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An acute subdural hematoma (SDH) requiring surgical intervention is treated with craniotomy or craniectomy, in part because it is generally accepted that coagulated blood present in the acute phase cannot be adequately evacuated by less-invasive means such as bur hole drainage. However, a hyperacute SDH in the first few hours after trauma can have mixed-density components on CT scans that are thought to represent subdural blood that is not yet fully coagulated. The authors report a case in which a hyperacute SDH in a patient receiving antiplatelet therapy was treated with the novel technique of temporizing subdural evacuation port system (SEPS) placement. Placement of an SEPS in the intensive care unit allowed for rapid surgical treatment of the patient's elevated intracranial pressure (ICP) by drainage of 70 ml of fresh subdural blood. After initial SEPS-induced stabilization, the patient underwent operative treatment of the SDH by craniotomy. The combined approach of emergency SEPS placement followed by craniotomy resulted in a dramatic recovery, with improvement from coma and extensor posturing to a normal status on neurological evaluation 5 weeks later. In appropriately selected cases, patients with a hyperacute SDH may benefit from SEPS placement to quickly treat elevated ICP, as a bridge to definitive surgical treatment by craniotomy.

Although decompressive hemicraniectomy with dural expansion and bone flap removal is a potentially life-saving procedure, concerns remain regarding the morbidity associated with this approach. We and others have noted the high rate of wound complications resulting from this technique, often associated with cerebrospinal fluid (CSF) absorption problems. Here, we present our experience with an improved technique for wound closure after unilateral decompressive hemicraniectomy with a wide cruciate durotomy. Data for all patients who underwent a decompressive hemicraniectomy at our institution from October 2005 to October 2009 were gathered prospectively. Starting in mid 2008, we adopted an alternate approach to operative wound closure, which involved skin closure with a running Monocryl absorbable stitch, and prolonged subgaleal drainage. We compared the rates of wound complication using this approach with those obtained with earlier conventional closure techniques. Over a 1year period, we dramatically reduced the rate of wound complications in patients undergoing hemicraniectomy at our hospital using this new (Monocryl technique, 0% (n=29) compared to other techniques, 35% (n=98), chi-squared [χ(2)] p

Traumatic brain injury caused by explosive or blast events is traditionally divided into four phases: primary, secondary, tertiary, and quaternary blast injury. These phases of blast-induced traumatic brain injury (bTBI) are biomechanically distinct and can be modeled in both in vivo and in vitro systems. The primary bTBI injury phase represents the response of brain tissue to the initial blast wave. Among the four phases of bTBI, there is a remarkable paucity of information about the cause of primary bTBI. On the other hand, 30 years of research on the medical application of shockwaves (SW) has given us insight into the mechanisms of tissue and cellular damage in bTBI, including both air-mediated and underwater SW sources. From a basic physics perspective, the typical blast wave consists of a lead SW followed by supersonic flow. The resultant tissue injury includes several features observed in bTBI, such as hemorrhage, edema, pseudoaneurysm formation, vasoconstriction, and induction of apoptosis. These are well-described pathological findings within the SW literature. Acoustic impedance mismatch, penetration of tissue by shock/bubble interaction, geometry of the skull, shear stress, tensile stress, and subsequent cavitation formation, are all important factors in determining the extent of SW-induced tissue and cellular injury. Herein we describe the requirements for the adequate experimental set-up when investigating blast-induced tissue and cellular injury; review SW physics, research, and the importance of engineering validation (visualization/pressure measurement/numerical simulation); and, based upon our findings of SW-induced injury, discuss the potential underlying mechanisms of primary bTBI.

Human electrophysiological research is generally restricted to scalp EEG, magneto-encephalography, and intracranial electrophysiology. Here we examine a unique patient cohort that has undergone decompressive hemicraniectomy, a surgical procedure wherein a portion of the calvaria is removed for several months during which time the scalp overlies the brain without intervening bone. We quantify the differences in signals between electrodes over areas with no underlying skull and scalp EEG electrodes over the intact skull in the same subjects. Signals over the hemicraniectomy have enhanced amplitude and greater task-related power at higher frequencies (60–115 Hz) compared with signals over skull. We also provide evidence of a metric for trial-by-trial EMG/EEG coupling that is effective over the hemicraniectomy but not intact skull at frequencies >60 Hz. Taken together, these results provide evidence that the hemicraniectomy model provides a means for studying neural dynamics in humans with enhanced spatial and temporal resolution.

Author(s): Si, Bing; Dumkrieger, Gina; Wu, Teresa; Zafonte, Ross; Valadka, Alex B; Okonkwo, David O; Manley, Geoffrey T; Wang, Lujia; Dodick, David W; Schwedt, Todd J; Li, Jing | Abstract: BackgroundThe current classification of traumatic brain injury (TBI) into "mild", "moderate", or "severe" does not adequately account for the patient heterogeneity that still exists within each of these categories. The objective of this study was to identify "sub-groups" of mild TBI (mTBI) patients based on data available at the time of the initial post-TBI patient evaluation and to determine if the sub-grouping correlates with patient outcomes at 90 and 180 days post-TBI.MethodsData from patients in the TRACK-TBI Pilot dataset who had a Glasgow Coma Scale (GCS) score of 13 to 15 at arrival to the Emergency Department and a closed head injury were included. Considering 53 clinical variables that are typically available during the initial evaluation of the patient with mild TBI, sparse heirarchial clustering with cluster quality assessment was used to identify the optimal number of patient sub-groups. Patient sub-groups were then compared for ten outcomes measured at 90 or 180 days post-TBI.ResultsAmongst the 485 patients with mTBI, optimal clustering was based on the inclusion of 12 clinical variables that divided the patients into 5 mild TBI sub-groups. Clinical variables driving the sub-clustering included: gender, employment status, marital status, TBI due to falling, brain CT scan result, systolic blood pressure, diastolic blood pressure, administration of IV fluids in the Emergency Department, alcohol use, tobacco use, history of neurologic disease, and history of psychiatric disease. These 5 mild TBI sub-groups differed in their 90 day and 180 day outcomes within several domains including global outcomes, persistence of TBI-related symptoms, and neuropsychological impairment.ConclusionsSub-groups of patients with mTBI can be identified according to clinical variables that are relatively easy to obtain at the time of initial patient evaluation. A patient's sub-group assignment is associated with multidimensional patient outcomes at 90 and 180 days. These findings support the notion that there are clinically meaningful subgroups of patients amongst those currently classified as having mTBI.

Key Points Question Do patients with mild traumatic brain injury (mTBI) receive adequate levels of follow-up care? Findings In a cohort study using data on 831 patients with mTBI presenting to the emergency department at 1 of 11 level I trauma centers across the United States, 42% of patients reported receiving educational material at discharge and 44% reported seeing a physician or other medical practitioner within 3 months after injury. Among patients with 3 or more moderate to severe postconcussive symptoms, only 52% reported having seen a practitioner within 3 months following the injury. Meaning A large proportion of patients with mTBI do not receive follow-up care after injury even when they experience ongoing postconcussive symptoms., This cohort study describes follow-up care for patients within 3 months of receiving treatment for mild traumatic brain injury (TBI) or concussion at US emergency departments of level I trauma centers., Importance Mild traumatic brain injury (mTBI) affects millions of Americans each year. Lack of consistent clinical practice raises concern that many patients with mTBI may not receive adequate follow-up care. Objective To characterize the provision of follow-up care to patients with mTBI during the first 3 months after injury. Design, Setting, and Participants This cohort study used data on patients with mTBI enrolled in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study between February 26, 2014, and August 25, 2016. We examined site-specific variations in follow-up care, the types of clinicians seen by patients receiving follow-up care, and patient and injury characteristics associated with a higher likelihood of receiving follow-up care. The TRACK-TBI study is a prospective, multicenter, longitudinal observational study of patients with TBI presenting to the emergency department of 1 of 11 level I US trauma centers. Study data included patients with head trauma who underwent a computed tomography (CT) scan within 24 hours of injury, had a Glasgow Coma Scale score of 13 to 15, were aged 17 years or older, and completed follow-up care surveys at 2 weeks and 3 months after injury (N = 831). Main Outcomes and Measures Follow-up care was defined as hospitals providing TBI educational material at discharge, hospitals calling patients to follow up, and patients seeing a physician or other medical practitioner within 3 months after the injury. Unfavorable outcomes were assessed with the Rivermead Post Concussion Symptoms Questionnaire. Results Of 831 patients (289 [35%] female; 483 [58%] non-Hispanic white; mean [SD] age, 40.3 [16.9] years), less than half self-reported receiving TBI educational material at discharge (353 patients [42%]) or seeing a physician or other health care practitioner within 3 months after injury (367 patients [44%]). Follow-up care varied by study site; adjusting for patient characteristics, the provision of educational material varied from 19% to 72% across sites. Of 236 patients with a positive finding on a CT scan, 92 (39%) had not seen a medical practitioner 3 months after the injury. Adjusting for injury severity and demographics, patient admission to the hospital ward or intensive care unit, patient income, and insurance status were not associated with the probability of seeing a medical practitioner. Among the patients with 3 or more moderate to severe postconcussive symptoms, only 145 of 279 (52%) reported having seen a medical practitioner by 3 months. Conclusions and Relevance There are gaps in follow-up care for patients with mTBI after hospital discharge, even those with a positive finding on CT or who continue to experience postconcussive symptoms.

