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Object There are several infusion methods available to estimate the outflow conductance (Cout) or outflow resistance (Rout = 1/Cout) of the CSF system. It has been stated that for unknown reasons, the bolus infusion method estimates a higher Cout than steady-state infusion methods. The aim of this study was to compare different infusion methods for estimation of Cout. Methods The following 3 different infusion methods were used: the bolus infusion method (Cout bol); the constant flow infusion method, both static (Cout stat) and dynamic (Cout dyn) analyses; and the constant pressure infusion method (Cout cpi). Repeated investigations were performed on an experimental model with well-known characteristics, with and without physiological pressure variations (B-waves, breathing, and so on). All 3 methods were also performed in a randomized order during the same investigation in 20 patients with probable or possible idiopathic normal-pressure hydrocephalus; 6 of these patients had a shunt and 14 did not. Results Without the presence of physiological pressure variations, the concordance in the experimental model was good between all methods. When they were added, the repeatability was better for the steady-state methods and a significantly higher Cout was found with the bolus method in the region of clinically relevant Cout (p < 0.05). The visual fit for the bolus infusion was dependent on subjective assessment by the operator. This experimental finding was confirmed by the clinical results, where significant differences were found in the investigations in patients without shunts between Cout of the visual bolus method and Cout stat, Cout dyn, and Cout cpi (4.58, 4.18, and 6.12 μl/[second × kPa], respectively). Conclusions This study emphasized the necessity for standardization of Cout measurements. An experienced operator could partly compensate for difficulties in correctly estimating the pressure parameters for the bolus infusion method, but for the general user this study suggests a steady-state method for estimating Cout.

Object The edema associated with brain swelling after traumatic brain injury (TBI) has been thought to be vasogenic in origin, but the results of previous laboratory studies by the authors have shown that a cellular form of edema is mainly responsible for brain swelling after TBI. In this study the authors used magnetic resonance (MR) imaging techniques to identify the type of edema that occurs in patients with TBI. Methods Diffusion-weighted MR imaging was used to evaluate the apparent diffusion coefficient (ADC) in 44 patients with TBI (Glasgow Coma Scale Score < 8) and in eight healthy volunteers. Higher ADC values have been associated with vasogenic edema, and lower ADC values with a predominantly cellular form of edema. Regional measurements of ADC in patients with focal and diffuse injury were computed. The water content of brain tissue was also assessed in absolute terms by using MR imaging to measure the percentage of water per gram of tissue. Cerebral blood flow (CBF) was measured using stable Xe–computerized tomography (CT) studies to rule out ischemia as a cause of cellular edema. The mean ADC value in the healthy volunteers was 0.82 ± 0.05 × 10−3 mm2/second. The ADC values in the patients with diffuse brain injury without swelling were close to the mean for the healthy volunteers. In contrast, the patients with brain swelling had increased brain water content and low ADC values (mean 0.74 ± 0.05 × 10−3 mm2/second). The ADC values correlated with CT classifications. In all patients with low ADC values, the CBF values were outside the range for ischemia. Conclusions The brain swelling observed in patients with TBI appears to be predominantly cellular, as signaled by low ADC values in brain tissue with high levels of water content.

Object. It is well established that posttraumatic secondary ischemia contributes to poor outcome. Ion dysfunction leading to cytotoxic edema is a primary force in the formation of ischemic brain edema and is a principal component of traumatic brain swelling. Because cell swelling is the result of net ion and water movement, it is crucial to have a thorough understanding of these transient phenomena. The purpose of this study was to characterize the effects of secondary ischemia following traumatic brain injury (TBI) on the ability to restore ion homeostasis. Methods. Twenty-four Sprague—Dawley rats were divided into four groups of six animals each. The rats underwent transient forebrain ischemia via bilateral carotid artery occlusion combined with hypotension: 15 minutes of forebrain ischemia (Group 1); 60 minutes of forebrain ischemia (Group 2); impact acceleration/TBI (Group 3); and impact acceleration/TBI followed by 15 minutes of ischemia (Group 4). Ischemia resulted in a rapid accumulation of [K+]e: 41.94 ± 13.65 and 66.33 ± 6.63 mM, respectively, in Groups 1 and 2, with a concomitant decrease of [Na+]e: 64 ± 18 mM and 72 ± 11 mM in Groups 1 and 2. Traumatic brain injury resulted in a less severe although identical trend in ion dysfunction ([K+]e 30.42 ± 11.67 mM and [Na+]e 63 ± 33 mM). Secondary ischemia resulted in prolonged and sustained ion dysfunction with a concomitant elevation of intracranial pressure (ICP). Conclusions. Analysis of these results indicates that ischemia and TBI are sublethal in isolation; however, when TBI is associated with secondary ischemia, ion dysfunction is sustained and is associated with elevated ICP.

