, respectively; V1aR was 1.00±0.06, 0.45±0.05, and 0.46±0.09; and AQP4 was 2.03±0.34, 0.49±0.04, and 0.92±0.22. Confocal immunohistochemistry gave analogous results. In CCI-vehicle, sham and CCI-SR49059 groups, fluorescence intensity of GFAP was 349±38, 56±5, and 244±30, respectively, V1aR was 601±71, 117.8±14, and 390±76, and AQP4 was 818±117, 158±5, and 458±55 (n=3/group). The results support that edema was predominantly cellular following CCI and documented that V1aR inhibition with SR49059 suppressed injury-induced up regulation of GFAP, V1A and AQP4, blunting edematous changes. Our findings suggest V1aR inhibitors may be potential therapeutic tools to prevent cellular swelling and provide treatment for post-traumatic brain edema.

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.

Object. High-flow microinfusion is a novel technique for delivery of compounds directly into brain parenchyma, bypassing the blood-brain barrier. The feasibility of this technique has been demonstrated with low-molecular-weight compounds, macromolecular dyes, and proteins. Delivery of antisense oligonucleotides into brain parenchyma represents an additional potential application of this technique not previously described. In this report the authors sought to examine the distribution and disposition of phosphorothioate oligodeoxynucleotide (PS-ODN) for this reason. Methods. An 18-mer 35S-PS-ODN (M r approximately 6000) was infused over 1 hour into the caudate putamen of Fischer 344 rats. At 1, 6, 12, 24, and 48 hours after beginning the infusion, the brains were extracted and analyzed using quantitative autoradiographic techniques. Cerebrospinal fluid (CSF) was also aspirated from the cisterna magna and was analyzed to determine the radioactivity and stability of the 35S-PS-ODN. At 1 hour, the infused ODN was uniformly distributed in brain tissue, with a maximum average concentration of 4806.5 ± 210.5 nCi/g. This represents a tissue concentration of 19.2 ± 0.84 µM. Extensive spread into surrounding parenchyma was observed over the ensuing 47 hours. The 35S-PS-ODN radioactivity peaked in the CSF at the end of the 1-hour infusion, containing 1% (50 ± 20 nCi) of the infused radioactivity. Activity then decayed exponentially over 11 hours, but stabilized at a lower CSF content of 0.2% (1 ± 0.1 nCi) thereafter. The volume of distribution was 105 ± 7.9 mm3 at 1 hour, representing a volume of distribution/volume of infusion ratio of 5.2. The volume of distribution increased to 443 ± 62.3 mm3 at the end of 48 hours, whereas the average minimum tissue concentration decreased from 15.2 µM to 3.2 µM. Undegraded 18-mer was observed throughout the 48-hour period by means of 20% polyacrylamide/7 M urea gel electrophoresis. The animals tolerated the infusion without evidence of toxicity and minimal structural changes in tissue were observed on histological investigation. Conclusions. The authors found that PS-ODNs can be safely delivered in high concentrations to wide areas of rat brain by using high-flow microinfusion and are stable even after 48 hours in situ.

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 (p0.01). Brain temperature was closely related to rectal temperature, brain oxygen, and cerebral blood flow. Patients who were spontaneously hypothermic had a poor outcome (p0.01). A fuller understanding of dynamic factors affecting brain metabolism and substrate delivery may be obtained with extended neuromonitoring.

Spinal cord injury (SCI) often results in irreversible and permanent neurological deficits and long-term disability. Vasospasm, hemorrhage, and loss of microvessels create an ischemic environment at the site of contusive or compressive SCI and initiate the secondary injury cascades leading to progressive tissue damage and severely decreased functional outcome. Although the initial mechanical destructive events cannot be reversed, secondary injury damage occurs over several hours to weeks, a time frame during which therapeutic intervention could be achieved. One essential component of secondary injury cascade is the reduction in spinal cord blood flow with resultant decrease in oxygen delivery. Our group has recently shown that administration of fluorocarbon (Oxycyte) significantly increased parenchymal tissue oxygen levels during the usual postinjury hypoxic phase, and fluorocarbon has been shown to be effective in stroke and head injury. In the current study, we assessed the beneficial effects of Oxycyte after a moderate-to-severe contusion SCI was simulated in adult Long-Evans hooded rats. Histopathology and immunohistochemical analysis showed that the administration of 5 mL/kg of Oxycyte perfluorocarbon (60% emulsion) after SCI dramatically reduced destruction of spinal cord anatomy and resulted in a marked decrease of lesion area, less cell death, and greater white matter sparing at 7 and 42 days postinjury. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining showed a significant reduced number of apoptotic cells in Oxycyte-treated animals, compared to the saline group. Collectively, these results demonstrate the potential neuroprotective effect of Oxycyte treatment after SCI, and its beneficial effects may be, in part, a result of reducing apoptotic cell death and tissue sparing. Further studies to determine the most efficacious Oxycyte dose and its mechanisms of protection are warranted.

