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The aim of this project was to develop evidenced based guidelines for the diagnosis and management of idiopathic normal pressure hydrocephalus (iNPH). An advisory panel consisting of the authors assisted by international experts met on several occasions and formulated preliminary guidelines for iNPH managemen. The authors developed evidentiary tables based on available literature from 1966 to the present. Additional meetings to refine the evidentiary tables and incorporate expert opinion when necessary resulted in the development the iNPH guidelines. Evidence based guidelines identifying the value of clinical examination, brain imaging, Tap Test, CSF drainage, ICP monitoring and Surgical Management in diagnosing and treating the iNPH patient were developed. These are the first international evidence based guidelines focused on iNPH. Class I data were scant and guidelines relied mostly on class II and III evidence. It became clear that more prospective randomized studies are needed to resolve some of the controversial issues such as iNPH classification and sensitivity of diagnostic tests for identifying shunt responsive iNPH.

The aim of this study was to evaluate the extent of mitochondrial injury by assessing N-Acetyl-Aspartate by MR spectroscopy in head injured patients and relating the extent of mitochondrial injury to outcome. The study population (n = 15) consisted of head injured patients (GCS < 8) in whom legal consent was obtained for MRS studies. Studies were performed on a 1.5 Tesla Vision/Siemens system. Size of Voxel equaled 8 cm3 with location determined from T1 images. Voxels were positioned adjacent to the lesion and in the contralateral hemisphere for focal and bilateral for diffuse. Mitochondrial impairment was considered as percent reduction in NAA/Cr ratio compared to matched controls. Mitochondrial impairment gradually increases soon after injury reaching a nadir at 10 days. Subsequently, mitochondria recover in patients with favorable outcome, but remains impaired in patients with poor outcome. The prognostic value of NAA/Cr to assist in management and also to serve as a surrogate endpoint for clinical trials appears promising.

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%).

The protein kinase C activator, phorbol 12-myristate 13-acetate (PMA), is known to interact with aquaporin-4 (AQP4), a water-selective transporting protein abundant in astrocytes and ependymal cells, that has been found to decrease osmotically-induced swelling. The purpose of this study was to examine whether PMA given at different time points following focal ischemia induced by middle cerebral artery occlusion (MCAO) reduces brain edema by AQP4 modulation. Male Sprague-Dawley rats were randomly assigned to sham procedure, vehicle, or PMA infusion (230 microg/kg), starting either 60 minutes before, or 30 or 60 minutes after MCAO (each group n = 12). After a 2-hour period of ischemia and 2 hours of reperfusion, the animals were sacrificed for assessment of brain water content, sodium, and potassium concentrations. AQP4 expression was assessed by immunoblotting. Statistical analysis was performed by ANOVA followed by Tukey's post hoc test. PMA treatment significantly reduced brain water content concentration in the infarcted area when started before or 30 minutes post-occlusion (p0.001, p = 0.022) and prevented the subsequent sodium shift (p0.05). Furthermore, PMA reduced ischemia-induced AQP4 up-regulation (p0.05). Attenuation of the ischemia-induced AQP4 up-regulation by PMA suggests that the reduction in brain edema formation following PMA treatment was at least in part mediated by AQP4 modulation.

Management of cerebral perfusion pressure is an important element of the treatment of traumatic brain injury. Vasopressors are accepted as a method of choice to increase mean arterial blood pressure and thus cerebral perfusion pressure in the face of rising intracranial pressure. There are, however, some unresolved issues and potential risks to this therapy.This study therefore examines the effects of dopamine on physiological changes as well as on brain edema and water content that can be readily assessed by MRI/MRS in (1) a rodent model of rapidly rising intracranial pressure, caused by diffuse injury with secondary insult and (2) a model of cortical contusion.Dopamine was capable of restoring cerebral perfusion pressure in the model of rapidly rising intracranial pressure. However, this was associated with only a partial restoration of cerebral blood flow. In the brain tissue two profiles of change in the apparent diffusion coefficient of water (ADCw) were seen; one in which ADCw recovered to baseline, and one in which ADCw remained persistently low. Despite that dopamine did not alter these profiles, MRI-assessed tissue water content was increased four hours after injury and dopamine increased cerebral water content in both subgroups of injury, especially in the subgroup with a persistently low ADCw (p0.01). In the contusion group dopamine significantly worsened the edema both in the injured and in the contralateral area of hippocampus and temporal cortex even though the ADCw values did not change, except for the contralateral hippocampus, where both water content and ADC, values rose with treatment, suggesting extracellular accumulation of water.The results suggest that dopamine has a double effect--while it temporarily and partially restores cerebral blood perfusion, at the same time it induces an increase in brain swelling and thus an increase in intracranial pressure in some cases. It is possible that in a subgroup of patients vasopressor treatment leads to an opposite effect several hours later. Vasopressor therapy in the clinical setting therefore should be cautiously applied.