The goal of our study was to determine the interobserver variability between observers with different backgrounds and experience when interpreting computed tomography (CT) imaging features of traumatic brain injury (TBI). We retrospectively identified a consecutive series of 50 adult patients admitted at our institution with a suspicion of TBI, and displaying a Glasgow Coma Scale scoreor =12. Noncontrast CT (NCT) studies were anonymized and sent to five reviewers with different backgrounds and levels of experience, who independently reviewed each NCT scan. Each reviewer assessed multiple CT imaging features of TBI and assigned every NCT scan a Marshall and a Rotterdam grading score. The interobserver agreement and coefficient of variation were calculated for individual CT imaging features of TBI as well as for the two scores. Our results indicated that the imaging review by both neuroradiologists and neurosurgeons were consistent with each other. The kappa coefficient of agreement for all CT characteristics showed no significant difference in interpretation between the neurosurgeons and neuroradiologists. The average Bland and Altman coefficients of variation for the Marshall and Rotterdam classification systems were 12.7% and 21.9%, respectively, which indicates acceptable agreement among all five reviewers. In conclusion, there is good interobserver reproducibility between neuroradiologists and neurosurgeons in the interpretation of CT imaging features of TBI and calculation of Marshall and Rotterdam scores.

In this article, we review past and current experience in clinical trials of traumatic brain injuries (TBIs), we discuss limitations and challenges, and we summarize current directions. The focus is on severe and moderate TBIs. A systematic literature search of the years from 1980 to 2009 revealed 27 large phase III trials in TBI; we were aware of a further 6 unpublished trials. Analysis of these 33 trials yielded interesting observations: There was a peak incidence of trial initiations that occurred in the mid-1990s with a sharp decline during the period from 2000 to 2004. Most trials that reported a significant treatment effect were studies on a therapeutic strategy (e. g., decompressive craniectomy, hypothermia), and these were single-center studies. Increasingly, studies have been shifting toward the Far East. The currently existing trial registries permit insight into ongoing or recently conducted trials. Compared with the past decade, the number of studies on neuroprotective agents taken forward into efficacy-oriented studies is low. In contrast, the number of studies on therapeutic strategies appears to be increasing again. The disappointing results in trials on neuroprotective agents in TBI have led to a critical reappraisal of clinical trial methodology. This has resulted in recommendations for preclinical workup and has triggered extensive analysis on approaches to improve the design and analysis of clinical trials in TBI. An interagency initiative toward standardization on selection and coding of data elements across the broad spectrum of TBI is ongoing, and will facilitate comparison of research findings across studies and encourage high-quality meta-analysis of individual patient data in the future.

BACKGROUND: Many factors may predict mortality and disability after traumatic brain injury (TBI), including age and injury severity. However, the role of raceethnicity has typically been studied tangentially or in homogeneous settings. We investigated whether raceethnicity was associated with medical outcomes at a single, diverse center. METHODS: We retrospectively identified patients with TBI older than 17 years with blunt injuries admitted to a Level I trauma center from 2001 to 2004. Glasgow Outcome Scale (GOS) was used to determine outcome at discharge. We performed multivariable logistic regression on two measures of outcome by dichotomizing Glasgow Outcome Scale scores. RESULTS: We identified 357 patients with TBI from five categories: whites (46.2%), Asians (19.9%), Hispanics (17.9%), blacks (10.9%), and other unknown (5.0%). Without adjusting for other factors, Asians experienced higher mortality (odds ratio [OR] = 2.25, p = 0.01) compared with whites but not degree of disability. After adjusting for age and Injury Severity Score, a weaker trend remained for higher mortality in Asians (OR = 1.38, p = 0.35), and after excluding cases of assault, the finding was again significant (OR = 2.00, p = 0.04). We also confirmed the recently reported OR of higher mortality among blacks (OR = 1.30). Hispanics seemed to do slightly better at discharge. CONCLUSIONS: The question of whether and how race plays a role in TBI is controversial. At a single, diverse center, we found that mortality is associated with race, age, and Injury Severity Score. Future clinical studies will benefit from detailed genotypic and phenotypic data and should balance larger sample sizes with ethnic diversity. Language: en

Brainstem hemorrhage can occur as a primary or secondary event in traumatic brain injury (TBI). Secondary brainstem hemorrhage that evolves from raised intracranial pressure and transtentorial herniation is referred to as Duret hemorrhage. Duret hemorrhage following TBI has been considered an irreversible and terminal event. The authors report on the case of a young adult patient with TBI who presented with a low Glasgow Coma Scale score and advanced signs of cerebral herniation. She underwent an urgent decompressive hemicraniectomy for evacuation of an acute epidural hematoma and developed a Duret hemorrhage postoperatively. In accordance with the family's wishes, aggressive TBI monitoring and treatment in the intensive care unit was continued even though the anticipated outcome was poor. After a lengthy hospital course, the patient improved dramatically and was discharged ambulatory, with good cognitive functioning and a Glasgow Outcome Scale score of 4. Duret hemorrhage secondary to raised intracranial pressure is not always a terminal event, and by itself should not trigger a decision to withdraw care. Aggressive intracranial monitoring and treatment of a Duret hemorrhage arising secondary to cerebral herniation may enable a good recovery in selected patients after severe TBI.

Recent demographics demonstrate an increase in the number of elderly spinal cord injury patients, motivating the desire for a better understanding of age effects on injury susceptibility. Knowing that age and disease affect neurological tissue, there is a need to better understand the sensitivity of spinal cord injury mechanics to variations in tissue behavior. To address this issue, a plane-strain, geometrically nonlinear, finite element model of a section of a generic human thoracic spinal cord was constructed to model the response to dorsal compression. The material models and stiffness responses for the grey and white matter and pia mater were varied across a range of reported values to observe the sensitivity of model outcomes to the assigned properties. Outcome measures were evaluated for percent change in magnitude and alterations in spatial distribution. In general, principal stresses (114–244% change) and pressure (75–119% change) were the outcomes most sensitive to material variation. Strain outcome measures were less sensitive (7–27% change) than stresses (74–244% change) to variations in material tangent modulus. The pia mater characteristics had limited (

The cerebral circulation is fundamental to the health and maintenance of brain tissue, but injury and disease may result in dysfunction of the vessels. Characterization of cerebral vessel mechanical response is an important step toward a more complete understanding of injury mechanisms and disease development in these vessels, paving the way for improved prevention and treatment. We recently reported a large series of uniaxial tests on fresh human cerebral vessels, but the multi-axial behavior of these vessels has not been previously described. Twelve arteries were obtained from the surface of the temporal lobe of patients undergoing surgery and were subjected to various combinations of axial stretch and pressure around typical physiological conditions before being stretched to failure. Axial and circumferential responses were compared, and measured data were fit to a four parameter, Fung-type hyperelastic constitutive model. Artery behavior was nonlinear and anisotropic, with considerably greater resistance to deformation in the axial direction than around the circumference. Results from axial failure tests of pressurized vessels resulted in a small shift in stress-stretch response compared to previously reported data from unpressurized specimens. These results further define the biaxial response of the cerebral arteries and provide data required for more rigorous study of head injury mechanisms and development of cerebrovascular disease.