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

Object. The goal of this study was to characterize a new model of an epidural mass lesion in rodents by means of neurophysiological monitoring, magnetic resonance imaging, and histopathological analysis. Methods. Changes in intracranial pressure (ICP), cerebral perfusion pressure (CPP), and laser Doppler flowmetry (LDF) values, intraparenchymal tissue partial oxygen pressure (PtiO2), and electroencephalography (EEG) activity were evaluated in the rat during controlled, epidural expansion of a latex balloon up to a maximum ICP of 60 mm Hg. The initial balloon inflation was followed by periods of sustained inflation (30 ± 1 minute) and reperfusion (180 ± 5 minutes). Histopathological analysis and magnetic resonance (MR) imaging were performed to characterize the lesion. The time to maximum balloon expansion and the average balloon volume were highly reproducible. Alterations in EEG activity during inflation first appeared when the CPP decreased to 57 mm Hg, the LDF value to 66% of baseline values, and the PtiO2 to 12 mm Hg. During maximum compression, the CPP was reduced to 34 mm Hg, the LDF value to 40% of baseline, and the PtiO2 to 4 to 5 mm Hg. The EEG tracing was isoelectric during prolonged inflation and the values of LDF and PtiO2 decreased due to accompanying hypotonia. After reperfusion, the CPP was significantly decreased (p < 0.05) due to the elevation of ICP. Both the LDF value and EEG activity displayed incomplete restoration, whereas the value of PtiO2 returned to normal. Histological analysis and MR imaging revealed brain swelling with a midline shift and a combined cortical—subcortical ischemic lesion beyond the site of balloon compression. Conclusions. This novel model of an epidural mass lesion in rodents closely resembles the process observed in humans. Evaluation of pathophysiological and morphological changes was feasible by using neurophysiological monitoring and MR imaging.

Object. Disruption of ionic homeostasis during ischemia is a well-characterized event and is identified by a rise in the concentration of extracellular potassium [K+]e, with a concomitant reduction in the concentration of extracellular sodium [Na+]e. Results of clinical studies in which microdialysis has been used, however, have shown only modest changes in the levels of extracellular ions. The object of this study was to measure [K+]e and [Na+]e by using ion-selective electrodes (ISEs) and to compare these measurements with those obtained using the well-established method of microdialysis. Methods. Fifteen Sprague—Dawley rats were separated into three groups. Five animals were subjected to a 15-minute period of ischemia, and another five animals to a 60-minute period of ischemia; animals in both of these groups received K+-free microdialysis perfusate. The third group of five rats underwent a 60-minute period of ischemia and received a reduced-Na+ microdialysis perfusate. Transient forebrain ischemia was produced by bilateral carotid artery occlusion combined with hypotension. A custom-fabricated glass Na+ electrode and a flexible plastic K+ and reference electrodes were used to monitor extracellular ion transients. Microdialysis samples were obtained with the aid of a 2-mm microdialysis probe that was perfused with K+-free mock cerebrospinal fluid at a rate of 2 µl/minute. Baseline measurements of [K+]e and [Na+]e, obtained using ISEs, were 3.41 ± 0.09 mM and 145 ± 7.75 mM, respectively. Ischemia resulted in a rapid accumulation of [K+]e (in animals subjected to 15 minutes of ischemia, the concentration was 41.9 ± 13.7 mM; and in animals subjected to 60 minutes of ischemia, the concentration was 66.9 ± 11.5 mM), with a concomitant decrease in [Na+]e (in animals subjected to 15 minutes of ischemia, the concentration was 71.7 ± 2.9 mM; and in animals subjected to 60 minutes of ischemia, the concentration was 74.7 ± 1.9 mM). A comparison of microdialysis and ISE methods revealed that microdialysis underestimated the [K+]e changes and was insensitive to concomitant [Na+]e alterations that occur during ischemia. Conclusions. Our results indicate that the flexible ISE is a reliable and accurate tool for monitoring ionic dysfunction that accompanies brain injury.