OBJECTIVE: The diagnosis and management of idiopathic normal-pressure hydrocephalus (INPH) remains unclear. Moreover, the value of supplementary tests to predict which patients would benefit from placement of a shunt has not been established. This report develops evidence-based guidelines for the use of supplementary tests as an aid in prognosis. METHODS: MEDLINE searches from 1966 to the present were undertaken by use of the query NPH, normal-pressure hydrocephalus, lumbar drain, CSF [cerebrospinal fluid] tap test, and external CSF drainage in humans. This resulted in 242 articles. To provide a scientific, evidence-based review, we have chosen to restrict our analysis to clinically relevant studies usually consisting of large numbers of shunted NPH patients. Studies that did not specify INPH or secondary NPH were considered in a separate evidentiary table. RESULTS: Evidence-based guidelines for use in supplementary tests have been developed. A positive response to a 40- to 50-ml tap test has a higher degree of certainty for a favorable response to shunt placement than can be obtained by clinical examination. However, the tap test cannot be used as an exclusionary test because of its low sensitivity (26–61%). Determination of the CSF outflow resistance via an infusion test carries a higher sensitivity (57–100%) compared with the tap test and a similar positive predictive value of 75 to 92%. Prolonged external lumbar drainage in excess of 300 ml is associated with high sensitivity (50–100%) and high positive predictive value (80–100%). CONCLUSION: To date, a single standard for the prognostic evaluation of INPH patients is lacking. However, supplemental tests can increase predictive accuracy for prognosis to greater than 90%. Additional multicenter prospective randomized clinical trials are needed.

OBJECTIVE: There are no currently accepted evidence-based guidelines for the diagnosis and management of the normal-pressure hydrocephalus (NPH) patient. As a result, an independent study group was assembled to address this issue and determine the feasibility of developing standardized guidelines, which would be acceptable in the United States and abroad and would be based on the available scientific evidence. The guidelines were to encompass value of clinical presentation, value of supplementary diagnostic tests, surgical management, and outcome assessment. METHODS: Initially, a series of 10 questions were formulated in the areas of pathophysiology, diagnosis, and treatment to obtain a consensus by panels of experts (see Acknowledgments) assembled in San Antonio, TX, in September 2000. This workshop provided significant insight into the difficulties in developing NPH guidelines, and a consensus was reached as to those questions involving expert opinion. Subsequently, evidentiary tables were developed on the basis of the available evidence. Only those studies with 20 or more idiopathic NPH (INPH) patients were included. RESULTS: Sensitivity, specificity, and positive and negative predictive values for INPH diagnostic criteria were assessed, and guidelines were developed on the basis of the available evidence. Recommendations for classification of INPH and additional studies were documented. CONCLUSION: The development of the guidelines was made difficult because systematic studies of INPH and patient numbers were few. It was decided to maintain the classification of NPH into two major categories, INPH and those of known cause (secondary NPH). Many studies “mixed” these classifications, and as a result, they could not be used in the evidentiary tables. Despite these problems, evidence-based guidelines were developed, and it is hoped that they will be useful in guiding clinical management of the INPH patient.

OBJECTIVE: The precise incidence and prevalence of idiopathic normal-pressure hydrocephalus (INPH) is not known, and evidence-based clinical diagnostic criteria have not been developed previously. This report contains evidence-based guidelines for clinical diagnosis of INPH that are intended to facilitate future epidemiological studies of INPH, promote earlier and more accurate diagnosis, and ultimately improve treatment outcome. METHODS: The criteria for the diagnosis of INPH are based on evidence from the medical literature, supplemented as necessary by expert opinion. From 1966 to 2003, 653 publications on “normal-pressure hydrocephalus” were cited in MEDLINE, including 29 articles that met the more stringent criteria of including “idiopathic normalpressure hydrocephalus” in their title. Additional studies were considered that explicitly identified INPH cases and/or specified the criteria for a diagnosis of INPH. Studies were graded according to the class of evidence and results summarized in evidentiary tables. For issues of clinical relevance that lacked substantive evidence from the medical literature, the opinions of consulting experts were considered and contributed to “Options.” RESULTS: Evidence-based guidelines for the clinical diagnosis of INPH have been developed. A detailed understanding of the range of clinical manifestations of this disorder and adherence to practice guidelines should improve the timely and accurate recognition of this disorder. CONCLUSION: It is recommended that INPH be classified into probable, possible, and unlikely categories. We hope that these criteria will be widely applied in clinical practice and will promote greater consistency in patient selection in future clinical investigations involving INPH.

Object. After traumatic brain injury (TBI), S100B protein is released by astrocytes. Furthermore, cerebrospinal fluid (CSF) and serum S100B levels have been correlated to outcome. Given that no data exist about the temporal profile of cerebral S100B levels following TBI and their correlation to serum levels, the authors examined whether proton magnetic resonance (MR) spectroscopy is capable of measuring S100B. Methods. Results of in vitro proton MR spectroscopy experiments (2.35-tesla magnet, 25 G/cm, point-resolved spatially localized spectroscopy) revealed an S100B-specific peak at 4.5 ppm and confirmed a positive correlation between different S100B concentrations (10 nM–1 µM) and the area under the curve (AUC) for the S100B peak (r = 0.991, p < 0.001). Thereafter, proton MR spectroscopy was performed in male Sprague—Dawley rats (7 × 5 × 5—mm voxel in each hemisphere, TR 3000 msec, TE 30 msec, 256 acquisitions). Exogenously increased CSF S100B levels (∼ 200 ng/ml) through the intraventricular infusion of S100B increased the AUC of the S100B peak from 0.06 ± 0.02 to 0.44 ± 0.06 (p < 0.05), whereas serum S100B levels remained normal. Two hours after lateral fluid-percussion injury, serum S100B levels increased to 0.61 ± 0.09 ng/ml (p < 0.01) and rapidly returned to normal levels, whereas the AUC of the S100B peak increased to 0.19 ± 0.04 at 2 hours postinjury and 0.41 ± 0.07 (p < 0.05) on Day 5 postinjury. Conclusions. Proton MR spectroscopy proves a strong correlation between the AUC of the S100B peak and S100B concentrations. Following experimental TBI, serum S100B levels increased for only a very short period, whereas cerebral S100B levels were increased up to Day 5 postinjury. Given that experimental data indicate that S100B is actively released following TBI, proton MR spectroscopy may represent a new tool to identify increased cerebral S100B levels in patients after injury, thus allowing its biological function to be better understood.

