Xenon-enhanced cerebral blood flow at 28% xenon provides uniquely safe access to quantitative, clinically useful cerebral blood flow information: a multicenter study.

BACKGROUND AND PURPOSE: Xe-CT measures CBF and can be used to make clinical treatment decisions. Availability has been limited, in part due to safety concerns. Due to improvements in CT technology, the concentration of inhaled xenon gas has been decreased from 32% to 28%. To our knowledge, no data exist regarding the safety profile of this concentration. We sought to better determine the safety profile of this lower concentration through a multicenter evaluation of adverse events reported by all centers currently performing xenon/CT studies in the US. MATERIALS AND METHODS: Patients were prospectively recruited at 7 centers to obtain safety and efficacy information. All studies were performed to answer a clinical question. All centers used the same xenon delivery system. CT imaging was used during a 4.3-minute inhalation of 28% xenon gas. Vital signs were monitored on all patients throughout each procedure. Occurrence and severity of adverse events were recorded by the principal investigator at each site. RESULTS: At 7 centers, 2003 studies were performed, 1486 (74.2%) in nonventilated patients. The most common indications were occlusive vascular disease and ischemic stroke; 93% of studies were considered clinically useful. Thirty-nine studies (1.9%) caused respiratory suppression of >20 seconds, all of which resolved spontaneously. Shorter respiratory pauses occurred in 119 (5.9%), and hyperventilation, in 34 (1.7%). There were 53 additional adverse events (2.9%), 7 of which were classified as severe. No adverse event resulted in any persistent neurologic change or other sequelae. CONCLUSIONS: Xe-CT CBF can be performed safely, with a very low risk of adverse events and, to date, no risk of permanent morbidity or sequelae. On the basis of the importance of the clinical information gained, Xe-CT should be made widely available.

Phenomenology of prolonged febrile seizures: results of the FEBSTAT study.

BACKGROUND: Febrile status epilepticus (FSE) has been associated with hippocampal injury and subsequent mesial temporal sclerosis and temporal lobe epilepsy. However, little is known about the semiology of FSE. METHODS: A prospective, multicenter study of the consequences of FSE included children, aged 1 month through 5 years, presenting with a febrile seizure lasting 30 minutes or more. Procedures included neurologic history and examination and an MRI and EEG within 72 hours. All information related to seizure semiology was reviewed by three epileptologists blinded to MRI and EEG results and to subsequent outcome. Inter-rater reliability was assessed by the kappa statistic. RESULTS: Among 119 children, the median age was 1.3 years, the mean peak temperature was 103.2 degrees F, and seizures lasted a median of 68.0 minutes. Seizure duration followed a Weibull distribution with a shape parameter of 1.68. Seizures were continuous in 52% and behaviorally intermittent (without recovery in between) in 48%; most were partial (67%) and almost all (99%) were convulsive. In one third of cases, FSE was unrecognized in the emergency department. Of the 119 children, 86% had normal development, 24% had prior febrile seizures, and family history of febrile seizures in a first-degree relative was present in 25%. CONCLUSIONS: Febrile status epilepticus is usually focal and often not well recognized. It occurs in very young children and is usually the first febrile seizure. Seizures are typically very prolonged and the distribution of seizure durations suggests that the longer a seizure continues, the less likely it is to spontaneously stop.

Traumatic brain edema in diffuse and focal injury: cellular or vasogenic?