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

Object. Excessive activity of excitatory amino acids released after head trauma has been demonstrated to contribute to progressive injury in animal models and human studies. Several pharmacological agents that act as antagonists to the glutamate receptor have shown promise in limiting this progression. The efficacy of the N-methyl-d-aspartate receptor antagonist Selfotel (CGS 19755) was evaluated in two parallel studies of severely head injured patients, defined as patients with postresuscitation Glasgow Coma Scale scores of 4 to 8.Methods. A total of 693 patients were prospectively enrolled in two multicenter double-blind studies. Comparison between the treatment groups showed no significant difference with regard to demographic data, previous incidence of hypotension, and severity of injury. As the study progressed, the Safety and Monitoring Committee became concerned about possible increased deaths and serious brain-related adverse events in the treatment arm of the two head injury trials, as well as deaths in the two stroke trials being monitored concurrently. The Selfotel trials were stopped prematurely because of this concern and because an interim efficacy analysis indicated that the likelihood of demonstrating success with the agent if the studies had been completed was almost nil.Conclusions. Subsequently, more complete data analysis revealed no statistically significant difference in mortality rates in all cases between the two treatment groups in the head injury trials. In this report the authors examine the studies in detail and discuss the potential application of the data to future trial designs.

Object. The authors present a quantitative in vivo magnetic resonance (MR) imaging method and propose its use for the accurate assessment of brain water in humans.Methods. With this technique, a pure T1-weighted image of a selected brain slice in a patient is generated, and the image is subsequently converted to a pure water image by means of an equation derived from a tissue relaxation model. The image intensity in the resulting water map directly yields absolute measures of water expressed in grams of water per gram of tissue at a given anatomical location. The method has been validated previously in a series of phantom experiments and in an infusion model of brain edema in cats. In this report, the authors evaluate the method by using samples of tissue harvested from patients who underwent surgery for brain tumor removal and apply the technique to a series of normal volunteers, providing average regional brain water content (fw) values for a range of tissues. Application of the method in pathological conditions such as head trauma, tumor, and hydrocephalus allows quantification of regional or global increases in fw that result from edema.Conclusions. It is now possible to obtain accurate brain water measurements with the anatomical resolution of MR imaging. This permits monitoring of the development and resolution of edema in a variety of clinical circumstances, thus enhancing understanding of the underlying pathophysiological processes.

Object. Recent animal studies demonstrate that excitatory amino acids (EAAs) play a major role in neuronal damage after brain trauma and ischemia. However, the role of EAAs in patients who have suffered severe head injury is not understood. Excess quantities of glutamate in the extracellular space may lead to uncontrolled shifts of sodium, potassium, and calcium, disrupting ionic homeostasis, which may lead to severe cell swelling and cell death. The authors evaluated the role of EEAs in human traumatic brain injury. Methods. In 80 consecutive severely head injured patients, a microdialysis probe was placed into the gray matter along with a ventriculostomy catheter or an intracranial pressure (ICP) monitor for 4 days. Levels of EAAs and structural amino acids were analyzed using high-performance liquid chromatography. Multifactorial analysis of the amino acid pattern was performed and its correlations with clinical parameters and outcome were tested. The levels of EAAs were increased up to 50 times normal in 30% of the patients and were significantly correlated to levels of structural amino acids both in each patient and across the whole group (p < 0.01). Secondary ischemic brain injury and focal contusions were most strongly associated with high EAA levels (27 ± 22 µmol/L). Sustained high ICP and poor outcome were significantly correlated to high levels of EAAs (glutamate > 20 µmol/L; p < 0.01). Conclusions. The release of EAAs is closely linked to the release of structural amino acids and may thus reflect nonspecific development of membrane micropores, rather than presynaptic neuronal vesicular exocytosis. The magnitude of EAA release in patients with focal contusions and ischemic events may be sufficient to exacerbate neuronal damage, and these patients may be the best candidates for treatment with glutamate antagonists in the future.