It is the general sense that mortality has been decreasing in recent years compared to earlier studies described by the NIH traumatic coma data bank. We studied mortality during the period of 1984 to 1996 to determine if indeed mortality from severe traumatic brain injury was decreasing and to identify factors which might account for the reduction. The study population (N = 1839) consisted of severely head injured patients extracted retrospectively from the TCDB (635), MCV (382), and 822 patients from clinical trial databases conducted in the United States. Mortality was obtained from each of the databases for the age range form 16 to 65. Penetrating injury and treatment groups in the clinical trial databases were excluded. Mortality in the year 1984 equaled 39% and gradually decreased to a level of 27% in 1996. When adjusting for age, motor score and pupil reaction, the mortality of the period from 1984 to 1987 was significantly higher (p < 0:05) than that of the period 1988 to 1996.

OBJECTIVE Few randomized clinical trials (RCTs) in the field of traumatic brain injury (TBI) have shown a significant treatment benefit. We critically reviewed the use of two types of secondary analyses, covariate adjustment and subgroup analysis, which are common in TBI trials. METHODS We performed a systematic review of therapeutic phase III RCTs, including adult patients with acute, moderate-to-severe TBI. Glasgow Outcome Scale (GOS) at > or =3 months as outcome, and > or =50 patients per arm were required. We compared the actual reporting of covariate adjustment and subgroup analyses with the Consolidated Standards of Reporting Trials (CONSORT) recommendations. Likewise, we reviewed six protocols of large multicenter RCTs and compared planned and reported subgroups. RESULTS We identified 18 RCTs (n = 6439). Sixteen trials used GOS at 6 months as outcome. Five RCTs reported covariate adjustment. The number of covariates was limited (< or =5), most frequently including age. Many covariates were outcome predictors. Four RCTs reported only adjusted treatment effects as the main efficacy parameter. Eleven RCTs reported subgroup analyses. Several subgroup factors (< or =7, mainly outcome predictors) and outcomes (< or =4) were included. The highest total number of subgroups was 15, and only three RCTs completely pre-specified subgroups. Notably, 10 of 11 RCTs performed inappropriate separate subgroup analyses. Of 11 RCTs, 5 gave subgroups the same emphasis as the overall effect. Reported subgroup analyses were insufficiently described and clearly differed from those planned in the protocol. CONCLUSION The reported covariate adjustment and subgroup analyses from TBI trials had several methodological shortcomings. Appropriate performance and reporting of covariate adjustment and subgroup analysis should be considerably improved in future TBI trials because interpretation of treatment benefits may be misleading otherwise.

OBJECTIVE: The combined effect of traumatic brain injury (TBI) and secondary insult on biochemical changes of cerebral tissue is not well known. For this purpose, we studied the time-course changes of parameters reflecting ROS-mediated oxidative stress and modifications of cell energy metabolism determined in rats subjected to cerebral insult of increasing severity. METHODS: Rats were divided into four groups: 1) sham-operated, 2) subjected to 10 minutes of hypoxia and hypotension (HH), 3) subjected to severe diffuse TBI, and 4) subjected to severe diffuse TBI + HH. Rats were killed at different times after injury, and analyses of malonclialclehyde, ascorbate, high-energy phosphates, nicotinic co-enzymes, oxypurines, nucleosides, and 4-acetylaspartate (NAA) were made by high-performance liquid chromatography on whole-brain tissue extracts. RESULTS: Data indicated a close relationship between degree of oxidative stress and severity of brain insult, as evidenced by the highest malondialdehyde values and lowest ascorbate levels in rats subjected to TBI + HH. Similarly, modifications of parameters related to cell energy metabolism were modulated by increasing severity of brain injury, as demonstrated by the lowest values of energy charge potential, nicotinic coenzymes, and NAA and the highest levels of oxypurines and nucleosides recorded in TBI + HH rats. Both the intensity of oxidative stress-mediated cerebral damage and perturbation of energy metabolism were minimally affected in rats subjected to HH only. CONCLUSION: These results showed that the severity of brain insult can be graded by measuring biochemical modifications, specifically, reactive oxygen species-mediated damage, energy metabolism depression, and NAA, thereby validating the rodent model of closed-head diffuse TBI coupled with HH and proposing NAA as a marker with diagnostic relevance to monitor the metabolic state of post-injured brain.

PURPOSE: The size distribution of fat globules from previously unopened, unexpired vials of Gensia Sicor's 1% propofol injectable lipid emulsion was studied. METHODS: Fat globules in 20-mL samples from 50- and 100-mL vials of Gensia Sicor's 1% propofol emulsion containing 0.025% sodium metabisulfite were measured and counted by a laser-based, single-particle optical sensing technique. Measurements were performed during May 2001, June 2002, and October 2002, corresponding, respectively, to 17-21, 5-9, and 1-5 months before the vials' expiration dates, depending on the lot. Between measurements, the vials were stored at 4-22 degrees C. It was assumed that the pH for all lots was 4.5-6.4. Two separate lots of the innovator propofol emulsion (AstraZeneca) containing EDTA and having a labeled pH of 7.0-8.5 were analyzed in October 2002 in a post hoc assessment as the vials neared their expiration date. RESULTS: In May 2001, the volume-weighted percentage of fat globules with a diameter of >5 microm (PFAT5) was