Object It has recently been suggested that the degree of intracranial pressure (ICP) above the treatment goal can be estimated by the area under the curve (AUC) of ICP versus time in patients with severe traumatic brain injury (TBI). The objective of this study was to determine whether the calculated “ICP dose”—the ICP AUC—is related to mortality rate, outcome, and Marshall CT classification. Methods Of 135 patients (age range 1–82 years) with severe TBI treated during a 5-year period at the authors' institution, 113 patients underwent ICP monitoring (84%). Ninety-three patients with a monitoring time > 24 hours were included for analysis of ICP AUC calculated using the trapezoidal method. Computed tomography scans were assessed according to the Marshall TBI classification. Patients with Glasgow Outcome Scale scores at 6 months and > 3 years were separated into 2 groups based on outcome. Results Sixty patients (65%) had ICP values > 20 mm Hg, and 12 (13%) developed severe intracranial hypertension and died secondary to herniation. A multiple regression analysis adjusting for Glasgow Coma Scale score, age, pupillary abnormalities and Injury Severity Scale score demonstrated that the ICP AUC was a significant predictor of poor outcome at 6 months (p = 0.034) and of death (p = 0.035). However, it did not predict long-term outcome (p = 0.157). The ICP AUC was significantly higher in patients with Marshall head injury Categories 3 and 4 (24 patients) than in those with Category 2 (23 patients, p = 0.025) and Category 5 (46 patients, p = 0.021) TBIs using the worst CT scan obtained. Conclusions The authors found a significant relationship between the dose of ICP, the worst Marshall CT score, and patient outcome, suggesting that the AUC method may be useful in refining and improving the treatment of ICP in patients with TBI.

In this study, we sought to determine the accuracy of a computer algorithm that automatically assesses head computed tomography (CT) studies in patients with suspected traumatic brain injury (TBI) for features of intracranial hemorrhage and mass effect, employing a neuroradiologist's interpretation as the gold standard. To this end, we designed a suite of computer algorithms that evaluates in a fully automated fashion the presence of intracranial blood and/or mass effect based on the following CT findings: (1) presence or absence of a subdural or epidural hematoma, (2) presence or absence of subarachnoid hemorrhage, (3) presence or absence of an intraparenchymal hematoma, (4) presence or absence of clinically significant midline shift (or=5 mm), and (5) normal, partly effaced, or completely effaced basal cisterns. The algorithm displays abnormal findings as color overlays on the original head CT images, and calculates the volume of each type of blood collection, the midline shift, and the volume of the basal cisterns, based on the above-described features. Thresholds and parameters yielding optimal accuracy of the computer algorithm were determined using a development sample of 33 selected, nonconsecutive patients. The software was then applied to a validation sample of 250 consecutive patients evaluated for suspicion of acute TBI at our institution in 2006-2007. Software detection of the presence of at least one noncontrast CT (NCT) feature of acute TBI demonstrated high sensitivity of 98% and high negative predictive value (NPV) of 99%. There was actually only one false negative case, where a very subtle subdural hematoma, extending exclusively along the falx, was diagnosed by the neuroradiologist, while the case was considered as normal by the computer algorithm. The software was excellent at detecting the presence of mass effect and intracranial hemorrhage, but showed some disagreements with the neuroradiologist in quantifying the degree of mass effect and characterizing the type of intracranial hemorrhage. In summary, we have developed a fully automated computer algorithm that demonstrated excellent sensitivity for acute intracranial hemorrhage and clinically significant midline shift, while maintaining intermediate specificity. Further studies are required to evaluate the potential favorable impact of this software on facilitating workflow and improving diagnostic accuracy when used as a screening aid by physicians with different levels of experience.

Aquaporins (AQPs) are critical for the transport of water and small solutes. The 13 known human AQPs are divided into those that transport only water molecules, the “orthodox” AQPs, and those that transport glycerol and small solutes in addition to water, the aquaglyceroporins. In humans, genetic variation in AQPs can cause phenotypes of abnormal water homeostasis. Cellular and human studies of naturally-occurring and synthetic mutations have provided insight into the biology and phenotypes of these variants. Many AQPs have not been well-characterized in terms of the effect of genetic variation on protein function and clinical phenotype. In this review, we discuss functional features in human AQPs and summarize previous studies of naturally-occurring variants. We focus on nonsynonymous mutations since they typically have the greatest effect on function. We develop a map of AQP variation and functional features and examine uncharacterized variants by sequence and structure analysis. We find that variation has been studied relative to the AQP pore, terminal domains, and sites critical to posttranslational modifications. Finally, we propose possible variant-based phenotypes for further research. Other open questions relate to the discovery of novel AQP gene variants as well as their functions and phenotypes. Hum Mutat 0, 1–10, 2008. © 2008 Wiley-Liss, Inc.

Object The “syndrome of the trephined” is an uncommon and poorly understood disorder of delayed neurological deficit following craniectomy. From the authors' extensive experience with decompressive hemicraniectomy for traumatic brain injury (TBI), they have encountered a number of patients who developed delayed motor deficits, also called “motor trephine syndrome,” and reversal of the weakness following cranioplasty repair. The authors set out to study motor function systematically in this patient population to define the incidence, contributing factors, and outcome of patients with motor trephine syndrome. Methods The authors evaluated patient demographics, injury characteristics, detailed motor examinations, and CT scans in 38 patients with long-term follow-up after decompressive hemicraniectomy for TBI. Results Ten patients (26%) experienced delayed contralateral upper-extremity weakness, beginning 4.9 ± 0.4 months (mean ± standard error) after decompressive hemicraniectomy. Motor deficits improved markedly within 72 hours of cranioplasty repair, and all patients recovered full motor function. The CT perfusion scans, performed in 2 patients, demonstrated improvements in cerebral blood flow commensurate with resolution of cerebrospinal fluid flow disturbances on CT scanning and return of motor strength. Comparisons between 10 patients with and 20 patients (53%) without delayed motor deficits identified 3 factors—ipsilateral contusions, abnormal cerebrospinal fluid circulation, and longer intervals to cranioplasty repair—to be strongly associated with delayed, reversible monoparesis following decompressive hemicraniectomy. Conclusions Delayed, reversible monoparesis, also called motor trephine syndrome, is common following decompressive hemicraniectomy for TBI. The results of this study suggest that close follow-up of motor strength with early cranioplasty repair may prevent delayed motor complications of decompressive hemicraniectomy.

Despite the growing clinical use of brain tissue oxygen monitoring, the specific determinants of low brain tissue oxygen tension (P(bt)O2) following severe traumatic brain injury (TBI) remain poorly defined. The objective of this study was to evaluate whether P(bt)O2 more closely reflects variables related to cerebral oxygen diffusion or reflects cerebral oxygen delivery and metabolism.Prospective observational study.Level I trauma center.Fourteen TBI patients with advanced neuromonitoring underwent an oxygen challenge (increase in FiO2 to 1.0) to assess tissue oxygen reactivity, pressure challenge (increase in mean arterial pressure) to assess autoregulation, and CO2 challenge (hyperventilation) to assess cerebral vasoreactivity.None.P(bt)O2 was measured directly with a parenchymal probe in the least-injured hemisphere. Local cerebral blood flow (CBF) was measured with a parenchymal thermal diffusion probe. Cerebral venous blood gases were drawn from a jugular bulb venous catheter. We performed 119 measurements of PaO2, arterial oxygen content (CaO2), jugular bulb venous oxygen tension (PVO2), venous oxygen content (CVO2), arteriovenous oxygen content difference (AVDO2), and local cerebral metabolic rate of oxygen (locCMRO2). In multivariable analysis adjusting for various variables of cerebral oxygen delivery and metabolism, the only statistically significant relationship was that between P(bt)O2 and the product of CBF and cerebral arteriovenous oxygen tension difference (AVTO2), suggesting a strong association between brain tissue oxygen tension and diffusion of dissolved plasma oxygen across the blood-brain barrier.Measurements of P(bt)O2 represent the product of CBF and the cerebral AVTO2 rather than a direct measurement of total oxygen delivery or cerebral oxygen metabolism. This improved understanding of the cerebral physiology of P(bt)O2 should enhance the clinical utility of brain tissue oxygen monitoring in patients with TBI.