✓ Cerebrospinal fluid (CSF) dynamics were correlated to the changes in ventricular size during the first 3 months posttrauma in patients with severe head injury (Glasgow Coma Scale score ≤ 8, 75 patients) to distinguish between atrophy and hydrocephalus as the two possible causes of posttraumatic ventriculomegaly. Using the bolus injection technique, the baseline intracranial pressure (ICP), pressure volume index, and resistance for CSF absorption (R0) provided a threedimensional profile of CSF dynamics that was correlated with ventricular size and Glasgow Outcome Scale (GOS) score at 3, 6, and 12 months posttrauma. Patients were separated into five different groups based on changes in ventricular size, presence of atrophy, and CSF dynamics. Group 1 (normal group, 41.3%) demonstrated normal ventricular size and normal ICP. Group 2 (benign intracranial hypertension group, 14.7%) showed normal ventricular size and elevated ICP. Group × (atrophy group, 24%) displayed ventriculomegaly, normal ICP, and normal R0. Group 4 (normal-pressure hydrocephalus group, 9.3%) had ventriculomegaly, normal ICP, and high R0. Group 5 (high-pressure hydrocephalus group, 10.7%) showed ventriculomegaly and elevated ICP with or without high R0. The GOS score in the nonhydrocephalic groups (Groups 1, 2, and 3) was better than in the hydrocephalic groups (Groups 4 and 5). It is concluded from these results that 44% of head injury survivors may develop posttraumatic ventriculomegaly. Posttraumatic hydrocephalus, as identified by abnormal CSF dynamics, was diagnosed in 20% of survivors and their outcome was significantly worse. This study demonstrates the importance of using CSF dynamics as an aid in diagnosis of posttraumatic hydrocephalus and identifying those patients who may benefit from shunt placement.

Currently, no ideal method exists for monitoring the injured brain. Recently, a single, compact, fiberoptic sensor has become available for measuring oxygen, CO2, pH and temperature in blood. We have adapted this instrument for continuous use in brain tissue to measure oxygen tension, carbon dioxide tension (pCO2), pH, and temperature. To evaluate this new technique, we produced hypercapnia, hypocapnia, intracranial pressure increase, and hypoxemia in seven normal cats. In an additional six animals, sensors were placed within a zone of focal brain ischemia induced by occluding the left middle cerebral artery. The sensor readings were compared with cerebral blood flow measurements, intracranial pressure, and brain histological findings. An in vitro experiment was also performed using human blood to test the accuracy of the sensor over a wide range of pCO2 and oxygen tension values. After careful precalibration and rigid cranium fixation, stable measurements could be obtained throughout the 6- to 8-hour experiments. In normal animals, brain oxygen was 42 +/- 9 mm Hg, brain CO2 was 59 +/- 14 mm Hg, brain pH was 7.0 +/- 0.2, and brain temperature was 36.7 +/- 0.7 degrees C. Hypocapnia and hypoxemia produced a significant decline in tissue oxygen ( or = 74 +/- 4 mm Hg; P < 0.001). Focal ischemia produced a rapid 42% decline in brain oxygen (25 +/- 7 mm Hg) and a 25% increase in tissue pCO2 (71 +/- 23 mm Hg). Brain oxygen further decreased to 19 +/- 6 mm Hg toward the end of the experiment, 4 hours later. After middle cerebral artery occlusion, the regional cerebral blood flow decreased to 10 +/- 5 ml per 100 g per minute, within the 1st hour, from a baseline value of 65 +/- 15 ml per 100 g per minute. It then gradually increased to 15 +/- 5 ml per 100 g per minute by the end of the 4-hour experiment. Brain pH was closely and inversely related to brain CO2. The brain temperature in the focally ischemic tissue decreased from 36.7 +/- 0.7 to 35.5 +/- 1.6 degrees C by the end of the experiment. The in vitro experiment demonstrated good linear correlation between the sensor readings and the blood gas analysis. Continuous monitoring of oxygen, CO2, pH, and temperature in damaged or at-risk brain tissue using a single sensor is now feasible and will, thus, allow improved continuous monitoring of neurosurgical patients who are at risk of significant secondary brain damage.

Predictors of outcome were examined in this prospective study of 151 patients severely injured by civilian gunshot wounds. Of the 151 patients, 133 (88%) died. Of the 123 patients with an initial Glasgow Coma Scale score of 3-5, 116 (94%) died, whereas of the 20 with an initial Glasgow Coma Scale score of 6-8, 14 (70%) died. There were no good outcomes, and only three moderate recoveries in patients who had initial scores of 8 or less. In those patients who survived long enough for intracranial pressure monitoring, intracranial hypertension predicted a very poor outcome. Computed tomographic scan characteristics such as midline shift, compression or obliteration of the mesencephalic cisterns, the presence of subarachnoid blood, intraventricular hemorrhage, and the presence of hyperdense or mixed-density lesions greater than 15 mL, either bilateral or unilateral, were all associated with a poor outcome. However, neither the caliber of gun nor the distance of the gun from the head significantly affected the risk of dying.