The aim of this study was to assess the effect of rapid or delayed surgical evacuation on the physiological consequence and brain edema formation in a rat model of acute subdural hematoma (SDH) coupled with either diffuse brain injury (DBI) or hypoxemia. The SDH was made by an autologous blood injection, while DBI was induced using the impact acceleration model (mild, 450 g/1 m; severe, 450 g/2 m). Physiological parameters measured included intracranial pressure (ICP), mean arterial blood pressure (MABP), cerebral blood flow (CBF), and brain tissue water content. At 1 h (rapid evacuation) or 4 h (delayed evacuation) after the SDH induction, surgical evacuation following a craniotomy was performed using saline irrigation and forceps. The study consisted of three different series, including 400 microL of SDH alone (Series 1), SDH400 + mild DBI (Series 2), and SDH300 + severe DBI + 20 min hypoxemia (Series 3). The hypoxemia was added in Group 3 to produce a steadily increasing ICP. In Series 1 and 2, all rats were randomized into the three following groups: non-, rapid, and delayed evacuation; Series 3 had two groups: non- and rapid evacuation. In Series 1, the surgical evacuation showed no beneficial effects on the brain edema formation assessed at 5 h post-injury. In Series 2, the rapid, but not delayed, evacuation significantly reduced both the increased ICP level and brain water content. The additional insult of hypoxemia (Series 3) resulted in a progressive ICP elevation, persistently depressed CBF, and severe brain swelling. Under this situation, the rapid evacuation exacerbated brain edema. These results have clinical implications for the management of severe traumatic SDH, especially its operative indication and timing.

Atrial natriuretic peptide (ANP) plays an important role in the regulation of water and sodium in the body via cyclic GMP (cGMP) pathway. Although ANP has been shown to be protective in cerebral ischemia or intracerebral hemorrhage, its role in traumatic brain injury (TBI) has yet to be elucidated. We herein assessed ANP effects on brain water and sodium in TBI. Controlled cortical impact (3 mm depth, 6 m/sec) was used to induce an experimental cortical contusion in rats. Continuous administration of ANP 0.2 (n = 6) or 0.7 μg/kg/24 h (n = 6), cGMP analogue (8-Bromo-cGMP) 0.1 (n = 5) or 0.3 mg/kg/24 h (n = 5), or vehicle (n = 6) was begun 15 minutes after injury, using a mini-osmotic pump implanted into the peritoneal cavity. At 24 hours after injury, ANP significantly exacerbated brain edema in the injured hemisphere in a dose-dependent manner while it reduced brain sodium concentrations in both hemispheres. These ANP effects could be mimicked by a cGMP analogue. In the second series (n = 20), BBB integrity was assessed by evaluating the extravasation of Evans blue dye. ANP or cGMP analogue significantly worsened BBB disruption in the injured hemisphere at 24 hours after injury. These findings suggest that ANP administration exacerbates brain edema after the experimental cortical contusion in rats, possibly because of an increase in the BBB permeability via cGMP pathway, whereas it reduces brain sodium levels.

Cyclosporin A (CsA) has been shown by our laboratory and others to be neuroprotective in the experimental animal model of traumatic brain injury. However, we found that the intrathecal administration resulted in a concomitant increase of brain edema. The aim of this study was to assess whether intravascular administration may also influence brain edema formation.

Our Laboratory has pursued the hypothesis that traumatic brain edema is predominantly cellular and recent supportive evidence has been obtained indicating a non-extracellular route for sodium and water entering brain. The aim of this study was to investigate if astrocytic endfeet are involved in this passage, using a potent activator of Protein Kinase C (phorbol ester) to modify and closing the Aquaporin 4 (AQP4), a water channel specific for astrocytic endfoot.

The generally held concept during the past several decades is that traumatic brain edema is predominately vasogenic emanating from the blood vessels subsequent to blood brain barrier compromise. Much of the experimental data has focused on cryogenic injury models where there clearly is a necrotic lesion surrounded by leaking vessels. However, in closed head injury where brain swelling remains a critical problem, the classification of the type of edema that develops is less clear. Most importantly, studies in the clinical setting have ruled out vascular engorgement as one potential mechanism and these studies have shown that edema and not blood volume is the culprit responsible for brain swelling. We have put forth the notion that traumatic brain edema is a combination of vasogenic and cellular with the cellular component predominating. This article provides an update of our current progress toward supporting this hypothesis and includes an update on the role of aquaporins in traumatic brain edema.

The pathogenesis of traumatic brain swelling remains unclear. The generally held view is that brain swelling is caused primarily by vascular engorgement and that edema plays a relatively minor role in the swelling process. The goal of this study was to examine the roles of cerebral blood volume (CBV) and edema in traumatic brain swelling.Both brain-tissue water and CBV were measured in 76 head-injured patients, and the relative contribution of edema and blood to total brain swelling was determined. Comparable measures of brain-tissue water were obtained in 30 healthy volunteers and CBV in seven volunteers. Brain edema was measured using magnetic resonance imaging, implementing a new technique for accurate measurement of total tissue water. Measurements of CBV in subgroup of 31 head-injured patients were based on consecutive measures of cerebral blood flow (CBF) obtained using stable xenon and calculation of mean transit time by dynamic computerized tomography scanning after a rapid bolus injection of iodinated contrast material.The mean (+/- standard deviation) percentage of swelling due to water was 9.37 +/- 8.7%, whereas that due to blood was -0.8 +/- 1.32%.The results of this study showed that brain edema is the major fluid component contributing to traumatic brain swelling. Moreover, CBV is reduced in proportion to CBF reduction following severe brain injury.