The objective of this study was to confirm the nature of the edema, cellular or vasogenic, in traumatic brain injury in head-injured patients using magnetic resonance imaging techniques. Diffusion-weighted imaging methods were quantified by calculating the apparent diffusion coefficients (ADC). Brain water and cerebral blood flow (CBF) were also measured using magnetic resonance and stable Xenon CT techniques. After obtaining informed consent, 45 severely injured patients rated 8 or less on Glasgow Coma Scale (32 diffuse injury, 13 focal injury) and 8 normal volunteers were entered into the study. We observed that in regions of edema, the ADC was reduced, signifying a predominantly cellular edema. The ADC values in diffuse injured patients without swelling were close to normal and averaged 0.89 +/- 0.08. This was not surprising, as ICP values for these patients were low. In contrast, in patients with significant brain swelling ADC values were reduced and averaged 0.74 +/- 0.05 (p < 0.0001), consistent with a predominantly cellular edema. We also found that the CBF in these regions was well above ischemic threshold at time of study. Taking these findings in concert, it is concluded that the predominant form of edema responsible for brain swelling and raised ICP is cellular in nature.

Bolus tracer delivery measured by MRI confirms edema without blood-brain barrier permeability in diffuse traumatic brain injury.

INTRODUCTION: Previous studies have shown that edema formation after diffuse traumatic brain injury (TBI) with secondary insult is cytotoxic and not vasogenic. This assumption is based on observations of reduced apparent diffusion coefficient (ADC) and lack of significant accumulation of intravascular tracer in brain tissue. However, ADC reduction does not exclude vasogenic edema, and intravascular tracer can only accumulate when it reaches the tissue and is not perfusion limited. This study aims to confirm tissue delivery of intravascular tracer and lack of BBB opening during a phase of rapid brain swelling after diffuse TBI. METHODS: Rats were exposed to either TBI using the impact acceleration model combined with 30 minutes of hypoxia and hypotension, or sham injury. At 2 or 4 hours after injury, ADC and tissue water content were assessed using MRI. Gd-DTPA was given followed by a combination of rapid T2 imaging (60 seconds) and T1 imaging (30 minutes). Signal intensity changes were analyzed to determine a bolus effect (dynamic susceptibility contrast) and longer-term tissue accumulation of Gd-DTPA. RESULTS: Mean increase in cortical water content on the left was 0.8% at 2 hours, 2.1% at 4 hours; on the right it was 0.5% at 2 hours and 1.7% at 4 hours (p < 0.05). Mean ADC reduction over 4 hours was 0.04 x 10(-3) mm2/s on the left and 0.06 x 10(-3) mm2/s on the right. Kinetic analysis of signal intensity changes after Gd-DTPA showed no significant difference in inward transfer coefficient (BBB permeability) between sham injury and 2 or 4 hours post-injury. T2 imaging showed consistent tissue delivery of a bolus of Gd-DTPA to the tissue at 2 and 4 hours post-injury, comparable to sham animals. CONCLUSIONS: Progressive cerebral edema formation after diffuse TBI occurred during ADC reduction and without continued BBB permeability. Tissue delivery of Gd-DTPA was confirmed, verifying that lack of tracer accumulation is due to an intact BBB and not to limited perfusion.

Effect of dimethyl sulfoxide on blood-brain barrier integrity following middle cerebral artery occlusion in the rat.

Dimethyl sulfoxide (DMSO) is widely used as a solvent for other drugs, i.e., for the protein kinase C activator phorbol 12-myristate 13-acetate (PMA) and the V1a receptor-antagonist SR49059, to reduce brain edema. We studied the effect of DMSO on blood-brain barrier (BBB) integrity following middle cerebral artery occlusion (MCAO) and the consequences on brain edema development. Male Sprague-Dawley rats were randomly assigned to sham procedure or infusion of 1% DMSO, PMA (230 microg/kg in 1% DMSO), or SR49059 (1 mg/kg in 1% DMSO) followed by MCAO (each group n = 10). After a 2-hour period of ischemia and 2 hours reperfusion, the animals were sacrificed for assessment of brain water content, sodium, and potassium concentration. BBB integrity was assessed by Evans blue extravasation. Statistical analysis was performed by ANOVA followed by a Tukey post hoc test. Low-dose DMSO treatment following MCAO significantly opened the BBB on the ischemic side (p < 0.037). PMA and SR49059 did not have any additional effect on BBB compromise compared to DMSO (p = 1.000, p < 0.957, respectively). We conclude that DMSO as a vehicle for drug administration may increase the drug concentration into the extracellular space, but since BBB permeability is increased, it may also provide an avenue for development of vasogenic edema.