Dysregulation of water homeostasis induces cerebral edema. Edema is a major cause of morbidity and mortality following traumatic brain injury (TBI). Aquaporin-1 (AQP-1), a water channel found in the brain, can function as a transporter for CO2 across the cellular membrane. Additionally, AQP-1's promoter contains a glucocorticoid response element. Thus, AQP-1 may be involved with edema-related brain injury and might be modulated by external conditions such as the pH and the presence of steroids. In this study, the authors investigated the hypotheses that: 1) AQP-1 participates in brain water homeostasis following TBI; 2) secondary injury (for example, acidosis) alters the expression of AQP-1 and exacerbates cerebral edema; and 3) corticosteroids augment brain AQP-1 expression and differentially affect cerebral edema under nonacidotic and acidotic conditions.Anesthetized Sprague-Dawley rats were subjected to moderate to severe TBI (2.5-3.5 atm) or surgery without injury, and they were randomized to receive a 3-mg/kg bolus of intravenous dexamethasone within 10 minutes after injury or surgery, a 3-mg/kg bolus of dexamethasone followed by 1-mg/kg maintenance doses every 8 hours for 24 hours, or saline boluses at similar time intervals. A second group of animals was subjected to respiratory acidosis with target arterial blood pH 6.8-7.2 for 1 hour following the surgery or injury. To evaluate selective blockage of AQP-1, some animals received a single intraperitoneal dose of HgCl2 (0.3-30.0 mmol/L) within 30 minutes of injury or surgery. At 4 or 24 hours postinjury, animals were killed and their brains were harvested for mRNA, protein, or water content analyses.The authors demonstrated elevated cerebral edema levels at 4 and 24 hours following TBI. Dexamethasone administration within 1 hour of TBI attenuated the cerebral edema under nonacidotic conditions but worsened it under acidotic conditions. Selective blockage of AQP-1 channels with HgCl2 attenuated the edematous effects of corticosteroids and acidosis. Reverse transcriptase polymerase chain reaction and immunohistochemical analyses demonstrated a paucity of AQP-1 in the cerebral cortices of the uninjured animals. In contrast, AQP-1 mRNA and protein levels were higher in the cerebral cortices of animals that sustained a TBI.These findings implicate an important, modifiable role for AQP-1 in water homeostasis within the CNS following TBI.

A robust and complex inflammatory cascade is known to be a prominent component of secondary injury following spinal cord injury (SCI). Specifically, the concept of trauma-induced autoimmunity has linked the lymphocyte population with neural tissue injury and neurologic deficit. FTY720, a sphingosine receptor modulator that sequesters lymphocytes in secondary lymphoid organs, has been shown to be effective in the treatment of a variety of experimental autoimmune disorders. Accordingly, by reducing lymphocyte infiltration into the spinal cord following SCI, this novel immunomodulator may enhance tissue preservation and functional recovery. In the present study, a moderate to severe contusion SCI was simulated in adult Long-Evans hooded rats. Using flow cytometry we showed that daily FTY720 treatment dramatically reduced T-cell infiltration into the SCI lesion site at 4 and 7 days post-injury, while other inflammatory cell populations were relatively unaltered. To assess functional recovery, three groups of injured animals (treated, vehicle, and injury only) were evaluated weekly for hindlimb recovery. Animals in the treated group consistently exhibited higher functional scores than animals in the control groups after 2 weeks post-injury. This finding was associated with a greater degree of white matter sparing at the lesion epicenter when cords were later sectioned and stained. Furthermore, treated animals were found to exhibit improved bladder function and a reduced incidence of hemorrhagic cystitis compared to control counterparts. Collectively these results demonstrate the neuroprotective potential of FTY720 treatment after experimental SCI.

The impact acceleration model of diffuse traumatic brain injury (DTBI), commonly referred to as the “Marmarou” weight drop model is widely utilized to replicate DTBI, without focal lesion to characterize changes that closely parallel abnormalities characteristic of human DTBI cause by motor vehicle accidents or falls. In this chapter, we describe in detail procedures used to replicate DTBI of varying degrees of severity; the clinically relevant condition of posttraumatic hypoxia and hypotension; and experimental paradigms utilized for intraoperative multiparameter, physiological monitoring. We provide brief summaries of reproducible outcome evaluations characteristic of this model inclusive of (1) intraoperative physiological responses including mean arterial blood pressure (MABP), pH, pO2, and pCO2, and intra-cranial pressure (ICP); (2) gross and neurohistopathological outcomes; (3) functional studies that highlight somatomotor and cognitive behavioral changes; (4) in vitro outcome evaluations employing magnetic resonance imaging (MRI), 1H Magnetic resonance spectroscopy (1H MRS); and (5) high-performance liquid chromatography (HPLC) for the analysis of changes in cellular function, brain edema and cerebral metabolites including N-acetyl-aspartate (NAA) and adenosine tri-phosphate. Finally, we describe the complications associated with the use of this model, mainly technical in nature, easily overcome with repetitious practice and state limitations of this model, notably the use of multiparameter intraoperative monitoring techniques that can be costprohibitive due to the expense of the required equipment. We conclude by stating the major advantage of this model; it has been used extensively in the laboratory to evaluate the effect of pharmacological intervention to treat DTBI. Importantly, these treatments have recently reached Phase II & III clinical trial status.