✓ The contribution of brain edema to brain swelling in cases of traumatic brain injury remains a critical problem. The authors believe that cellular edema, the result of complex neurotoxic events, is the major contributor to brain swelling and that vasogenic edema, secondary to blood-brain barrier compromise, may be overemphasized. The objective of this study, therefore, was to quantify temporal water content changes and document the type of edema that forms during the acute and late stages of edema development following closed head injury (CHI). The measurement of brain water content was based on magnetic resonance imaging—determined values of tissue longitudinal relaxation time (T1-weighted imaging) and their subsequent conversion to percentage of water, whereas the differentiation of edema formation (cellular vs. vasogenic) was based on the measurement of the apparent diffusion coefficient (ADC) by diffusion-weighted imaging. A new impact-acceleration model was used to induce CHI. Thirty-six adult Sprague—Dawley rats were separated into two groups: Group I, control (six animals); and Group II, trauma (30 animals). Fast ADC measurements (localized, single-voxel) were obtained sequentially (every minute) up to 1 hour postinjury. The T1-weighted images, used for water content determination, and the diffusion-weighted images (ADC measurement with conventional diffusion-weighted imaging) were obtained at the end of the 1st hour postinjury and on Days 1, 3, 7, 14, 28, and 42 in animals from the trauma and control groups. In the animals subjected to trauma, the authors found a significant increase in ADC (10 ± 5%) and brain water content (1.3 ± 0.9%) during the first 60 minutes postinjury. This is consistent with an increase in the volume of extracellular fluid and vasogenic edema formation as a result of blood-brain barrier compromise. This transient increase, however, was followed by a continuing decrease in ADC that began 40 to 60 minutes postinjury and reached a minimum value on Days 7 to 14 (10 ± 3% reduction). Because the water content of the brain continued to increase during the first 24 hours postinjury (1.9 ± 0.9%), it is suggested that the decreased ADC indicated cellular edema formation, which started to develop soon after injury and became dominant between 1 and 2 weeks postinjury. The study provides supportive evidence that cellular edema is the major contributor to posttraumatic swelling in diffuse CHI and defines the onset and duration of the increase in cellular volume.

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

✓ The authors present data describing the temporal progress of 786 severely head-injured patients from discharge to 12 months postinjury. Changes in outcome over time are characterized and the effects on these changes of patient age, Glasgow Coma Scale score, pupillary response, and type of injury are investigated. The feasibility of using these factors and the outcome at 3 months postinjury to predict the outcome at 6 months posttrauma is explored via logistic regression analysis. The data indicate that a significant proportion of patients improve continuously during the first 6 months after injury; outcome tends to stabilize thereafter, which suggests that the response at this time may be the appropriate end point for clinical trials in severe head injury. Dichotomized outcomes are predictable with approximately 94% accuracy at 6 months postinjury; therefore, missing outcomes may safely be replaced by the corresponding predicted outcomes. The findings also indicate striking improvement over time in patients who are in a vegetative state at discharge, suggesting that decisions regarding withdrawal of supportive care should be postponed until 6 months after injury in these patients.

There are several infusion methods available to estimate the outflow conductance (Cout) or outflow resistance (Rout=1/Cout) of the CSF system. It has been stated that for unknown reasons, the bolus infusion method estimates a higher C(out) than steady-state infusion methods. The aim of this study was to compare different infusion methods for estimation of Cout.The following 3 different infusion methods were used: the bolus infusion method (Cout bol); the constant flow infusion method, both static (Cout stat) and dynamic (Cout dyn) analyses; and the constant pressure infusion method (Cout cpi). Repeated investigations were performed on an experimental model with well-known characteristics, with and without physiological pressure variations (B-waves, breathing, and so on). All 3 methods were also performed in a randomized order during the same investigation in 20 patients with probable or possible idiopathic normal-pressure hydrocephalus; 6 of these patients had a shunt and 14 did not.Without the presence of physiological pressure variations, the concordance in the experimental model was good between all methods. When they were added, the repeatability was better for the steady-state methods and a significantly higher Cout was found with the bolus method in the region of clinically relevant Cout (p0.05). The visual fit for the bolus infusion was dependent on subjective assessment by the operator. This experimental finding was confirmed by the clinical results, where significant differences were found in the investigations in patients without shunts between Cout of the visual bolus method and Cout stat, Cout dyn, and Cout cpi (4.58, 4.18, and 6.12 μl/[second×kPa], respectively).This study emphasized the necessity for standardization of Cout measurements. An experienced operator could partly compensate for difficulties in correctly estimating the pressure parameters for the bolus infusion method, but for the general user this study suggests a steady-state method for estimating Cout.

✓ Increased brain tissue stiffness following severe traumatic brain injury is an important factor in the development of raised intracranial pressure (ICP). However, the mechanisms involved in brain tissue stiffness are not well understood, particularly the effect of changes in systemic blood pressure. Thus, controversy exists as to the optimum management of blood pressure in severe head injury, and diverging treatment strategies have been proposed. In the present study, the effect of induced alterations in blood pressure on ICP and brain stiffness as indicated by the pressure-volume index (PVI) was studied during 58 tests of autoregulation of cerebral blood flow in 47 comatose head-injured patients. In patients with intact autoregulation mechanisms, lowering the blood pressure caused a steep increase in ICP (from 20 ± 3 to 30 ± 2 mm Hg, mean ± standard error of the mean), while raising blood pressure did not change the ICP. When autoregulation was defective, ICP varied directly with blood pressure. Accordingly, with intact autoregulation, a weak positive correlation between PVI and cerebral perfusion pressure was found; however, with defective autoregulation, the PVI was inversely related to cerebral perfusion pressure. The various blood pressure manipulations did not significantly alter the cerebral metabolic rate of oxygen, irrespective of the status of autoregulation. It is concluded that the changes in ICP can be explained by changes in cerebral blood volume due to cerebral vasoconstriction or dilatation, while the changes in PVI can be largely attributed to alterations in transmural pressure, which may or may not be attenuated by cerebral arteriolar vasoconstriction, depending on the autoregulatory status. The data indicate that a decline in blood pressure should be avoided in head-injured patients, even when baseline blood pressure is high. On the other hand, induced hypertension did not consistently reduce ICP in patients with intact autoregulation and should only be attempted after thorough assessment of the cerebrovascular status and under careful monitoring of its effects.