Aquaporin-4 (AQP4) is the major water channel expressed at fluid–tissue barriers throughout the brain and plays a crucial role in cerebral water balance. To assess whether these channels influence brain extracellular space (ECS) under resting physiological conditions, we used the established real-time iontophoresis method with tetramethylammonium (TMA+) to measure three diffusion parameters: ECS volume fraction (α), tortuosity (λ), and TMA+loss (k′).In vivomeasurements were performed in the somatosensory cortex of AQP4-deficient (AQP4−/−) mice and wild-type controls with matched age. Mice lacking AQP4 showed a 28% increase in α (0.23 ± 0.007 vs 0.18 ± 0.003) with no differences in λ (1.62 ± 0.04 vs 1.61 ± 0.02) andk′(0.0045 ± 0.0001 vs 0.0031 ± 0.0009 s−1). Additional recordings in brain slices showed similarly elevated α in AQP4−/−mice, and no differences in λ andk′between the two genotypes. This is the first direct comparison of ECS properties in adult mice lacking AQP4 water channels with wild-type animals and demonstrates a significant enlargement of the volume fraction but no difference in hindrance to TMA+diffusion, expressed as tortuosity. These findings provide direct evidence for involvement of AQP4 in modulation of the ECS volume fraction and provide a basis for future modeling of water and ion transport in the CNS.

Object Traumatic brain injury (TBI) often occurs as part of a multisystem trauma that may lead to hemorrhagic shock. Effective resuscitation and restoration of oxygen delivery to the brain is important in patients with TBI because hypotension and hypoxia are associated with poor outcome in head injury. We studied the effects of hemoglobin-based oxygen-carrying (HBOC)–201 solution compared with lactated Ringer (LR) solution in a large animal model of brain injury and hemorrhage, in a blinded prospective randomized study. Methods Swine underwent brain impact injury and hemorrhage to a mean arterial pressure (MAP) of 40 mm Hg. Twenty swine were randomized to undergo resuscitation with HBOC-201 (6 ml/kg) or LR solution (12 ml/kg) and were observed for an average of 6.5 ± 0.5 hours following resuscitation. At the end of the observation period, magnetic resonance (MR) imaging was performed. Histological studies of swine brains were performed using Fluoro-Jade B, a marker of early neuronal degeneration. Results Swine resuscitated with HBOC-201 had higher MAP, higher cerebral perfusion pressure (CPP), improved base deficit, and higher brain tissue oxygen tension (PbtO2) than animals resuscitated with LR solution. No significant difference in total injury volume on T2-weighted MR imaging was observed between animals resuscitated with HBOC-201 solution (1155 ± 374 mm3) or LR solution (1246 ± 279 mm3; p = 0.55). On the side of impact injury, no significant difference in the mean number of Fluoro-Jade B–positive cells/hpf was seen between HBOC-201 solution (61.5 ± 14.7) and LR solution (48.9 ± 17.7; p = 0.13). Surprisingly, on the side opposite impact injury, a significant increase in Fluoro-Jade B–positive cells/hpf was seen in animals resuscitated with LR solution (42.8 ± 28.3) compared with those resuscitated with HBOC-201 solution (5.6 ± 8.1; p < 0.05), implying greater neuronal injury in LR-treated swine. Conclusions The improved MAP, CPP, and PbtO2 observed with HBOC-201 solution in comparison with LR solution indicates that HBOC-201 solution may be a preferable agent for small-volume resuscitation in brain-injured patients with hemorrhage. The use of HBOC-201 solution appears to decrease cellular degeneration in the brain area not directly impacted by the primary injury. Hemoglobin-based oxygen-carrying–201 solution may act by improving cerebral blood flow or increasing the oxygen-carrying capacity of blood, mitigating a second insult to the injured brain.

Object Brain edema can increase intracranial pressure (ICP), potentially leading to ischemia, herniation, and death. Edema and elevated ICP are often treated with osmotic agents to remove water from brain tissue. Mannitol is the osmotic diuretic most commonly used in the intensive care unit; however, despite its clinical importance, treatment protocols vary from center to center, and the dose–response relationship is not understood. The goal of this metaanalysis was to aggregate and analyze data from studies in which authors have described the dose–response relationship between mannitol and ICP. Methods The authors identified 18 studies that quantitatively characterized the dose–response relationship of mannitol and ICP. We also examined study designs and mannitol administration protocols. Results Meta-regression found a weak linear relationship between change in ICP (ΔICP) and dose (ΔICP = 6.6 × dose − 1.1; p = 0.27, R2 = 0.05). The lack of statistical significance could reflect the variation in protocols among studies and the variation in patients both within and among studies. However, the authors found a highly significant difference (p < 0.001) in decrease in ICP when the initial ICP was higher or lower than 30 mm Hg. Nonlinear regression suggested that ICP decrease is greatest shortly after mannitol is given (R2 = 0.63). Finally, the authors found that recent studies tend to include fewer patients and set a lower ICP threshold for mannitol administration but report more parameters of interest; the duration of mannitol's effect was the most frequently unreported parameter. Conclusions Despite its clinical importance, the determination of the mannitol dose–response curve continues to be challenging for many reasons. This metaanalysis highlights the need for a consensus of methods and results required to determine this important relationship.

Early coagulopathy after traumatic brain injury (TBI) is thought to be the result of injury-mediated local release of tissue factor, although the precise mechanisms that cause hypoperfusion and early systemic coagulopathy in TBI patients are unknown. We have previously reported that early systemic coagulopathy after trauma is present only when tissue injury is associated with severe hypoperfusion leading to the activation of the protein C pathway. However, the role of hypoperfusion as an important mechanism for the development of coagulopathy early after TBI is unclear. The objective of the present study was to determine the importance of hypoperfusion and protein C activation in causing early coagulopathy in TBI patients.We performed a prospective cohort study including patients with isolated brain injury admitted to a single trauma center. Blood was drawn on average 32 minutes after injury. Plasma samples were assayed for protein C and thrombomodulin by standard laboratory techniques. Routine coagulation measures (prothrombin time, partial thromboplastin time) and arterial blood gas analysis were performed concurrently. Severe hypoperfusion was evidenced by the presence of an arterial base deficit greater than 6.Thirty-nine TBI patients were included in the study during a 15-month period. TBI patients without concurrent hypoperfusion (n = 28) did not develop an early coagulopathy after trauma, no matter the severity of injury. In contrast, patients with TBI who also had severe hypoperfusion (BD6) (n = 11) were coagulopathic early after injury. Indeed, these patients had higher prothrombin time and partial thromboplastin time, compared with those with TBI and a BD6 (17.6 +/- 3.6 vs. 14.3 +/- 2.3, p0.005; and 43.13 +/- 18.3 vs. 27.4 +/- 3.8, p0.0001). Unactivated protein C levels were lower in the TBI group with BD6 (56 +/- 32 vs. 85 +/- 35, p = 0.03) and thrombomodulin levels were significantly higher (48 +/- 26 vs. 35 +/- 10, p = 0.04). Without hypoperfusion, there was no effect of increasing brain injury on protein C pathway or fibrinolysis pathway mediators.TBI alone does not cause early coagulopathy, but must be coupled with hypoperfusion to lead to coagulation derangements, associated with the activation of the protein C pathway. This novel finding has significant implications for the treatment of coagulopathy after severe brain injury.