Magnetic resonance imaging was performed in 13 patients with trigeminal neuralgia and 18 control patients with facial pain of other types. Among trigeminal neuralgia patients, eight (62%) had vessels seen abutting, or immediately adjacent to, the trigeminal nerve on the side of their symptoms. Only three control patients (17%) had such vessels. The proportion of patients having a trigeminal region vessel associated with their symptoms was significantly higher in patients with trigeminal neuralgia than in controls (p = 0.0086). These findings provide evidence supporting the theory that trigeminal neuralgia is associated with vascular compression of the fifth cranial nerve.

✓ This report describes the methods used by the Traumatic Coma Data Bank (TCDB) for acquisition and recording of intracranial pressure (ICP) data of severely head-injured patients. Direct computerization of physiological data from all four participating locations within the United States and transmission to a central data bank was found to be logistically complex and costly. A simple manual method for recording ICP, blood pressure, and concomitant ICP therapy at the bedside is described. The method documents the temporal course of these variables for the duration of monitoring. The importance of relating ICP to the therapy intensity level used for ICP management is emphasized. Concomitant analysis of the therapy intensity level is considered imperative in correlative patient studies. The methods described in this report have been in use among all four TCDB hospitals. Examples of ICP data retrieved from the TCDB are presented to illustrate the adequacy of the methods for assessing temporal trends. Of 1030 patients admitted to the TCDB, 654 severely head-injured patients had at least 4 hours of monitoring recorded; elevated ICP (> 20 mm Hg) was observed in 72% of these 654 patients.

✓ This study describes the relationship between raised intracranial pressure (ICP), hypotension, and outcome from severe head injury. The study is based on information derived from the Traumatic Coma Data Bank where ICP records from a relatively large number of patients were available to help delineate the major factors influencing outcome. From the total data base of 1030 patients, 428 met minimum monitoring duration criteria for inclusion in the present analysis. Outcome was classified according to the Glasgow Outcome Scale score determined at 6 months postinjury. Arrays of comparably defined summary measures describing the patient's course were considered for ICP, blood pressure (BP), central perfusion pressure, and therapy intensity level. For instance, the array of ICP summary descriptors included the proportion of ICP readings greater than x, for x = 0 to 80 mm Hg by increments of 5 mm Hg. A total of 187 candidate summary descriptors were considered. A stepwise ordinal logistic regression was used to select the subset of candidate summary descriptors that best explained the 6-month outcome. As established previously, age, admission motor score, and abnormal pupils were each highly significant in explaining outcome. Beyond these factors, the proportion of hourly ICP readings greater than 20 mm Hg was next selected and was also highly significant in explaining outcome (p < 0.0001). In addition to the ICP factor, the cutoff point of 20 mm Hg was selected by the procedure as most indicative of outcome. With these four factors modeled, the next selected factor was the proportion of hourly BP readings less than 80 mm Hg. Again, the BP factor was highly significant in explaining outcome (p < 0.0001). As with the ICP factor, the BP cutoff point of 80 mm Hg was objectively selected as most indicative of outcome. In summary, the incidence of mortality and morbidity resulting from severe head trauma is strongly related to raised ICP and hypotension measured during the course of ICP management. Moreover, these ICP and BP factors provide a better indication of outcome than the similarly defined factors of central perfusion pressure or therapy intensity level.

The present investigation examined the incidence of alcohol use, drug use and criminal behaviour among persons with traumatic brain injury referred for supported employment services. Primary caretakers of 74 consecutive referrals completed the General Health and History Questionnaire, the brief version of the Michigan Alcohol Screening Test, and the Quantity-Frequency-Variability Index. Pre-injury, a fifth of the sample were abstinent from alcohol and 66% were labelled as moderate or heavy drinkers. Post-injury alcohol use declined. Half of the sample were abstinent and 28% were moderate or heavy drinkers. Thirty-six percent reported illicit drug use pre-injury. Reportedly, post-injury drug use declined to an incidence of 4%. Nearly 20% of the sample had been arrested pre-injury and 10% were arrested post-injury. Implications for further research and programme development are discussed.