Management of cerebral perfusion pressure (CPP) is thought to be important for the treatment of traumatic brain injury (TBI). Vasopressors have been advocated as a method of increasing mean arterial blood pressure (mABP) and cerebral perfusion pressure (CPP) in the face of rising intracranial pressure (ICP). There are unresolved issues and theoretical risks about this therapy. This study therefore examined the effects of dopamine on physiological and MRI/MRS parameters in (1) a rodent model of rapidly rising intracranial pressure, caused by diffuse injury with secondary insult and (2) a model of cortical contusion. Dopamine was capable of restoring CPP in the model of rapidly rising ICP. This CPP restoration was associated with a partial restoration of CBF. Two profiles of change in the Apparent Diffusion Coefficient of water (ADCw) were seen; one in which ADCw recovered to baseline, and one in which ADCw remained persistently low. Dopamine did not alter these profiles. MRI assessed tissue water content was increased four hours after injury and dopamine increased cerebral water content in both subgroups of injury; significantly in the group with a persistently low ADCw (p0.01). In contusional injury, dopamine significantly worsened edema in both the ipsi- and contralateral hippocampus and temporal cortex. This occurred in the absence of ADCw changes, except in the contralateral hippocampus, where both water content and ADCw values rose with treatment, suggesting extracellular accumulation of water. In conclusion, although dopamine is capable of partially restoring CBF after injury, situations exist in which dopamine therapy worsens the swelling process. It is possible therefore that subgroups of patients exist who experience adverse effects of vasopressor treatment, and consequently the effects of vasopressor therapy in the clinical setting need to be more carefully evaluated.

Of all the possible clinical factors affecting the outcome of patients suffering acute subdural hematomas (SDH), timing of surgical evacuation is certainly the most debated. The purpose of this study was to develop an experimental model able to reproduce the clinical behavior of post-traumatic SDH as observed in head injured patients. We present a novel model of SDH combined with diffuse brain injury (DBI), and investigate the effects of early and delayed surgical evacuation.

Introduction Waveform analysis of ICP and mABP provideqs important information about cerebrovascular reactivity and intracranial compliance. Traditionally spectral analysis and correlation statistics have been used despite certain limitations. Approximate entropy (ApEn) is an established measure of system regularity; which can change with pathology. This study defines a novel method for application of ApEn to the ICP/mABP waveform, and reports changing ApEn with pathophysiology in the rodent brain.

Neurochemical damage following brain injury can be assessed non-invasively by measurement of N-Acetyl-Aspartate (NAA) using Proton Magnetic Resonance Spectroscopy (*HMRS). This report documents results of applying Chemical Shift Imaging (CSI) postprocessing for measuring NAA in traumatically injured brain.

Head Trauma associated with acute sudural hematoma (SDH) and complicated by secondary insult is a grave clinical combination with complex pathophysiology. The aim of this study was to develop a clinically relevant injury model, which can be used to study the interaction between injury mechanisms. We present a novel model of SDH combined with diffuse brain injury (DBI) and a hypoxic secondary insult, and investigate the effects of surgical evacuation. Adult Sprague-Dawley rats were given a 300 microliters SDH and 20 minute-hypoxia following Impact Acceleration DBI. Hematoma was evacuated at one hour post-injury. Physiological parameters were measured for 5 hours, together with assessment of brain water content. Secondary insult after traumatic SDH was associated with significant brain swelling and stimulated refractory rise in ICP. In traumatic SDH complicated by secondary insult, brain swelling is exacerbated by surgical evacuation.

The risk of vasopressors worsening cerebral edema has been raised. Previously we have reported that dopamine was able to restore cerebral blood flow in a model of monotonically rising intracranial pressure. In this study the effects of dopamine on cortical contusion and diffuse injury with secondary insult are examined. Adult male rats were divided into two groups: group 1 (n = 32) - Impact Acceleration Injury (IAM) with 30 minutes hypoxia and hypotension; group 2 (n = 12) - controlled cortical impact (6.0 m/ sec, 3 mm depth). Dopamine was administered 2 hours post-injury (10–60 µg/kg/min iv). Cerebral water content and apparent diffusion coefficients (ADC) values were measured at baseline and four hours post-injury using MRI. Preinjury water content was the same in each group. Group 1 was subdivided into Groups 1A & 1B based on the ADC profile. Post-injury water content in Group 1A did not differ between saline or dopamine treated animals. Water content was higher in Group 1B-dopamine (83.4 ± 1.1%) than Group IB-saline animals (81.4 ± 1.3%, p = 0.006). Contusion caused significant edema formation, however there was no significant difference between the dopamine treated or untreated group when considering either ipsilateral or contralateral cortex. Dopamine however significantly worsened edema in ipsilateral and contralateral hippocampus and both temporal cortices. ADC remained unchanged except in the contralateral hippocampus where both water content and ADC rose with dopamine suggesting precipitation of a vasogenic edema. In this study dopamine clearly worsened edema formation in two models of traumatic brain injury, and we conclude that there may be analogous clinical situations; therefore pressors should not be considered a ‘blanket’ therapy for all patients with a low cerebral perfusion pressure.

Having determined that edema and not vascular engorgement is the major factor leading to traumatic brain swelling, the objective of this study was to determine which type of edema, cellular or vasogenic, is responsible for increased tissue water in patients with focal lesions. Severely head injured patients (GCS 8 or less) were transported to imaging suites for measurement of brain water and apparent diffusion coefficient (ADC) using magnetic resonance technique. Cerebral blood flow by stable Xenon method was also measured in the regions of interest. Brain water was increased significantly in the hemisphere with lesion. The increase in water was associated with reduced ADC signifying a predominant cellular edema. The ADC in the contralateral hemisphere was near normal value. Cerebral blood flow values in the regions of interest were above ischemic levels suggesting that factors other than ischemia are responsible for the cytotoxic swelling in patients with focal injury.