Protective effect of the V1a receptor antagonist SR49059 on brain edema formation following middle cerebral artery occlusion in the rat.

There exists no pharmacological treatment for fulminating brain edema. Since evidence indicates that brain aquaporin-4 (AQP4) water channels are modulated by vasopressin V1a receptors, we examined the edema-reducing properties of the selective V1a receptor antagonist, SR49059, following middle cerebral artery occlusion (MCAO). Male Sprague-Dawley rats were randomly assigned to sham procedure, vehicle, or SR49059 infusion at different dosages (each n = 6,480 microL/hr, 640 microL/hr, 720 microL/hr) and starting 60 minutes before or after MCAO. 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 concentration. Statistics were performed using an ANOVA followed by a Tukey post hoc analysis. SR049059 treatment reduced brain water content in the infarcted area given at 640 microL/hr (p = 0.036), 720 microL/hr 60 minutes before (p = 0.002) or 60 minutes after (p = 0.005) MCAO. The consecutive sodium shift into the brain was prevented (p = 0.001), while the potassium loss was inhibited only by pre-treatment (p = 0.003). These findings imply that in ischemia-induced brain edema, the selective V1a receptor-antagonist SR49059 inhibits brain edema and the subsequent sodium shift into brain. This substance offers a new avenue in brain edema treatment and prompts further study into AQP4 modulation.

Brain tissue water content in patients with idiopathic normal pressure hydrocephalus.

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. Ten patients who were diagnosed and treated for idiopathic NPH in our clinic were selected for study. Magnetic resonance imaging (MRI) techniques were used to obtain anatomical image slices for quantitative brain water measurements. Apparent diffusion coefficient measures were also extracted from regions of interest. To our knowledge, this is the first study to confirm that periventricular lucency seen on MRI represents increased water content in the extracellular space that is markedly elevated prior to shunting.

Modulation of AQP4 expression by the protein kinase C activator, phorbol myristate acetate, decreases ischemia-induced brain edema.

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 (p < 0.001, p = 0.022) and prevented the subsequent sodium shift (p < 0.05). Furthermore, PMA reduced ischemia-induced AQP4 up-regulation (p < 0.05). 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.

The importance of translational research in brain injury.

Progress in the understanding of the pathophysiologic process and management of brain injury provides a unique challenge to the young investigator. Currently, there are teams both in the laboratory and clinical settings which may or may not interact as a result of the depth and breadth of the problems before them. For example, laboratory teams may be focused on cellular or molecular mechanisms of injury while the clinical investigator is attempting to deal with refractory ICP and it's treatment. It is clear that many aspects of biological research must indeed be approached using molecular techniques of neuroscience and much has been learned. However, the translational aspect of this effort may be elusive as it is unclear at present how these molecular techniques translate into the intensive care unit and the patient. For many, the research paths taken in the laboratory and ICU will always remain independent. For those who desire a more direct pathway to treatment, the "bench to bedside" approach is one which is more likely to yield results. Several examples will be given to strengthen the notion that we must not abandon the translational aspect of research but to embrace the process if we are to further improve outcome from brain injury.

Mitochondrial injury measured by proton magnetic resonance spectroscopy in severe head trauma patients.

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.

Three-year outcome of shunted idiopathic NPH patients.

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%). With proper diagnosis and management of iNPH, shunting of patients is associated with a favorable risk/benefit ratio that is reasonably long lasting.

Guidelines for management of idiopathic normal pressure hydrocephalus: progress to date.

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.

Contribution of raised ICP and hypotension to CPP reduction in severe brain injury: correlation to outcome.