Few therapies have consistently demonstrated effectiveness in preserving O2 delivery after spinal cord injury (SCI). Perfluorocarbons (PFCs) offer great promise to carry and deliver O2 more efficiently than conventional measures. The authors investigated the use of Clark-type microelectrodes to monitor spinal cord oxygenation directly (intraparenchymal [IP] recording) and indirectly (cerebrospinal fluid [CSF] recording) in the context of SCI, O2 therapy, and PFC treatment.After placement of a subdural/CSF Licox probe in rats, incremental increases in the fraction of inspired O2 (FiO2) up to 100% were administered to establish a dose-response curve. The probe was then placed in the parenchyma of the same animals for a second dose-response curve. In a second study, rats with CSF or IP probes underwent SCI with the NYU Impactor and treatment with O2, followed by administration of PFC, or saline in the control group.All animals in the first experiment responded to the FiO2 dose increase, with changes in PO2 evident in both CSF and IP levels. The SCI in the second experiment caused a marked drop in PO2 from a mean of 21.4 to 10.4 mm Hg, with most animals dropping to less than half their preinjury value. All animals responded to 100% O2 treatment. Every animal that received PFCs showed significant improvement, with a mean increase in PO2 of 23.3 mm Hg. Only 1 saline-treated animal showed any benefit. Oxygen values in the PFC treatment group reached up to 6 times the normal level.Oxygen levels in SCI show a profound drop almost immediately postinjury. Administration of PFCs combined with 100% O2 therapy can reverse tissue hypoxia and holds promise for reducing ischemic injury.

The scientific and anecdotal information available suggests that broken cell wall preparations and extracts of Chlorella pyrenoidosa in the diet provides important nutrients necessary to maintain good health, resist infection, and restore immune functions in immunocompromised patients. Our clinical study of Chlorella pyrenoidosa (provided by YSK International Corporation, Kyoto, Japan) was designed to test these properties in patients with a history of glioma. Patients with this type of primary brain tumor have a poor prognosis and either because of the tumor itself or due to the treatments applied to kill it, they have compromised immune functions leading to a greater than normal susceptibility to infection. Chlorella was added to the diet of 21 patients; 15 had a glioblastoma, four with low-grade astrocytoma, one had an anaplastic astrocytoma, and one with a high-grade oligodendroglioma. Each patient's general health was monitored by monthly physical and neurological examinations as long as they survived or for at least 2 years. Imaging studies of the brain and blood tests were performed at 3–4 months intervals. Complete blood counts, differentials, cytometric determinations of natural killer cells and T cell subsets, and in vitro lymphocyte activation assays to assess level of immunosuppression were performed on blood samples. Our results with patients taking Chlorella, although limited, suggest that the cellular components and functions of the immune system remain at near-normal levels and are less adversely affected when patients are undergoing chemotherapy and/or taking immunosuppressive medications such as steroids. Over the 2 year course of our investigation, we have observed our patients to have had fewer respiratory infections and flu-like illnesses. 7 of the 20 evaluable patients were alive and had yet to show any reappearance of their glioma after 2 years in the study. Although, our results suggest that our glioma patients may have benefited from adding Chlorella pyrenoidosa to their diet, more controlled clinical studies and animal experiments will be required to define its mechanism of action and limitations.

Relatively little is known regarding the water content of brain tissue in idiopathic normal-pressure hydrocephalus (NPH) patients. The objective of our study was to determine absolute water content non-invasively in hydrocephalic patients, particularly in the anterior and posterior ventricular horns and in the periventricular white matter.

The incidence of idiopathic normal pressure hydrocephalus (iNPH) has increased as a result of improved longevity. This report describes the 3-year outcome of shunted iNPH patients compared to three-month outcome after shunting. Patients (n = 50) (Age 70.4 ± 8.9) admitted to our service were diagnosed and treated according to a fixed protocol for management of iNPH and after shunting were followed at least three times per year in clinic. The outcome of 50 patients was graded according to the level of improvement in symptoms as Excellent/Good, Partial or None in each category of Gait, Incontinence and Dementia. If we lump favorable (excellent, good, partial recovery) vs poor recovery (none), we found from 3 months to 3 years, a moderate decline in gait performance (91% to 75%), a retention of memory improvement (80%-80%) and an improvement in incontinence occurred over time (70%–82.5%).

Background Animal stroke models demonstrate excitatory amino acid (EAA) release in ischemic tissue, as measured by microdialysis. Currently glutamate antagonist drugs are being developed to protect brain tissue after ischemic events. However, the role of EAAs in human occlusive stroke is not well known. We therefore measured glutamate and aspartate release in a patient after occlusive stroke. Case Description We describe a case of occlusive stroke in a 50-year-old man. A partial temporal lobectomy was done to remove infarcted tissue and to prevent brain stem compression as well as uncal herniation. A microdialysis probe was placed into the cortex to measure EAAs. Massively increased levels of glutamate and aspartate were detected in the extracellular fluid in this patient (>300 times normal levels 6 days after infarction). Conclusions These findings indicate that EAAs are tremendously increased in brain tissue after occlusive stroke. The time course of the release of EAAs is much longer than animal studies have suggested previously. Administration of EAA antagonists to patients with ischemic stroke may therefore be beneficial.

Sacral schwannoma is a rare lesion (23 reported cases) with a tendency to reach large proportions. Symptoms are back and leg pain, leg weakness, hypoesthesias, paresthesias, constipation, and incontinence. The peak incidence is between ages 30 and 50. Radiographs of the sacrum are abnormal in nearly all cases. Computed tomography and magnetic resonance imaging may reveal large lesions with bony erosion and involvement of the soft tissues. The treatment of this lesion is complete removal, which is curative.