This work investigates the accuracy of an in vivo estimation of absolute N-acetyl aspartate (NAA) concentrations by magnetic resonance spectroscopy (MRS) using cerebral water as an internal reference standard. Single-voxel, proton spectroscopy was carried out in two groups of rats (normal and diffuse head injury), using a PRESS sequence with TR = 3 s, TE = 135 ms. Fully relaxed water spectra and water-suppressed proton spectra were obtained from a 7 x 5 x 5 mm3 volume of tissue. MRI-based brain water content measurements were also performed. Following MRS, HPLC determinations of NAA were carried out. In the normal rats the MRS yielded 10.98 ± 0.83 mmol/kg w.w. vs 10.76 ± 0.76 for HPLC with a mean absolute difference of 0.8. In the injured rats the corresponding results were 9.41 ± 1.78 (MRS) and 8.16 ± 0.77 (HPLC) with a mean absolute difference of 1.66. The in vivo absolute method accurately documented the temporal NAA changes compared to the NAA/Cr approach.

It is traditionally believed that edema associated with brain contusion is vasogenic. The objective of this study was to quantify and characterize the edema in cortical contusion coupled with early hypoxia and hypotension.

The contribution of blood brain barrier opening to traumatic brain edema is not known. This study compares the course of traumatic BBB disruption and edema formation, with the hypothesis that they are not obligately related. Sprague-Dawley rats were divided into three groups: Group A (n = 47) - Impact Acceleration (IAM); Group B (n = 104) - lateral cortical impact (CCI); Group C (n = 26) - IAM + hypoxia & hypotension (THH). BBB integrity was assessed using iv markers (Evan’s Blue, or gadolinium-DTPA). Edema formation was evaluated with gravimetry, and T1-weighted MRI.

An ion-pairing high-performance liquid chromatographic method for the determination of N -acetylaspartate and N -acetylglutamate using a C-18 column and a UV detection at 210 nm wavelength, by means of a diode array detector, is presented. A buffer containing 2.8 mM tetrabutylammonium hydroxide, 25 mM KH 2 PO 4 , 1.25% methanol, pH 7.00, is utilized for the isocratic separation of these N-acetylated amino acids, at a flow rate of 1 ml/min and a column temperature of 23°C. The suitability of this chromatographic separation (without additional chromatographic steps prior to HPLC assay) to monitor variations both of N -acetylaspartate and of N -acetylglutamate in perchloric acid brain extracts from rats subjected to the impact acceleration model of diffuse brain injury is also reported. According to the data presented, this HPLC method allows the separation of the two N-acetylated amino acids considered from the many possible interfering compounds, commonly present in extracts of cerebral tissue, which have high extinction coefficients at 210 nm wavelength. Values of N -acetylaspartate and N -acetylglutamate determined by this method showed that cerebral trauma negatively affects both compounds, according to the severity of trauma itself.

It is well-documented that acute subdural hematoma (ASDH) following diffuse traumatic brain injury (dTBI) contributes to severe disability and high mortality. The objective of this study was to characterize edema formation in a model of ASDH and ASDH following dTBI.

It is well established in mechanical head trauma that posttraumatic secondary insults, such as hypoxia and hypotension exacerbate neuronal injury and lead to worse outcome. In this study, the neuroprotective effect of hypothermia on the reduction of supraventricular subcortical neuronal damage was evaluated using an impact-acceleration model of diffuse traumatic brain injury coupled with both moderate and severe periods of hypoxia and hypotension. A total of 135 adult male Sprague-Dawley rats (340-375 g) were divided into three experimental studies: (I) physiological evaluation (n = 36); (II) quantitative analysis of the effect of trauma coupled with moderate and severe hypotension on neuronal damage assessed at 4 (n = 39) and 24 h (n = 24); and (III) the neuroprotective effect of hypothermia following moderate secondary insult (n = 36). Induction of hypothermia occurred at 15 min postinjury, to a level of 30 degrees C for 60 min. At the designated time points (4 and 24 h), the animals were sacrificed via standard transcardial perfusion techniques for histological processing. Quantitative assessment of neuronal damage using routine HE staining at 4 hours showed neuronal damage which correlated with the severity of secondary insult. Animals exposed to trauma alone had a mean number of damaged neurons of 7.61 +/- 3.08/high powered field (hpf) compared with a mean of 1.21 +/- 0.30/hpf in the sham operated group (p = 0.015). Animals exposed to trauma with 10 min of hypoxia and hypotension (THH-10) showed a statistically significant number of damaged neurons compared to the sham-operated animals (7.50 +/- 2.15 damaged neurons/hpf, p = 0.013), whereas, neuronal damage in animals undergoing trauma with a 30-min secondary insult of hypoxia and hypotension (THH-30) was markedly increased (100 +/- 30.20/hpf, p = 0.002). Statistical analysis showed no significant difference in neuronal damage in animals subjected to secondary insult alone. At 24 h, the evolution of neuronal damage in the trauma alone group (5.08 +/- 1.63/hpf) was relatively static; however, there was a remarkable increase in the neuronal damage of the THH-10 group (29.88 50 +/- 8.20/hpf). However, hypothermia provided nearly complete protection against secondary insults, and neuronal damage was equal to that of the trauma alone group (p = 0.42). The results of this study confirm that hypothermia provides remarkable protection against the adverse effects of neuronal damage exacerbated by secondary injury. This study also presents a new model of secondary insult, which can be used experimentally to further define the mechanism of increased vulnerability of the injured brain.