✓Despite decades of research into the pathogenesis of cerebral edema, nonsurgical therapy for brain swelling has advanced very little after more than half a century. Recent advancements in our understanding of molecular water transport have generated interest in new targets for edema therapy. Aquaporin-4 (AQP4) is the primary cellular water channel in the brain, localized to astrocytic foot processes along the blood–brain barrier and brain–cerebrospinal fluid interface. Multiple studies of transgenic mice with a complete deficiency or altered expression of AQP4 suggest a prominent role for AQP4 in cerebral water transport. In models of cellular (cytotoxic) edema, AQP4 deletion or alteration has been shown to be protective, reducing edema burden and improving overall survival. In contrast, AQP4 deletion in extra-cellular (vasogenic) edema results in decreased edema clearance and greater progression of disease. The data strongly support the conclusion that AQP4 plays a pivotal role in cerebral water transport and is an essential mediator in the formation and resorption of edema fluid from the brain parenchyma. These findings also suggest that drug therapy targeting AQP4 function and expression may dramatically alter our ability to treat cerebral edema.

The incidence of traumatic brain injury (TBI) in the United States was 3.5 million cases in 2009, according to the Centers for Disease Control and Prevention. It is a contributing factor in 30.5% of injury-related deaths among civilians. Additionally, since 2000, more than 260,000 service members were diagnosed with TBI, with the vast majority classified as mild or concussive (76%). The objective assessment of TBI via imaging is a critical research gap, both in the military and civilian communities. In 2011, the Department of Defense (DoD) prepared a congressional report summarizing the effectiveness of seven neuroimaging modalities (computed tomography [CT], magnetic resonance imaging [MRI], transcranial Doppler [TCD], positron emission tomography, single photon emission computed tomography, electrophysiologic techniques [magnetoencephalography and electroencephalography], and functional near-infrared spectroscopy) to assess the spectrum of TBI from concussion to coma. For this report, neuroimaging experts identified the most relevant peer-reviewed publications and assessed the quality of the literature for each of these imaging technique in the clinical and research settings. Although CT, MRI, and TCD were determined to be the most useful modalities in the clinical setting, no single imaging modality proved sufficient for all patients due to the heterogeneity of TBI. All imaging modalities reviewed demonstrated the potential to emerge as part of future clinical care. This paper describes and updates the results of the DoD report and also expands on the use of angiography in patients with TBI.

Data-driven discovery in complex neurological disorders has potential to extract meaningful syndromic knowledge from large, heterogeneous data sets to enhance potential for precision medicine. Here we describe the application of topological data analysis (TDA) for data-driven discovery in preclinical traumatic brain injury (TBI) and spinal cord injury (SCI) data sets mined from the Visualized Syndromic Information and Outcomes for Neurotrauma-SCI (VISION-SCI) repository. Through direct visualization of inter-related histopathological, functional and health outcomes, TDA detected novel patterns across the syndromic network, uncovering interactions between SCI and co-occurring TBI, as well as detrimental drug effects in unpublished multicentre preclinical drug trial data in SCI. TDA also revealed that perioperative hypertension predicted long-term recovery better than any tested drug after thoracic SCI in rats. TDA-based data-driven discovery has great potential application for decision-support for basic research and clinical problems such as outcome assessment, neurocritical care, treatment planning and rapid, precision-diagnosis., Data-driven discovery in complex neurological disorders has potential to extract meaningful knowledge from large, heterogeneous datasets. Here the authors apply topological data analysis to assess therapeutic effects in preclinical traumatic brain injury and spinal cord injury research studies.

Mild traumatic brain injury (mTBI) results in variable clinical outcomes, which may be influenced by genetic variation. A single-nucleotide polymorphism in catechol-o-methyltransferase (COMT), an enzyme which degrades catecholamine neurotransmitters, may influence cognitive deficits following moderate and/or severe head trauma. However, this has been disputed, and its role in mTBI has not been studied. Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether the COMT Val (158) Met polymorphism influences outcome on a cognitive battery 6 months following mTBI-Wechsler Adult Intelligence Test Processing Speed Index Composite Score (WAIS-PSI), Trail Making Test (TMT) Trail B minus Trail A time, and California Verbal Learning Test, Second Edition Trial 1-5 Standard Score (CVLT-II). All patients had an emergency department Glasgow Coma Scale (GCS) of 13-15, no acute intracranial pathology on head CT, and no polytrauma as defined by an Abbreviated Injury Scale (AIS) score of a parts per thousand yen3 in any extracranial region. Results in 100 subjects aged 40.9 (SD 15.2) years (COMT Met (158) /Met (158) 29 %, Met (158) /Val (158) 47 %, Val (158) /Val (158) 24 %) show that the COMT Met (158) allele (mean 101.6 +/- SE 2.1) associates with higher nonverbal processing speed on the WAIS-PSI when compared to Val (158) /Val (158) homozygotes (93.8 +/- SE 3.0) after controlling for demographics and injury severity (mean increase 7.9 points, 95 % CI [1.4 to 14.3], p = 0.017). The COMT Val (158) Met polymorphism did not associate with mental flexibility on the TMT or with verbal learning on the CVLT-II. Hence, COMT Val (158) Met may preferentially modulate nonverbal cognition following uncomplicated mTBI. Registry: ClinicalTrials.gov Identifier NCT01565551.

OBJECT Previous studies that have evaluated the prognostic value of abnormal changes in signals on T2-weighted MRI scans of an injured spinal cord have focused on the longitudinal extent of this signal abnormality in the sagittal plane. Although the transverse extent of injury and the degree of spared spinal cord white matter have been shown to be important for predicting outcomes in preclinical animal models of spinal cord injury (SCI), surprisingly little is known about the prognostic value of altered T2 relaxivity in humans in the axial plane. METHODS The authors undertook a retrospective chart review of 60 patients who met the inclusion criteria of this study and presented to the authors’ Level I trauma center with an acute blunt traumatic cervical SCI. Within 48 hours of admission, all patients underwent MRI examination, which included axial and sagittal T2 images. Neurological symptoms, evaluated with the grades according to the American Spinal Injury Association (ASIA) Impairment Scale (AIS), at the time of admission and at hospital discharge were correlated with MRI findings. Five distinct patterns of intramedullary spinal cord T2 signal abnormality were defined in the axial plane at the injury epicenter. These patterns were assigned ordinal values ranging from 0 to 4, referred to as the Brain and Spinal Injury Center (BASIC) scores, which encompassed the spectrum of SCI severity. RESULTS The BASIC score strongly correlated with neurological symptoms at the time of both hospital admission and discharge. It also distinguished patients initially presenting with complete injury who improved by at least one AIS grade by the time of discharge from those whose injury did not improve. The authors’ proposed score was rapid to apply and showed excellent interrater reliability. CONCLUSIONS The authors describe a novel 5-point ordinal MRI score for classifying acute SCIs on the basis of axial T2-weighted imaging. The proposed BASIC score stratifies the SCIs according to the extent of transverse T2 signal abnormality during the acute phase of the injury. The new score improves on current MRI-based prognostic descriptions for SCI by reflecting functionally and anatomically significant patterns of intramedullary T2 signal abnormality in the axial plane.

Disease classification is central to the practice of medicine; it systematizes clinical knowledge and experience. Classification is essential for diagnosis and effective treatment of human disease. Progress in classifying traumatic brain injury (TBI) for targeted treatment has lagged behind other diseases such as cancer, and has contributed to a lack of progress in the field. Today TBI is most frequently classified as mild, moderate, or severe using the Glasgow Coma Scale (GCS). However, the GCS is symptoms-based and does not allow for targeting of specific pathology. Here we review general schemas for disease classification and how they have evolved over time. We discuss the characteristics of an ideal classification system and the unique challenges inherent to achieving such a system for TBI. Current means of classifying TBI are reviewed, as are the strengths and limitations of these approaches. Generating the data required to modernize TBI classification and to perhaps facilitate a targeted, precision medicine approach to its management will require a highly collaborative international effort. Fortunately these efforts are underway and will benefit from the lessons and tools that have come from other areas of medicine that have already found success with this approach.