Object. Bone grafts used in anterior cervical fusion (ACF) may subside postoperatively. The authors reviewed a recent series in which instrument-assisted ACF was performed to determine the degree of subsidence with respect to fusion length, use of segmental screws, and patient smoking status, age, and sex. Methods. Charts and implant records were reviewed for all 70 patients who underwent instrument-assisted ACF during a 2-year period. The procedures, grafting materials, plate types/lengths, and patient smoking status were recorded. The immediate postoperative and follow-up lateral radiographs were analyzed. The plate lengths and lengths of the fused segments were measured in a standardized fashion. The mean intraoperative and follow-up fusion segment lengths were 54.3 and 51.9 mm, respectively. Greater subsidence occurred in multilevel fusions than in single-level fusions. There were noticeable changes in the position of plates or screws on 14 of 70 follow-up x-ray films. No new neurological deficits related to graft subsidence occurred, and the reoperation rate was 3%. There was no statistical relation between subsidence and the following variables: segmental fixation, smoking status, sex, age, or dowel size when corrected for length of the plate. Hardware migration correlated significantly with plate length in cases of two- and three-level fusions. Conclusions. The length of a fusion segment decreases in the immediate weeks following instrument-assisted ACF. Construct length is the most important determinant of subsidence. When designing multilevel cervical constructs, consideration of the effects of graft subsidence may help to avoid hardware-related complications.

Object. Currently, there are no good clinical tools to identify the onset of secondary brain injury and/or hypoxia after traumatic brain injury (TBI). The aim of this study was to evaluate simultaneously early changes of cerebral metabolism, acid—base homeostasis, and oxygenation, as well as their interrelationship after TBI and arterial hypoxia. Methods. Cerebral biochemistry and O2 supply were measured simultaneously in a feline model of fluid-percussion injury (FPI) and secondary hypoxic injury. After FPI, brain tissue PO2 decreased from 33 ± 5 mm Hg to 10 ± 4 mm Hg and brain tissue PCO2 increased from 55 ± 2 mm Hg to 81 ± 9 mm Hg, whereas cerebral pH fell from 7.1 ± 0.06 to 6.84 ± 0.14 (p < 0.05 for all three measures). After 40 minutes of hypoxia, brain tissue PO2 and pH decreased further to 0 mm Hg and 6.48 ± 0.28, respectively (p < 0.05), whereas brain tissue PCO2 remained high at 83 ± 13 mm Hg. Secondary hypoxic injury caused a drastic increase in cerebral lactate from 513 ± 69 µM/L to 3219 ± 490 µM/L (p < 0.05). The lactate/glucose ratio increased from 0.7 ± 0.1 to 9.1 ± 2 after hypoxia was introduced. The O2 consumption decreased significantly from 18.5 ± 1.1 µl/mg/hr to 13.2 ± 2.1 µl/mg/hr after hypoxia was induced. Conclusions. Cerebral metabolism, O2 supply, and acid—base balance were severely compromised ultra-early after TBI, and they declined further if arterial hypoxia was present. The complexity of pathophysiological changes and their interactions after TBI might explain why specific therapeutic attempts that are aimed at the normalization of only one component have failed to improve outcome in severely head injured patients.

Glucose (Glue) 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: 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.

The survival of traumatized brain tissue depends on energy substrate delivery and consumption. Excitatory amino acids produce a disturbance of ion homeostasis and thus, increase energy demand. In head-injured patients, massive release of glutamate has been reported, especially in patients with focal contusions. Therefore, we studied the interrelationship between glutamate, glucose and lactate in relation to the type of injury. We investigated 37 severely headinjured patients in which a microdialysis probe was placed next to a focal contusion (n = 14) or together with a ventricular catheter in diffusely injured tissue (n = 23). Within-subject Spearman-rank correlation revealed an overall strong relationship between glutamate and lactate (p < 0.001) and glutamate and glucose (p < 0.01 ), but not between glucose and lactate (n.s.). The interrelationship was more pronounced in diffusely injured brain (normal CT appearance) compared to the contused tissue.

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 ≤ 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 ≤ 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.

In previous studies, Katayama and our group have documented a massive increase in excitatory amino acid release following traumatic brain injury, in both rat fluid percussion, and humans [2,5]. To test the hypothesis that the magnitude of this “Excitotoxic Surge” plays a significant role in determining 6-month patient outcome. We have studied 83 consecutive severely head injured patients at the Medical College of Virginia for inclusion into this study. A microdialysis probe was placed within the cortex to continuously measure dialysate excitatory amino acids (Glutamate and Aspartate), along with several other analytes for approximately 5 days after injury. ICP, CPP, and MABP measurements were also time linked with each analyte measurement to create a neurochemical, clinical, and physiological “profile” for each patient. Outcome was determined by follow up using the Glasgow 6-Month outcome scale. A very strong correlation existed between the release of the EAA’s glutamate and aspartate after TBI (p < 0.0001). Patients with significantly elevated mean glutamate values for the entire monitoring period were most likely to exhibit elevated levels of ICP. The magnitude of glutamate released significantly correlates with 6-month patient outcome (p = 0.0234). When patients were subdivided by the CT diagnosis of lesion type, we found that those patients with contusions displayed the highest overall of EAA’s.