✓ The Traumatic Coma Data Bank is a collaborative project to prospectively collect data on the clinical course and outcome of severely head-injured patients. The objectives were to further define the natural history of traumatic head injury, to identify prognostic factors, and to provide planning data for future studies. A brief historical development and a description of the organizational structure and methods are given. The characteristics of the cohort at baseline for the 1030 patients enrolled between January, 1984, and September, 1987, are presented, including a summary of the patients' demographic profile, mechanisms of injury, and intracranial diagnoses. The utility and limitations of these data are discussed.

✓ A new classification of head injury based primarily on information gleaned from the initial computerized tomography (CT) scan is described. It utilizes the status of the mesencephalic cisterns, the degree of midline shift in millimeters, and the presence or absence of one or more surgical masses. The term “diffuse head injury” is divided into four subgroups, defined as follows: Diffuse Injury I includes all diffuse head injuries where there is no visible pathology; Diffuse Injury II includes all diffuse injuries in which the cisterns are present, the midline shift is less than 5 mm, and/or there is no high- or mixed-density lesion of more than 25 cc; Diffuse Injury III includes diffuse injuries with swelling where the cisterns are compressed or absent and the midline shift is 0 to 5 mm with no high- or mixed-density lesion of more than 25 cc; and Diffuse Injury IV includes diffuse injuries with a midline shift of more than 5 mm and with no high- or mixed-density lesion of more than 25 cc. There is a direct relationship between these four diagnostic categories and the mortality rate. Patients suffering diffuse injury with no visible pathology (Diffuse Injury I) have the lowest mortality rate (10%), while the mortality rate in patients suffering diffuse injury with a midline shift (Diffuse Injury IV) is greater than 50%. When used in conjunction with the traditional division of intracranial hemorrhages (extradural, subdural, or intracerebral), this categorization allows a much better assessment of the risk of intracranial hypertension and of a fatal or nonfatal outcome. This more accurate categorization of diffuse head injury, based primarily on the result of the initial CT scan, permits specific subsets of patients to be targeted for specific types of therapy. Patients who would appear to be at low risk based on a clinical examination, but who are known from the CT scan diagnosis to be at high risk, can now be identified.

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

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

✓ There is still controversy over whether or not patients should be hyperventilated after traumatic brain injury, and a randomized trial has never been conducted. The theoretical advantages of hyperventilation are cerebral vasoconstriction for intracranial pressure (ICP) control and reversal of brain and cerebrospinal fluid (CSF) acidosis. Possible disadvantages include cerebral vasoconstriction to such an extent that cerebral ischemia ensues, and only a short-lived effect on CSF pH with a loss of HCO3− buffer from CSF. The latter disadvantage might be overcome by the addition of the buffer tromethamine (THAM), which has shown some promise in experimental and clinical use. Accordingly, a trial was performed with patients randomly assigned to receive normal ventilation (PaCO2 35 ± 2 mm Hg (mean ± standard deviation): control group), hyperventilation (PaCO2 25 ± 2 mm Hg: HV group), or hyperventilation plus THAM (PaCO2 25 ± 2 mm Hg: HV + THAM group). Stratification into subgroups of patients with motor scores of 1–3 and 4–5 took place. Outcome was assessed according to the Glasgow Outcome Scale at 3, 6, and 12 months. There were 41 patients in the control group, 36 in the HV group, and 36 in the HV + THAM group. The mean Glasgow Coma Scale score for each group was 5.7 ± 1.7, 5.6 ± 1.7, and 5.9 ± 1.7, respectively; this score and other indicators of severity of injury were not significantly different. A 100% follow-up review was obtained. At 3 and 6 months after injury the number of patients with a favorable outcome (good or moderately disabled) was significantly (p < 0.05) lower in the hyperventilated patients than in the control and HV + THAM groups. This occurred only in patients with a motor score of 4–5. At 12 months posttrauma this difference was not significant (p = 0.13). Biochemical data indicated that hyperventilation could not sustain alkalinization in the CSF, although THAM could. Accordingly, cerebral blood flow (CBF) was lower in the HV + THAM group than in the control and HV groups, but neither CBF nor arteriovenous difference of oxygen data indicated the occurrence of cerebral ischemia in any of the three groups. Although mean ICP could be kept well below 25 mm Hg in all three groups, the course of ICP was most stable in the HV + THAM group. It is concluded that prophylactic hyperventilation is deleterious in head-injured patients with motor scores of 4–5. When sustained hyperventilation becomes necessary for ICP control, its deleterious effect may be overcome by the addition of THAM.