Atlas of emergency neurosurgery , Atlas of emergency neurosurgery , کتابخانه الکترونیک و دیجیتال - آذرسا

Glial fibrillary acidic protein and its breakdown products (GFAP-BDP) are brain-specific proteins released into serum as part of the pathophysiological response after traumatic brain injury (TBI). We performed a multi-center trial to validate and characterize the use of GFAP-BDP levels in the diagnosis of intracranial injury in a broad population of patients with a positive clinical screen for head injury. This multi-center, prospective, cohort study included patients 16-93 years of age presenting to three level 1 trauma centers with suspected TBI (loss of consciousness, post-trauma amnesia, and so on). Serum GFAP-BDP levels were drawn within 24 h and analyzed, in a blinded fashion, using sandwich enzyme-linked immunosorbent assay. The ability of GFAP-BDP to predict intracranial injury on admission computed tomography (CT) as well as delayed magnetic resonance imaging was analyzed by multiple regression and assessed by the area under the receiver operating characteristic curve (AUC). Utility of GFAP-BDP to predict injury and reduce unnecessary CT scans was assessed utilizing decision curve analysis. A total of 215 patients were included, of which 83% suffered mild TBI, 4% moderate, and 12% severe; mean age was 42.1 +/- 18 years. Evidence of intracranial injury was present in 51% of the sample (median Rotterdam Score, 2; interquartile range, 2). GFAP-BDP demonstrated very good predictive ability (AUC=0.87) and demonstrated significant discrimination of injury severity (odds ratio, 1.45; 95% confidence interval, 1.29-1.64). Use of GFAP-BDP yielded a net benefit above clinical screening alone and a net reduction in unnecessary scans by 12-30%. Used in conjunction with other clinical information, rapid measurement of GFAP-BDP is useful in establishing or excluding the diagnosis of radiographically apparent intracranial injury throughout the spectrum of TBI. As an adjunct to current screening practices, GFAP-BDP may help avoid unnecessary CT scans without sacrificing sensitivity (Registry: ClinicalTrials.gov Identifier: NCT01565551).

Although the majority of patients with mild traumatic brain injury (mTBI) recover completely, some still suffer from disabling ailments at 3 or 6 months. We validated existing prognostic models for mTBI and explored predictors of poor outcome after mTBI. We selected patients with mTBI from TRACK-TBI Pilot, an unselected observational cohort of TBI patients from three centers in the United States. We validated two prognostic models for the Glasgow Outcome Scale Extended (GOS-E) at 6 months after injury. One model was based on the CRASH study data and another from Nijmegen, The Netherlands. Possible predictors of 3- and 6-month GOS-E were analyzed with univariate and multi-variable proportional odds regression models. Of the 386 of 485 patients included in the study (median age, 44 years; interquartile range, 27-58), 75% (n=290) presented with a Glasgow Coma Score (GCS) of 15. In this mTBI population, both previously developed models had a poor performance (area under the receiver operating characteristic curve, 0.49-0.56). In multivariable analyses, the strongest predictors of lower 3- and 6-month GOS-E were older age, pre-existing psychiatric conditions, and lower education. Injury caused by assault, extracranial injuries, and lower GCS were also predictive of lower GOS-E. Existing models for mTBI performed unsatisfactorily. Our study shows that, for mTBI, different predictors are relevant as for moderate and severe TBI. These include age, pre-existing psychiatric conditions, and lower education. Development of a valid prediction model for mTBI patients requires further research efforts.

Disease classification is central to the practice of medicine; it systematizes clinical knowledge and experience. Classification is essential for diagnosis and effective treatment of human disease. Progress in classifying traumatic brain injury (TBI) for targeted treatment has lagged behind other diseases such as cancer, and has contributed to a lack of progress in the field. Today TBI is most frequently classified as mild, moderate, or severe using the Glasgow Coma Scale (GCS). However, the GCS is symptoms-based and does not allow for targeting of specific pathology. Here we review general schemas for disease classification and how they have evolved over time. We discuss the characteristics of an ideal classification system and the unique challenges inherent to achieving such a system for TBI. Current means of classifying TBI are reviewed, as are the strengths and limitations of these approaches. Generating the data required to modernize TBI classification and to perhaps facilitate a targeted, precision medicine approach to its management will require a highly collaborative international effort. Fortunately these efforts are underway and will benefit from the lessons and tools that have come from other areas of medicine that have already found success with this approach.

The goals of this study were to determine the incidence and duration of hypotension and hypoxia in the prehospital setting in patients with potentially survivable brain injuries, and to prospectively examine the association of these secondary insults with mortality and disability at hospital discharge.Trauma patients with suspected brain injuries underwent continuous blood pressure and pulse oximetry monitoring during helicopter transport. Postadmission inclusion criteria were (1) diagnosis of acute traumatic brain injury (TBI) confirmed by computed tomography (CT) scan, operative findings, or autopsy findings; and (2) Head Abbreviated Injury Scale (AIS) score ofor = 3 or Glasgow Coma Scale (GCS) score ofor = 12 within the first 24 hours of admission. Patients were excluded with (1) no abnormal intracranial findings on the patient's CT scan; (2) determination of a nonsurvivable injury (based on an AIS score of 6 for any body region; or, (3) death in less than 12 hours after injury. Primary outcome measures included mortality and Disability Rating Scale score at discharge.We enrolled 150 patients into the study. Fifty-seven patients had at least one secondary insult; 37 had only hypoxic episodes, 14 had only hypotensive episodes, and 6 patients had both. Demographics and injury characteristics did not differ between those with and those without secondary insults. The mortality for patients without secondary insults was 20%, compared with 37% for patients with hypoxic episodes, 8% for patients with hypotensive episodes, and 24% for patients with both. The Disability Rating Scale score at discharge was significantly higher in patients with secondary insults. Using multivariate analysis, the calculated odds ratio of mortality caused by prehospital hypoxia after head injury was 2.66 (p0.05).Secondary insults after TBI are common, and these insults are associated with disability. Hypoxia in the prehospital setting significantly increases the odds of mortality after brain injury controlled for multiple variables.

The glial water channel aquaporin-4 (AQP4) has been hypothesized to modulate water and potassium fluxes associated with neuronal activity. In this study, we examined the seizure phenotype of AQP4 -/- mice using in vivo electrical stimulation and electroencephalographic (EEG) recording. AQP4 -/- mice were found to have dramatically prolonged stimulation-evoked seizures after hippocampal stimulation compared to wild-type controls (33 +/- 2 s vs. 13 +/- 2 s). In addition, AQP4 -/- mice were found to have a higher seizure threshold (167 +/- 17 microA vs. 114 +/- 10 microA). To assess a potential effect of AQP4 on potassium kinetics, we used in vivo recording with potassium-sensitive microelectrodes after direct cortical stimulation. Although there was no significant difference in baseline or peak [K(+)](o), the rise time to peak [K(+)](o) (t(1/2), 2.3 +/- 0.5 s) as well as the recovery to baseline [K(+)](o) (t(1/2), 15.6 +/- 1.5 s) were slowed in AQP4 -/- mice compared to WT mice (t(1/2), 0.5 +/- 0.1 and 6.6 +/- 0.7 s, respectively). These results implicate AQP4 in the expression and termination of seizure activity and support the hypothesis that AQP4 is coupled to potassium homeostasis in vivo.