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 (≥;30-min) of high sodium in dialysates (≥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 μM) 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 ± 3mM; 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.

OBJECTIVE Current neuromonitoring techniques in severe human head injury often fail to detect the causes of clinical deterioration. A sensor is now available for continuous monitoring of brain oxygen tension, carbon dioxide tension, and pH values. In this study, brain tissue oxygen tension was used to differentiate patients at risk for brain ischemia and to predict outcome. METHODS The multiparameter sensor was inserted into brain tissue, along with a standard ventriculostomy catheter and a microdialysis probe, in 24 patients. Lactate and glucose were measured by high-pressure liquid chromatography in hourly dialysate samples. RESULTS Patients who experienced a good recovery (n = 8) sustained a mean brain partial oxygen pressure of 39 +/- 4 mm Hg, brain partial carbon dioxide pressure (PCO2) of 50 +/- 8 mm Hg, and a brain pH of 7.14 +/- 0.12. Patients with moderate to severe disability (n = 6) sustained a mean brain partial oxygen pressure of 31 +/- 5 mm Hg, brain PCO2 of 47 +/- 2 mm Hg, and a brain pH of 7.11 +/- 0.12. Ten patients who died or remained vegetative sustained a mean brain partial oxygen pressure of 19 +/- 8 mm Hg, a brain PCO2 of 64 +/- 21 mm Hg, and a brain pH of 6.85 +/- 0.41. Mean brain PCO2 levels of 90 to 150 mm Hg were consistently observed after cerebral circulatory arrest or brain death. Dialysate lactate and glucose were less clearly correlated to outcome than brain oxygen tension. Dialysate glucose was extremely low in all patients and zero in most patients who died. CONCLUSION Brain oxygen pressure, brain carbon dioxide pressure, and brain pH measurements, as well as a microdialysis probe for glucose and lactate analysis, may optimize the management of comatose neurosurgical patients by allowing a fuller understanding of the dynamic factors affecting brain metabolism.

Background and Purpose Cerebral ischemia and stroke are leading causes of morbidity and mortality. An approach to protecting the brain during ischemia is to try to increase the delivery of oxygen via the residual blood flow through and around ischemic tissue. To test this hypothesis, we used a novel oxygen delivery agent, RSR-13 (2-[4-[[(3,5-dimethylanilino)-carbonyl]-methyl]phenoxy]-2-methylpropionic acid). Intravenous administration of RSR-13 increases oxygen delivery through allosteric modification of the hemoglobin molecule, resulting in a shift in the hemoglobin/oxygen dissociation curve in favor of oxygen delivery. Methods We studied RSR-13 in a feline model of permanent middle cerebral artery occlusion to assess its effects on cerebral oxygenation and infarct size. A randomized, blinded study of RSR-13 (n=6) versus 0.45% saline (n=12) was conducted, after an RSR-13 dose-escalation study (n=4). Drug was administered as a preocclusion bolus followed by a continuous infusion for the duration of the experiment (5 hours). Brain oxygen was measured continuously with the use of a Clark oxygen electrode. Infarct size was measured at 5 hours after occlusion with computer-assisted volumetric analysis. Results The drug treatment group had consistently higher mean brain oxygen tension than controls (33±5 and 27±6 mm Hg, respectively) and significantly smaller infarcts (21±9% versus 33±9%, respectively; P Conclusions These results are evidence that allosteric hemoglobin modification is protective to the brain after acute focal ischemia, providing a new opportunity for neuroprotection and raising the possibility of enhancing the protective effect of thrombolysis and ion channel blockade.

Brain edema and vascular engorgement have been used interchangeably to describe brain swelling associated with severe brain trauma and their relative contribution of these compartments to the swelling process remains controversial. In this report, imaging techniques for measurement of brain water and blood volume have been used to study the relative contribution of blood volume and tissue water to the swelling process in severely brain injured patients. More specifically, magnetic resonance techniques for non-invasive tissue water measures founded on mathematical models and later substantiated in laboratory and clinical studies were used for measure of brain tissue water. These studies were combined with measures of cerebral blood volume utilizing indicator dilution methods. Studies indicated that brain water was increased while blood volume decreased. These studies provide compelling evidence that the major contributor to brain swelling is brain edema and not blood volume. Therapies should now be targeted toward preventing edema development and enhancing edema resolution.