The aim of this study was to determine to what degree hypotension and ICP contribute to the reduction of cerebral perfusion pressure (CPP), particularly in light of the shift in emphasis to CPP management by the use of pressors. The study population consisted of severely head injured patients extracted retrospectively from the Traumatic Coma Data Bank and compared with 139 patients from the Smith Kline component of the American Brain Injury Consortium database where outcome was available. The percentage time that ICP exceeded 20 mm Hg and CPP less than 60 mm Hg was computed for 5 days post injury. At each hour when CPP was less than 60 mm Hg the contribution of raised ICP and low arterial pressure or both was determined. In the first cohort, hypotension was the predominant factor leading to CPP reduction. With use of the CPP concept of treatment, the major contribution to CPP shifted to ICP and arterial hypotension played less of a role. Overall, CPP management has been associated with improved outcome.

Mortality from traumatic brain injury.

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. During the period 1984 through 1996, mortality from severe brain injury steadily declined. Factors other than age, motor score and pupil reactivity over time are responsible for this reduction. This reduction over time is an important factor for prognostic modeling of TBI.

Clinical trials in traumatic brain injury: current problems and future solutions.

Over the past decade many neuroprotective agents have been developed with the hope of being able to improve outcome in patients with traumatic brain injury. Unfortunately, none of the phase III trials performed have convincingly demonstrated efficacy in the overall population. A common misconception is that consequently these agents are ineffective. Such has not been proven and some trials show evidence of efficacy in subgroups of the population studied. The negative results, as reported in the overall population, may in part be caused by specific aspects of the TBI population, as well as by aspects of clinical trial design and analysis. Clinical trials in TBI pose several complicated design issues. Methodological challenges relate particularly to heterogeneity of the population and to outcome assessment. Heterogeneity pertains both to the range of pathologies included in TBI, and to prognostic factors, each causing specific problems. Mechanistic and/or prognostic targeting, as well as possibilities for covariate adjustment, are suggested as possible solutions to deal with the problems of heterogeneity. The aim in most trials was to demonstrate a 10% absolute improvement in favorable outcome in patients with head injury. This may be considered overoptimistic and unrealistic in relation to the heterogeneous patient population. Specific problems are further incurred by the use of the dichotomized Glasgow Outcome Scale as primary outcome measure. Optimal statistical power may expected to be present when the point of dichotomization results in a 50:50 distribution of outcome categories. It is proposed to differentiate the point of dichotomization according to prognostic risk profile, in order to maintain statistical power. Solutions described may be expected to enhance chances of demonstrating benefit of potentially effective neuroprotective agents in future studies. The complexity of problems occurring in clinical trial design and analysis in TBI is such that a strong and sustained multidisciplinary input and effort is required from all experts involved in the field of neurotrauma.

Modulation of aquaporin-4 water transport in a model of TBI.

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. Anaesthetized Sprague-Dawley rats were subjected to an intracerebroventricular bolus of phorbol ester (50 pmol/4 microl) or vehicle, in the right hemisphere and after 30 minutes they were exposed to the well-established conical contusion model (3 mm depth at 6 m/sec) on the same side. After trauma, they were subjected to 5 hours of drug continuous infusion, then sacrificed. Water content measurements for both right (injured) and left (uninjured) hemispheres were calculated using the wet weight/dry weight technique. Results of these experiments showed a significant decrease in water content in injured phorbol treated animals, underlying that AQP4 regulation plays an important role in brain edema following stroke, and supporting the concept of cellular formation for edema via astrocytic foot processes.

The effect of cyclosporin A on brain edema formation following experimental cortical contusion.