✓ The outcome of severe head injury was prospectively studied in patients enrolled in the Traumatic Coma Data Bank (TCDB) during the 45-month period from January 1, 1984, through September 30, 1987. Data were collected on 1030 consecutive patients admitted with severe head injury (defined as a Glasgow Coma Scale (GCS) score of 8 or less following nonsurgical resuscitation). Of these, 284 either were brain-dead on admission or had a gunshot wound to the brain. Patients in these two groups were excluded, leaving 746 patients available for this analysis. The overall mortality rate for the 746 patients was 36%, determined at 6 months postinjury. As expected, the mortality rate progressively decreased from 76% in patients with a postresuscitation GCS score of 3 to approximately 18% for patients with a GCS score of 6, 7, or 8. Among the patients with nonsurgical lesions (overall mortality rate, 31%), the mortality rate was higher in those having an increased likelihood of elevated intracranial pressure as assessed by a new classification of head injury based on the computerized tomography findings. In the 276 patients undergoing craniotomy, the mortality rate was 39%. Half of the patients with acute subdural hematomas died — a substantial improvement over results in previous reports. Outcome differences between the four TCDB centers were small and were, in part, explicable by differences in patient age and the type and severity of injury. This study describes head injury outcome in four selected head-injury centers. It indicates that a mortality rate of approximately 35% is to be expected in such patients admitted to experienced neurosurgical units.

✓ To better understand the relationship between patient age and clinical outcome following traumatic coma, the data for 661 patients, aged 15 years or older at the time of receiving a nonpenetrating head injury, were analyzed. All patients were prospectively followed and the information was entered into the Traumatic Coma Data Bank. This information was statistically analyzed to determine trends and interactions between patient age and other prognostic indicators. Older patients had higher rates of mortality overall; vegetative survival was seen in 4.8% to 8.0% of patients and did not exhibit a trend related to age. Injury severity, as assessed by motor score or Glasgow Coma Scale score, did not significantly differ according to age. The injury mechanism was age-related, with a greater frequency of falls and pedestrian accidents in older patients. Multiple injury was less frequent in older patients. Medical complications and systemic trauma were considered to be the primary cause of death in less than 25% of patients, with the exception of those between 45 and 55 years of age. When the data were studied in univariate fashion, no factor was identified that accounts for the adverse effect of age on head-injury outcome. Multivariate logistic regression, performed to assess the combined effect of multiple variables on outcome, failed to eliminate patient age as an independent predictor. Based upon this analysis, it is likely that the effect of age on outcome following head injury is dependent upon an alteration in the pathophysiological response of the aging central nervous system to severe trauma and not an increased incidence of non-neurological complications or other clinical parameters.

✓ Prediction tree techniques are employed in the analysis of data from 555 patients admitted to the Medical College of Virginia hospitals with severe head injuries. Twenty-three prognostic indicators are examined to predict the distribution of 12-month outcomes among the five Glasgow Outcome Scale categories. A tree diagram, illustrating the prognostic pattern, provides critical threshold levels that split the patients into subgroups with varying degrees of risk. It is a visually useful way to look at the prognosis of head-injured patients. In previous analyses addressing this prediction problem, the same set of prognostic factors (age, motor score, and pupillary response) was used for all patients. These approaches might be considered inflexible because more informative prediction may be achieved by somewhat different combinations of factors for different patients. Tree analysis reveals that the pattern of important prognostic factors differs among various patient subgroups, although the three previously mentioned factors are still of primary importance. For example, it is noted that information concerning intracerebral lesions is useful in predicting outcome for certain patients. The overall predictive accuracy of the tree technique for these data is 77.7%, which is somewhat higher than that obtained via standard prediction methods. The predictive accuracy is highest among patients who have a good recovery or die; it is lower for patients having intermediate outcomes.