✓ The investigators undertook a retrospective analysis of ventriculostomy infections to evaluate their relationship to monitoring duration and prophylactic catheter exchange. In 1984, the results of an epidemiological study of ventriculostomy-related infection were published. One of the conclusions of the paper was that the incidence of ventriculostomy-related infections rose after 5 days of monitoring. This led to the recommendation that catheters be prophylactically changed at 5-day intervals if prolonged monitoring was required. A recent randomized prospective study on central venous catheters showed no reduction in infection with prophylactic catheter exchanges. This has led the authors to reexamine their experience with ventriculostomy infections. Data on 584 severely head injured patients with ventriculostomies were prospectively collected in two data banks, The Traumatic Coma Data Bank and The Medical College of Virginia Neurocore Data Bank. These data were retrospectively analyzed for factors associated with ventriculostomy related infections. It was found that there is a relationship of ventriculitis to monitoring duration but it is not simple or linear. There is a rising risk of infection over the first 10 days, but infection then becomes very unlikely despite a population that continues to be at risk. Patients in whom catheters were replaced prior to 5 days did not have a lower infection rate than those whose catheters were exchanged at more than 5-day intervals. Based on these data, it is recommended that ventriculostomy catheters for intracranial pressure monitoring be removed as quickly as possible, and in circumstances in which prolonged monitoring is required, there appears to be no benefit from catheter exchange.

We examined the effects of an exogenous mu opioid agonist and antagonist on systemic physiology and neurological outcome following TBI in the rat. Experiment I: [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) (0.1 nMol or 0.3 nMol in 5 microliters) (n = 10) or artificial CSF (n = 10) was administered 5 min prior to fluid-percussion brain injury (2.1 atmospheres). Motor performance was assessed on days 1-5 after TBI. The mu receptor agonist, DAMGO significantly reduced both beam-walking latency and body weight loss after injury (p < 0.05). DAMGO-treated rats (n = 5) did not differ from CSF-treated rats (n = 5) on either systemic arterial blood pressure or heart rate responses to injury. Experiment II: Beta-funaltrexamine (beta-FNA) (20.0 nMol in 5.0 microliters) (n = 10) or artificial CSF (n = 10) was administered (icv) to rats 5 min prior to fluid-percussion brain injury (1.8 atmospheres). Motor performance was assessed on days 1-5 after TBI. The mu receptor antagonist, beta-FNA, significantly increased beam-walking latency after injury (p < 0.05). beta-FNA-treated rats (n = 5) did not differ from CSF-treated rats (n = 5) on either systemic arterial blood pressure or heart rate responses to injury. Experiment III: Neither beta-FNA nor DAMGO affected motor performance in uninjured rats. These results suggest that activation of mu opioid receptors by exogenous agonists may provide protection against deficits in motor performance produced by fluid percussion brain injury.

In many of the conditions that result in acute cerebral damage, the role of excitatory amino acids has become the focus of current investigation [1, 2]. The demonstration of excitatory amino acid release has been shown in several animal models of brain trauma, and has been associated with both structural damage and metabolic abnormalities [3–5]. These changes may be reversed by administration of excitatory amino acid antagonists, and this group of compounds has shown a greater magnitude of neuroprotective effect than any other series of drugs in the laboratory [3, 6]. As part of an ongoing study, we have recently measured release of excitatory amino acids (EAAs) and ions in 17 acutely head-injured patients in our institution, with the aim of determining the circumstances that are responsible for glutamate release and their possible role as an exacerbating factor in causing secondary brain damage after severe human head injury.

The foundation of our understanding of ICP dynamics rests on the assumption that venous outflow pressure, considered the superior saggital sinus, remains constant. As it is further considered that the cortical vein pressure must be slightly higher than ICP to prevent collapse, it follows that a pressure gradient should exist between the cortical veins and saggital sinus [5]. According to this concept, the gradient of pressure is developed along the bridging veins and lateral lacunae.

The deleterious effect of raised ICP following traumatic brain injury has been well recognized. However, it remains unclear whether the primary disruption of volume homeostasis and subsequent development of pressure is caused by brain edema or vascular engorgement. Primary traumatic swelling usually involves both hemispheres and in the more recent data obtained from the traumatic coma data bank (TCDB), of 595 patients studied, 31% of patients showed evidence of brain swelling [1]. Heretofore, it has not been possible to assess the contribution of increased water because of methodological problems in volume assessment. However, the recent introduction of magnetic resonance (MR) methods and the inherent sensitivity of changes in relaxation time to brain water has led to the development of quantitative methods capable of determining spatial distribution of edema non-invasively [2, 3].

We have been focusing on potential metabolic derangement associated with severe head injury and a clinical trial directed toward treating brain tissue acidosis is currently underway. More specifically, we based this study on the hypothesis that following brain trauma brain tissue acidosis develops which may contribute to the prolongation of coma and neurologic deficit. Tromethamine (THAM), a safe and low toxicity agent which buffers in major part by causing a hypocapnic alkalosis, was selected for trial. Patients admitted with GCS < 8 were randomized into one of three arms: control; THAM plus hyperventilation; hyperventilation alone. Each regimen was maintained for 5 days post injury. Our analysis of 3 and 6 months Glasgow outcome score showed that prophylactic hyperventilation retards recovery, and the use of THAM overcomes the apparent deleterious effects of hyperventilation. One explanation is that the reduced ICP instability observed in THAM treated patients may account for this improvement. Is THAM effective in buffering traumatized brain tissue? What factors account for improvement in ICP stability?