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. This project includes two independent series in which different doses of CsA were intravenously given to Sprague-Dawley rats of each group. In the first series, the animals were exposed to focal brain injury by a controlled cortical impact (CCI, 6 m/sec, 3 mm depth) and randomized into the following two groups: 20 mg/kg CsA and control vehicle. In the second series, animals were also injured by CCI and randomized into 35 mg/kg CsA and control vehicle. The intravenous continuous (1 h) infusion was begun 30 minutes after the insult. All animals were sacrificed at 24 hours post injury to assess the brain water content using the gravimetric method. Intravenously-administrated CsA of either 20 or 35 mg/kg did not significantly change the brain water content. We therefore suggest that an intravascular route may be better for CsA administration because the intrathecal injection may exacerbate brain edema as found in our previous study.

Pathophysiology of traumatic brain edema: current concepts.

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.

Approximate entropy: a regularity statistic for assessment of intracranial pressure.

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. METHODS: Nine Sprague-Dawley rats were anesthetized for mABP, and ICP recording. Rats were exposed to 15 minutes hypotension (45-50 mmHg), followed by resuscitation, equilibration and infusion of a 500 ul subdural hematoma. Raw data, ApEn(RAW), and wave-period, ApEn(PERIOD), were assessed for stochastic fluctuations using ApEn (m = 2, r = 0.2 SD). Results were compared with the established parameters: standard deviation, harmonic transfer function, Pressure Reactivity Index and Correlation Coefficient. RESULTS: At baseline, ApEn(ABP-PERIOD) and ApEn(ICP-PERIOD) were 1.464 +/- 0.003, and 0.690 +/- 0.020 respectively, suggesting that random heart rate fluctuations are damped during transfer to the ICP waveform. ApEn(ICP-PERIOD) consistently rose during hypotension (ICP 7 +/- 2: ApEn(ICP-PERIOD) 1.086 +/- 0.074, p < 0.05) and after SDH infusion (ICP 35 +/- 12: ApEn(ICP-PERIOD) 1.24 +/- 0.03, p < 0.01). These values were closer to mABP and suggest enhanced transfer of random fluctuations. Significant changes in ApEn were seen in the absence of significant changes in other parameters. CONCLUSIONS: This study defines a system for analyzing the transfer of random fluctuations in mABP waveform to the ICP waveform. ApEn appears to be responsive to changes in intracranial compliance and/or cerebrovascular resistance, therefore more formal studies of the sensitivity and specificity of this novel measure are warranted. These initial findings suggest that ApEn may be a useful adjunct measure of the ICP waveform.

Secondary insults worsen blood brain barrier dysfunction assessed by MRI in cerebral contusion.

OBJECT: Understanding the cause of post-traumatic intracranial hypertension requires information about the pathophysiology of edema formation. Secondary insults are known to exacerbate edema formation following experimental contusion, however the influence of these insults on blood brain barrier (BBB) integrity is not known. This study non-invasively assesses the influence of hypoxia and hypotension on BBB permeability following experimental cortical contusion. METHODS: Sprague-Dawley rats (350-380 g) were divided into three groups. Group A: (n = 3) Sham, Group B (n = 8) focal injury (controlled cortical impact 6.0 m/sec, 3 mm depth), Group C (n = 8), focal injury with secondary insult. Cortical BBB integrity was assessed four hours post-trauma using an i.v. bolus of 0.2 mmol/kg Gd-DTPA with serial T1 MR images, over 30 minutes. Absolute tissue concentrations of Gd were measured empirically using known references. The time course of accumulation was analyzed with respect to BBB permeability. RESULTS: BBB permeability was greatest in the site of contusion, and Gd accumulation was greatly enhanced by secondary insult (p < 0.01). Regions of lowest ADC and maximal swelling correlated with regions of maximal BBB permeability (p < 0.05). CONCLUSIONS: Secondary insults enhance BBB dysfunction in contusion. Positive relationships between low ADC, tissue swelling and BBB dysfunction suggest synergy between underlying cytotoxic swelling and BBB permeability in contusion. These data also suggest that restoration of BBB integrity after injury may be an energy dependent process. These findings have important implications for the pathophysiology of ICP elevations following cerebral contusion.