Elevated intra-abdominal pressure (IAP) increases intracranial pressure (ICP) and reduces cerebral perfusion pressure (CPP). We evaluated a nonsurgical means of reducing IAP to reverse this process.Swine with a baseline ICP of 25 mm Hg produced by an intracranial balloon catheter were studied. In group 1 (n = 5), IAP was increased by 25 mm Hg. Continuous negative abdominal pressure (CNAP) was then applied. Group 2 (n = 4) had neither IAP elevation nor CNAP. Group 3 (n = 4) had CNAP without IAP elevation.Elevation of IAP by 25 mm Hg above baseline led to deleterious changes in ICP (25.8+/-0.8 to 39.0+/-2.8; p0.05) and CPP (85.2+/-2.0 to 64.8+/-2.6; p0.05). CNAP led to a reduction in IAP (30.2+/-1.2 to 20.4+/-1.3; p0.05) and improvements in cerebral perfusion (ICP, 33+/-2.7; CPP, 74.4+/-1.2; both p0.05). Group 2 had stable ICP (25.8+/-0.25 to 28.7+/-1.7; p0.05) and CPP (80.8+/-1.4 to 80.5+/-1.8; p0.05). In group 3, CNAP decreased cardiac index (2.9+/-0.2 to 1.1+/-0.4; p0.05), mean arterial pressure (105.2+/-4.0 to 38.2+/-12.0; p0.05), and CPP (74.2+/-4.7 to 14.5+/-12.2; p0.05).Elevations in IAP led to increased ICP and decreased CPP. CNAP ameliorated these intracranial disturbances. With normal IAP, CNAP impaired cerebral perfusion.

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.

Status epilepticus (SE) is a common neurological and medical emergency. Despite the significant mortality associated with SE, no human data have been available regarding cardiovascular changes prior to death in patients with this condition. This study was conducted to measure hemodynamic trends in the 24 h prior to death in a series of 24 prospectively evaluated SE patients. Two distinct cardiovascular patterns of mean arterial pressure (MAP) and heart rate (HR) were observed. Ten patients had a gradual decline in MAP and/or HR, and this group was designated as having gradual cardiac decompensation (GCD). The remaining 14 patients showed no significant changes in either MAP or HR up to the time of death. This group of patients was designated as having acute cardiac decompensation (ACD). The changes in MAP and HR over the last 24 h prior to death between the GCD and ACD groups were statistically significant. Ninety percent of the GCD patients had a history of multiple risk factors for arteriosclerotic cardiovascular disease (ASCVD), while only 30% of the ACD group had a history of multiple risk factors for ASCVD. The results provide the first human data of cardiovascular events immediately preceding death in SE patients. We propose that further investigation of the cardiovascular pathophysiology of SE may provide new therapeutic interventions which could decrease the significant mortality associated with SE.

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.

We hypothesized, that with atrophy, the correlation between water content and specific gravity of brain solids would break down signifying the onset of the atrophic process. The correlation between tissue water content, specific gravity of solids and ventricular size was studied in an impact acceleration model of closed head injury of the rat. Adult Sprague Dawley rats weighing 350 to 375 grams (n = 63) were separated into two groups: Group I: Sham (n = 21), Group II: Trauma (n = 42). Water content was assessed using both gravimetric method and drying-weighing method at 1 hour, on days 1, 3, 7, 14, 28, and 42 in the trauma group as well as in the control group. Ventricular size was measured in cm2 on the MRI computer console in the coronal section at the coronal suture at the same time points. In the trauma group we found a significant increase (p < 0.01) in water content during the first week except on day 3 and there was a good correlation between the results of water content using both methods (p < 0.001). However, this relationship was poorly correlated after day 14 (p = 0.25). Although the ventricular size was the smallest at 1 hour post trauma, it significantly increased over the next 3 days (p < 0.001). On day 7 and 14 ventricular size decreased to normal size, yet gradually increased and then reached a significantly larger size on 42 days post trauma again (p < 0.01). We may consider, that brain edema following CHI begins immediately following trauma and resolves within 2 weeks. After 14 days degenerative change occurs in the cortex, as detected by specific gravity measurements which signifies the onset of the atrophic process and subsequent post traumatic ventricular dilatation.

The objective of this study was to quantify the temporal water content changes and document the type of edema (cellular versus vasogenic) that is occurring during both the acute and the late stages of edema development following closed head injury.

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 objective of this study was to determine the early time course of blood-brain barrier (BBB) changes in diffuse closed head injury (CHI) and to what extent BBB is affected by secondary insult.

The objective of this study was to detect the threshold between reversible and irreversible secondary insult of hypoxia and hypotension following closed head injury as measured by MRI.

Accumulation of potassium and excitatory amino acids (EAA) in the extracellular space (ECS) following ischemia has been well documented. Careful monitoring of these transients is crucial to gain a better understanding of CNS pathophysiology. This study was initiated to determine if CSF concentrations of EAAs reflect those measured in the ECS. Transient global ischemia, 20 minutes in duration, was produced by clamping the left subclavian and innominate arteries combined with hemorrhagic hypotension. The accumulation of glutamate and electrolytes were measured in CSF and the extracellular fluid (ECF) of cerebral cortex. Microdialysis (MD) was utilized to measure the extracellular concentrations while direct sampling of CSF was provided via cannulation of the cisterna magna. Hydrogen clearance and laser doppler methods were used to monitor regional cortical CBF.