Background: Age has been shown to be a primary determinant of survival following isolated traumatic brain injury (TBI). We have previously reported that patients ≥65 years who survived mild TBI have decreased functional outcome at 6 months compared with younger patients. The purpose of this study was to further investigate the effect of age on outcome at 1 year in all patients surviving isolated TBI. Methods: The Western Trauma Association multicenter prospective study included all patients sustaining isolated TBI defined as Abbreviated Injury Scale score for Head ≥ 3 with an Abbreviated Injury Scale score in any other body area £ 1. Outcome data included discharge disposition, Glasgow Outcome Scale score (1 = dead to 5 = full recovery) and modified Functional Independence Measure (FIM) score measuring feeding, expression, and locomotion (1 = total dependence to 4 = total independence) for each component at discharge and 1 year. Results: In all, 295 patients were enrolled with a follow-up of 82%, resulting in 241 study patients. An additional five patients died from non-TBI causes and were excluded. The mean and median times for the last follow-up in the 236 remaining patients were 307 and 357 days, respectively. Patients were divided into four age ranges: 18 to 29 years (n = 66), 30 to 44 years (n = 54), 45 to 59 years (n = 50), and ≥60 years (n = 65). More severe THIS, as measured by admitting Glasgow Coma Scale (GCS), were observed in the youngest group compared with all others but there were no differences in mean GCS between the remaining three groups. There were no differences in neurosurgical intervention between the groups. Age was a major determinant in the outcome at discharge and last follow-up. Patients over 60 years discharged with a GOS ≤4 were less likely to improve at 1 year than all other groups (37% versus 63 to 85%; p ≤ 0.05). Patients between 18 and 29 years of age had the lowest mean Glasgow Outcome Scale and discharge FIM scores, which correlated with the low admission GCS. Despite the increased severity of TBI, this group had the best FIM score at 1 year. In contrast, patients older than 60 years had the least improvement and had a significantly lower final FEM score at 1 year compared with all other groups. Conclusion: Older patients following isolated TBI have poorer functional status at discharge and make less improvement at 1 year compared with all other patients. These worse outcomes occur despite what appears to be less severe TBI as measured by a higher GCS upon admission. Differences in outcome begin to appear even in patients between 45 and 59 years. Further investigations with more detailed outcome instruments are required to better understand the qualitative limitations of a patient's recovery and to devise strategies to maximize functional improvement following TBL Age is an exceedingly important parameter affecting recovery from isolated TBI.

OBJECTIVE Mannitol is the standard of care for patients with increased intracranial pressure (ICP), but multiple administrations of mannitol risk renal toxicity and fluid accumulation in the brain parenchyma with consequent worsening of cerebral edema. This preliminary study assessed the safety and efficacy of small-volume injections of 23.4% sodium chloride solution for the treatment of intracranial hypertension in patients with traumatic brain injury who became tolerant to mannitol. METHODS We retrospectively reviewed the charts of 13 adult patients with traumatic brain injury who received mannitol and 23.4% sodium chloride independently for the treatment of intracranial hypertension at San Francisco General Hospital between January and October 2003. Charts were reviewed to determine ICP, cerebral perfusion pressure, mean arterial pressure, serum sodium values, and serum osmolarity before and after treatment with 23.4% sodium chloride and mannitol. Complications were noted. RESULTS The mean reductions in ICP after treatment were significant for both mannitol (P < 0.001) and hypertonic saline (P < 0.001); there were no significant differences between reductions in ICP when comparing the two agents (P = 0.174). The ICP reduction observed for hypertonic saline was durable, and its mean duration of effect (96 min) was significantly longer than that of mannitol treatment (59 min) (P = 0.016). No complications were associated with treatment with hypertonic saline. CONCLUSION This study suggests that 23.4% hypertonic saline is a safe and effective treatment for elevated ICP in patients after traumatic brain injury. These results warrant a rigorous evaluation of its efficacy as compared to mannitol in a prospective randomized controlled trial.

Brain abscess is associated with local vasogenic edema, which leads to increased intracranial pressure and significant morbidity. Aquaporin-4 (AQP4) is a water channel expressed in astroglia at the blood-brain and brain-CSF barriers. To investigate the role of AQP4 in brain abscess-associated edema, live Staphylococcus aureus (10(5) colony-forming units) was injected into the striatum to create a focal abscess. Wild-type and AQP4-deficient mice had comparable immune responses as measured by brain abscess volume (approximately 3.7 mm3 at 3 days), bacterial count and cytokine levels in brain homogenates. Blood-brain barrier permeability was increased comparably in both groups as assessed by extravasation of Evans blue dye. However, at 3 days the AQP4 null mice had significantly higher intracranial pressure (mean +/- SEM 27 +/- 2 vs. 17 +/- 2 mmHg; p < 0.001) and brain water content (81.0 +/- 0.3 vs. 79.3 +/- 0.5 % water by weight in the abscess-containing hemisphere; p < 0.01) than wild-type mice. Reactive astrogliosis was found throughout the abscess-containing hemisphere; however, only a subset of astrocytes in the peri-abscess region of wild-type mice had increased AQP4 immunoreactivity. Our findings demonstrate a protective effect of AQP4 on brain swelling in bacterial abscess, suggesting that AQP4 induction may reduce vasogenic edema associated with cerebral infection.

The NeurOptics ForSite quantitative dynamic pupillometer is manufactured by NeurOptics, Inc., 2600 Michelson Drive, Suite 980, Irvine, CA 92612, telephone 949/250-9792, www.neuroptics.com.

Continuous monitoring of physiologic vital signs is routine in neurocritical care. However, this patient information is usually only recorded intermittently (most often hourly) in the medical record. It is unclear whether this is sufficient to represent the occurrence of secondary brain insults (SBIs) or whether more frequent data collection will provide more comprehensive information for patient care. In 16 patients, physiologic data were acquired concurrently via two methods: per clinical routine, usually hourly, in the medical record (MR) and every minute via a custom data acquisition system (DA). SBIs were defined as a mean arterial pressure90 mmHg, an intracranial pressure20 mmHg or a temperature37.5 degrees C. Number of events, cumulative duration of events and area under the curve (AUC) were compared between the two methods and 95% limits of agreement were assessed for various methods of MR data interpolation. For all three parameters, analysis of the DA and MR data frequently differed with regard to number of events, total duration of events and AUC. MR data tended to underestimate the number of total events. 95% limits of agreement were most narrow for trapezoidal interpolation of MR data, but even these limits were fairly broad. Assessment of secondary brain insults is highly dependent on (1) the temporal resolution of the method used to acquire patient data and on (2) the interpolation method if data are acquired intermittently. High frequency data acquisition may be necessary for more precise evaluation of secondary brain injury in neurocritical care.

Pupillary size and reactivity have long been a critical component of the clinical assessment of patients with neurological disorders. The pupillary examination may provide critical information related to new or worsening intracranial pathology and facilitate prompt intervention to minimize further neuronal damage. With this in mind, intensive care nurses caring for neurologically impaired patients frequently must perform pupillary examinations in concert with assigning a Glasgow Coma Scale score. The purpose of this study was to test the accuracy and reliability of an automated pupillometer compared with the standard manual examination as a preliminary step in assessing the usefulness of automated pupillometry in the critical care setting. Twenty patients in the intensive care units of a teaching hospital were examined by two groups of three examiners using both the manual examination with a penlight or similar light source and a portable automated pupillometer capable of measuring pupil size and reaction. Measurements by a static pupillometer before and after each pupillary examination were used to determine the mean "true" size of the pupil. This study found that the automated pupillometer is more accurate and reliable than the manual examination in measuring pupil size and reactivity. For these reasons, such a device may be a beneficial addition in the clinical assessment of neurologically impaired patients.

Introduction: Brain tissue oxygen (PbrO2) monitoring is an emerging technique for detection of secondary brain injury in neurocritical care. Although it has been extensively reported in traumatic brain injury and aneurysmal subarachnoid hemorrhage, its use in nontraumatic intracerebral hemorrhage (ICH) has not been well described. We report complementary preliminary studies in a large animal model and in patients that demonstrate the feasibility of PbrO2 monitoring after ICH. Methods: To assess early events after ICH, Licox Clark-type oxygen probes were inserted in the bilateral frontal white matter of four anesthetized swine that subsequently underwent right parietal hematoma formation in an experimental model of ICH. Intracranial pressure (ICP) was monitored as well. Seven patients with acute ICH, who were undergoing ICP monitoring as part of standard neurocritical care, had placement of a frontal oxygen probe, with subsequent monitoring for up to 7 days. Results: In the swine ICH model, a rise in ICP early after hematoma formation was accompanied by a decrease in ipsilateral and contralateral PbrO2. Secondary increases in hematoma volume resulted in further decreases in PbrO2 over the first hour after ICH. In patients undergoing oxygen monitoring, low PbrO2 (