✓ The metabolic brain acidosis after trauma has been thought to be harmful and to contribute to neurological deterioration. Amelioration of the brain acidosis either by systemic buffering agents or by hyperventilation has been proposed as a method of treatment. The objective of this study was to explore with magnetic resonance (MR) spectroscopy the metabolic changes in brain that occur with the use of hyperventilation, THAM (tromethamine; tris[hydroxymethyl]aminomethane), and a combination (THAM and hyperventilation) therapy in experimental fluid-percussion injury. Brain lactate, brain pH, inorganic phosphate (Pi), and adenosine triphosphate levels were measured by 1H and 31P MR spectroscopy. Arterial and cerebrovenous lactate and water content in brain tissue was determined in 29 cats using the specific gravimetric technique. Following injury, the phosphocreatine (PCr)/Pi ratio, which is an index of cerebral energy depletion, decreased to 76% in four untreated animals, to 79% in 11 THAM-treated animals, to 68% in seven animals receiving hyperventilation, and to 66% in seven animals with combination THAM and hyperventilation therapy. The PCr/Pi ratio returned to a normal level in 8 hours in animals treated with THAM and THAM in combination with hyperventilation. The brain lactate index increased to 157% in the hyperventilation group after trauma. In cats receiving THAM plus hyperventilation, the brain lactate index was reduced to 142%, while the minimum rise of 126% was associated with treatment of THAM alone. In the THAM-treatment and combination-treatment groups, the water content of the white and gray matter was significantly decreased compared with that in untreated cat brains. Prolonged hyperventilation provided relative ischemia in brain tissue and promoted more production of brain lactate, no recovery of the PCr/Pi ratio, and no decrease in brain edema. On the other hand, administration of THAM decreased production of brain lactate and brain edema and promoted the recovery of cerebral energy dysfunction. It was found that THAM ameliorates the deleterious effects of hyperventilation by minimizing energy disturbance and that it also decreases brain edema. The authors conclude that THAM may be effective in reducing brain tissue acidosis and helpful as a metabolic stabilizing agent following severe head injury.

Object The goal of this study was to demonstrate the posttraumatic neurochemical damage in normal-appearing brain and to assess mitochondrial dysfunction by measuring N-acetylaspartate (NAA) levels in patients with severe head injuries, using proton (1H) magnetic resonance (MR) spectroscopy. Methods Semiquantitative analysis of NAA relative to creatine-containing compounds (Cr) and choline (Cho) was carried out from proton spectra obtained by means of chemical shift (CS) imaging and single-voxel (SV) methods in 25 patients with severe traumatic brain injuries (TBIs) (Glasgow Coma Scale scores ≤ 8) using a 1.5-tesla MR unit. Proton MR spectroscopy was also performed in 5 healthy volunteers (controls). Results The SV studies in patients with diffuse TBI showed partial reduction of NAA/Cho and NAA/Cr ratios within the first 10 days after injury (means ± standard deviations 1.59 ± 0.46 and 1.44 ± 0.21, respectively, in the patients compared with 2.08 ± 0.26 and 2.04 ± 0.31, respectively, in the controls; nonsignificant difference). The ratios gradually declined in all patients as time from injury increased (mean minimum values NAA/Cho 1.05 ± 0.44 and NAA/Cr 1.05 ± 0.30, p < 0.03 and p < 0.02, respectively). This reduction was greater in patients with less favorable outcomes. In patients with focal injuries, the periphery of the lesions revealed identical trends of NAA/Cho and NAA/Cr decrease. These reductions correlated with outcome at 6 months (p < 0.01). Assessment with multivoxel methods (CS imaging) demonstrated that, in diffuse injury, NAA levels declined uniformly throughout the brain. At 40 days postinjury, initially low NAA/Cho levels had recovered to near baseline in patients who had good outcomes, whereas no recovery was evident in patients with poor outcomes (p < 0.01). Conclusions Using 1H-MR spectroscopy, it is possible to detect the posttraumatic neurochemical damage of the injured brain when conventional neuroimaging techniques reveal no abnormality. Reduction of NAA levels is a dynamic process, evolving over time, decreasing and remaining low throughout the involved tissue in patients with poor outcomes. Recovery of NAA levels in patients with favorable outcomes suggests marginal mitochondrial impairment and possible resynthesis from vital neurons.