✓ The authors posit that cellular edema is the major contributor to brain swelling in diffuse head injury and that the contribution of vasogenic edema may be overemphasized. The objective of this study was to determine the early time course of blood-brain barrier (BBB) changes in diffuse closed head injury and to what extent barrier permeability is affected by the secondary insults of hypoxia and hypotension. The BBB disruption was quantified and visualized using T1-weighted magnetic resonance (MR) imaging following intravenous administration of the MR contrast agent gadolinium—diethylenetriamine pentaacetic acid. To avoid the effect of blood volume changes, the maximum signal intensity (SI) enhancement was used to calculate the difference in BBB disruption. A new impact-acceleration model was used to induce closed head injury. Forty-five adult Sprague—Dawley rats were separated into four groups: Group I, sham operated (four animals), Group II, hypoxia and hypotension (four animals), Group III, trauma only (23 animals), and Group IV, trauma coupled with hypoxia and hypotension (14 animals). After trauma was induced, a 30-minute insult of hypoxia (PaO2 40 mm Hg) and hypotension (mean arterial blood pressure 30 mm Hg) was imposed, after which the animals were resuscitated. In the trauma-induced animals, the SI increased dramatically immediately after impact. By 15 minutes permeability decreased exponentially and by 30 minutes it was equal to that of control animals. When trauma was coupled with secondary insult, the SI enhancement was lower after the trauma, consistent with reduced blood pressure and blood flow. However, the SI increased dramatically on reperfusion and was equal to that of control by 60 minutes after the combined insult. In conclusion, the authors suggest that closed head injury is associated with a rapid and transient BBB opening that begins at the time of the trauma and lasts no more than 30 minutes. It has also been shown that addition of posttraumatic secondary insult—hypoxia and hypotension—prolongs the time of BBB breakdown after closed head injury. The authors further conclude that MR imaging is an excellent technique to follow (time resolution 1–1.5 minutes) the evolution of trauma-induced BBB damage noninvasively from as early as a few minutes up to hours or even longer after the trauma occurs.

✓ 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.

Objective : To study the effects of elevated intra-abdominal pressure (IAP) upon intracranial (ICP) and cerebral perfusion pressure (CPP) before and after intravascular volume resuscitation. Materials and Methods : Intra-abdominal pressure was increased in five anesthetized swine by inflating an intraperitoneal balloon until the IAP was 25 mm Hg above baseline. Intravascular volume was then expanded and finally abdominal decompression was performed. Changes in ICP and systemic and pulmonary hemodynamic parameters secondary to increasing IAP were measured. The effect upon CPP was derived from these measurements. Pao 2 and Paco 2 were maintained relatively constant by increasing ventilatory rate. Measurements and Main Results : Elevated IAP significantly increased ICP (7.6 ± 1.2 vs. 21.4 ± 1.0), pleural pressure and central venous pressure ; whereas cardiac index and CPP (82.2 ± 6.3 vs. 62.0 ± 10.0) decreased significantly. Intravascular volume expansion further significantly increased ICP (27.8 ± 1.0), and significantly increased both mean arterial pressure (83.4 ± 14.0 versus 103.4 ± 8.9) and CPP (75.6 ± 9.0). Abdominal decompression returned ICP (11.2 ± 1.8) toward baseline and further increased CPP (79.8 ± 9.7). Conclusions : Elevated IAP increases ICP and decreases CPP and cardiac index. Volume expansion further increases ICP yet improves CPP via its greater positive effect upon mean arterial pressure (*p < 0.05, analysis of variance. All measurements are mean ± SEM in mm Hg).

✓ The objective of this study was to use diffusion-weighted magnetic resonance imaging (DWI) to help detect the type of edema that develops after experimental trauma and trauma coupled with hypotension and hypoxia (THH). Reduction in the apparent diffusion coefficients (ADCs) is thought to represent cytotoxic edema. In a preliminary series of experiments, the infusion edema model and middle cerebral artery occlusion models were used to confirm the direction of ADC change in response to purely extracellular and cytotoxic edema, respectively. The ADCs increased (p < 0.05) in the case of extracellular edema and decreased (p < 0.001) in cytotoxic edema.Following these initial experiments, a new impact acceleration model was used to induce traumatic brain injury. Thirty-six adult Sprague-Dawley rats were separated into four groups: sham, trauma alone, hypoxia and hypotension (HH), and THH. Following trauma, a 30-minute insult of hypoxia (PaO2of 40 mm Hg) and hypotension (mean arterial blood pressure (MABP) of 30 mm Hg) were imposed and the animals were resuscitated. The DWI was carried out at four 1-hour intervals postinjury, and MABP, intracranial pressure (ICP), cerebral perfusion pressure (CPP), and cerebral blood flow (CBF) were monitored. The ADCs in the control and HH groups remained unchanged. The ADCs in the THH group rapidly decreased from a control level of 0.68 ± 0.05 × 10−3mm2/second to 0.37 ± 0.09 3 10−3mm2/second by 3 hours posttrauma (p < 0.001). In this group, the decreased CBF and CPP during secondary insult remained low despite resuscitation, with the ICP increasing to 56 6 7 mm Hg by 3 hours. In the trauma alone group, the rise in ICP reached a maximum value (28 ± 3 mm Hg) at 30 minutes with a significant and sustained increase in CBF despite a gradual decrease in CPP. The ADCs in this group were not significantly reduced. The data lead the authors to suggest that the rise in ICP following severe trauma coupled with secondary insult in this model is predominately caused by cytotoxic edema and that ischemia plays a major role in the development of brain edema after head injury.

This article provides a brief description of the American Brain Injury Consortium (ABIC), a group of clinical scientists focused on the design and implementation of clinical trials in the United States to improve outcome of the brain injured patient. The structure of the consortium, guidelines for participation, relationship with pharmaceutical industry, and the instruments used for acquisition and analysis of data gathered are described.