Objectives: Prior studies suggest that the emergency department (ED) occurrence of secondary brain insults (SBIs), such as systemic hypotension and hypoxia, worsens outcome in patients with traumatic brain injury. However, previous methods of assessing SBIs have been relatively crude, generally only determining the incidence and duration of events. The authors hypothesized that a new method that accounts for the cumulative depth and duration of SBIs would provide a more informative measure that better correlates with outcome. Methods: The authors developed a computer algorithm to calculate the total ‘‘dose’’ of an SBI (in this case, hypotension and hypoxia) as the area under the curve between a cut-point value and a measured vital sign over time. To test this method, the authors used an existing data set of head trauma patients for whom occurrence in the ED of any hypotension had been shown to be associated with in-hospital mortality. The authors applied the algorithm using the cut-point values from the prior study (systolic blood pressure #90 mm Hg and oxygen saturation #92%). The effects of SBIs on inhospital mortality and three-month Glasgow Outcome Scale score were evaluated. Results: Of 107 patients overall, 26 had hypotension (dose range 0.2–898 mm Hg min) and 40 had hypoxia (dose range 0.005–6.7% min). Moderate and high doses of hypotension were more strongly associated with outcome than the measures from the initial study (any hypotension and number of hypotensive episodes). Hypoxia had no effect. Conclusions: New methods of measuring SBIs that take into account depth and duration of episodes may more accurately reflect the influence of these events on outcome after head trauma. Key words: secondary brain insults; hypotension; hypoxia; traumatic brain injury; head trauma. ACADEMIC EMERGENCY MEDICINE 2005; 12:1–6.

Elderly patients (aged 60 years and older) have been demonstrated to have an increased mortality after isolated traumatic brain injury (TBI); however, the prognosis of those patients surviving their hospitalization is unknown. We hypothesized that surviving elderly patients would also have decreased functional outcome, and this study examined the functional outcome of patients with isolated TBI at discharge and at 6 months posthospitalization.This was a multicenter prospective study of all patients with isolated moderate to severe TBI defined as Head Abbreviated Injury Scale score of 3 with an Abbreviated Injury Scale score in any other body area of 1. Patients surviving to discharge gave their consent and were enrolled. Data collected included demographics, Glasgow Coma Scale (GCS) score at admission, and neurosurgical interventions. Outcome data included discharge disposition and Glasgow Outcome Scale score and modified Functional Independence Measure (FIM) score at discharge and at 6 months.Two hundred thirty-five patients were enrolled, with 44 (19%) aged greater than or equal to 65 years. Mechanisms of injury were falls (34%), assaults (28%), motor vehicle collisions (14%), pedestrian (11%), and other (12%). Falls were more common in the older patients and assaults in the younger group. The mean admitting GCS score was 12.8 (95% confidence interval [CI], 12.4-13.3), with older patients having a higher mean GCS score, 14.1 (95% CI, 13.6-14.6) versus 12.5 (95% CI, 12.0-13.1; p = 0.03). There were no differences in the percentage of patients admitted to the intensive care unit or requiring neurosurgical intervention between younger and older patients. Because there were few elderly patients with low GCS scores who survived to discharge, outcome measures focused on those patients with GCS scores of 13 to 15. A greater percentage of elderly were discharged to rehabilitation (28% vs. 16%, p =0.08). The mean discharge FIM score was 10.4 (95% CI, 9.8-11.0) for the elderly versus 11.4 (95% CI, 11.1-11.7) for the young (p =0.001), with 68% elderly and 89% young discharged with total independent scores of 11 to 12. At 6 months, the difference narrowed, but the mean FIM score was still greater for the young group, 11.7 (95% CI, 11.6-11.9) versus 11.0 (95% CI, 10.6-11.4; p0.001).Functional outcome after isolated mild TBI as measured by the Glasgow Outcome Scale and modified FIM is generally good to excellent for both elderly and younger patients. Older patients required more inpatient rehabilitation and lagged behind their younger counterparts but continued to recover and improve after discharge. Although there were statistically significant differences in the FIM score at both discharge and 6 months, the clinical importance of these small differences in the mean FIM score to the patient's quality of life is less clear. Measurable improvement in functional status during the first 6 months after injury is observed in both groups. Aggressive management and care of older patients with TBI is warranted, and efforts should be made to decrease inpatient mortality. Continued follow-up is ongoing to determine whether these outcomes persist at 12 months.

Traumatic brain injury, stroke, and subarachnoid hemorrhage remain a significant cause of death and disability. Cerebral ischemia plays a pivotal role in the pathogenesis of brain injury. Patients with these insults are also at risk for secondary injury from hypoxia and hypotension. The focus of care for these patients is the detection and prevention of secondary insults to the brain. However, standard neuromonitoring is limited to the measurement of intracranial pressure and calculation of cerebral perfusion pressure. Recently, new devices have been developed for the direct monitoring of cerebral oxygenation and metabolism. One of these devices, the brain tissue oxygen monitor, has been gaining acceptance as studies have detailed its ease of use, accuracy, and prognostic value for pathological events. The technical aspects and physiological principles of brain tissue oxygen monitoring are reviewed, and the clinical application of this technology is discussed.

Aquaporins (AQPs) are membrane proteins involved in water transport in many fluid-transporting tissues. Aquaporins AQP1, AQP4, and AQP9 have been identified in brain and hypothesized to participate in brain water homeostasis. Here we use reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting and immunohistochemistry to describe the expression and immunolocalization of AQPs in adult mouse spinal cord. AQP4 was expressed in glial cells, predominantly in gray matter, and in astrocytic end-feet surrounding capillaries in spinal cord white matter. AQP9 expression extensively co-localized with glial fibrillary acidic protein-immunoreactive astrocytes, located predominantly in the white matter. AQP5 was detected by RT-PCR but not by immunohistochemical analysis. Interestingly, AQP8 was detected primarily in ependymal cells lining the fluid-filled central canal. The aquaporin expression pattern in spinal cord suggests involvement in water homeostasis and diseases associated with abnormal water fluxes such as spinal cord injury and syringomyelia.

Despite their diverse histological types, most brain tumours cause brain oedema, which is a significant cause of patient morbidity and mortality. Brain tumour oedema occurs when plasma-like fluid enters the brain extracellular space through impaired capillary endothelial tight junctions in tumours. Under-expression of the tight junction proteins occludin, claudin-1 and claudin-5 are key molecular abnormalities responsible for the increased permeability of tumour endothelial tight junctions. Recent evidence suggests that the membrane water channel protein aquaporin-4 (AQP4) also plays a role in brain tumour oedema. AQP4-deficient mice show remarkably altered brain water balance after various insults, including brain tumour implantation. AQP4 expression is strongly upregulated around malignant human brain tumours in association with reduced extracellular volume, which may restrict the flow of extracellular fluid from the tumour bed into the brain parenchyma. Elimination of excess fluid leaking into brain parenchyma requires passage across three AQP4-rich barriers: a) the glia limitans externa, b) the glia limitans interna/ependyma, and c) the blood-brain barrier. Modulation of the expression and/or function of endothelial tight junction proteins and aquaporins may provide novel therapeutic options for reducing brain tumour oedema.

Human cerebral blood vessels are frequently damaged in head impact, whether accidental or deliberate, resulting in intracranial bleeding. Additionally, the vasculature constitutes the support structure for the brain and, hence, plays a key role in the cranial load response. Quantification of its mechanical behavior, including limiting loads, is thus required for a proper understanding and modeling of traumatic brain injury—as well as providing substantial assistance in the development and application of preventive measures. It is believed that axial stretching is the dominant loading mode for the blood vessels, regardless of the nature of the insult. Eighteen arteries and fourteen veins were obtained from the cortical surface of the cerebral temporal lobe of patients undergoing surgery. These vessels were stretched to failure in the longitudinal direction, either quasi-statically or dynamically. The significance of specimen and experiment parameters was determined using multivariate analysis of variance (MANOVA) testing. Results demonstrate that the arteries were considerably stiffer than the veins, carrying approximately twice as much stress at failure but withstanding only half as much stretch. No significant rate dependence was measured over a strain rate range of more than four orders of magnitude (0.01 to 500 s−1).