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

Excessive activity of excitatory amino acids released after head trauma has been demonstrated to contribute to progressive injury in animal models and human studies. Several pharmacological agents that act as antagonists to the glutamate receptor have shown promise in limiting this progression. The efficacy of the N-methyl-D-aspartate receptor antagonist Selfotel (CGS 19755) was evaluated in two parallel studies of severely head injured patients, defined as patients with post resuscitation Glasgow Coma Scale scores of 4 to 8.A total of 693 patients were prospectively enrolled in two multicenter double-blind studies. Comparison between the treatment groups showed no significant difference with regard to demographic data, previous incidence of hypotension, and severity of injury. As the study progressed, the Safety and Monitoring Committee became concerned about possible increased deaths and serious brain-related adverse events in the treatment arm of the two head injury trials, as well as deaths in the two stroke trials being monitored concurrently. The Selfotel trials were stopped prematurely because of this concern and because an interim efficacy analysis indicated that the likelihood of demonstrating success with the agent if the studies had been completed was almost nil.Subsequently, more complete data analysis revealed no statistically significant difference in mortality rates in all cases between the two treatment groups in the head injury trials. In this report the authors examine the studies in detail and discuss the potential application of the data to future trial designs.

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

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

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

✓ Appropriate management of intracranial pressure (ICP) in severely head injured patients depends in part on the cerebral vessel reactivity to PCO2; loss of CO2 reactivity has been associated with poor outcome. This study describes a new method for evaluating vascular reactivity in head-injured patients by determining the sensitivity of ICP change to alterations in PCO2. This method was combined with measurements of the pressure volume index (PVI), which allowed calculation of blood volume change necessary to alter ICP. The objective of this study was to investigate the ICP response and the blood volume change corresponding to alterations in PCO2 and to examine the correlation of responsivity and outcome as measured on the Glasgow Outcome Scale. The PVI and ICP at different end-tidal PCO2 levels produced by mild hypo- and hyperventilation were obtained in 49 patients with Glasgow Coma Scale scores of less than 8 and over a wide range of PCO2 (25 to 40 mm Hg) in eight patients. Given the assumption that the PVI remained constant during alteration of PaCO2, the estimated blood volume change per torr change of PCO2 was calculated by the following equation: BVR = PVI × Δlog(ICP)/ΔPCO2, where BVR = blood volume reactivity. The data in this study showed that PVI remained stable with changes in PCO2, thus validating the assumption used in the blood volume estimates. Moreover, the response of ICP to PCO2 alterations followed an exponential curve that could be described in terms of the responsivity indices to capnic stimuli. It was found that responsivity to hypocapnia was reduced by 50% compared to responsivity to hypercapnia measured within 24 hours of injury (p < 0.01). The sensitivity of ICP to estimated blood volume changes in patients with a PVI of less than 15 ml was extremely high with only 4 ml of blood required to raise ICP by 10 mm Hg. The authors conclude from these data that, following traumatic injury, the resistance vessels are in a state of persistent vasoconstriction, possibly due to vasospasm or compression. Furthermore, BVR correlates with outcome on the Glasgow Coma Scale, indicating that assessment of cerebrovascular response within the first 24 hours of injury may be of prognostic value.

✓ This report describes the development of an experimental head injury model capable of producing diffuse brain injury in the rodent. A total of 161 anesthetized adult rats were injured utilizing a simple weight-drop device consisting of a segmented brass weight free-falling through a Plexiglas guide tube. Skull fracture was prevented by cementing a small stainless-steel disc on the calvaria. Two groups of rats were tested: Group 1, consisting of 54 rats, to establish fracture threshold; and Group 2, consisting of 107 animals, to determine the primary cause of death at severe injury levels. Data from Group 1 animals showed that a 450-gm weight falling from a 2-m height (0.9 kg-m) resulted in a mortality rate of 44% with a low incidence (12.5%) of skull fracture. Impact was followed by apnea, convulsions, and moderate hypertension. The surviving rats developed decortication flexion deformity of the forelimbs, with behavioral depression and loss of muscle tone. Data from Group 2 animals suggested that the cause of death was due to central respiratory depression; the mortality rate decreased markedly in animals mechanically ventilated during the impact. Analysis of mathematical models showed that this mass-height combination resulted in a brain acceleration of 900 G and a brain compression gradient of 0.28 mm. It is concluded that this simple model is capable of producing a graded brain injury in the rodent without a massive hypertensive surge or excessive brain-stem damage.

✓ A new model producing diffuse brain injury, without focal brain lesions, has been developed in rats. This has been achieved by allowing a weight of 450 gm to fall onto a metallic disc fixed to the intact skull of the animal which is supported by a foam bed. Two levels of injury were examined by adjusting the height of the falling weight to either 1 m or 2 m. Two groups of animals were studied. Group 1 animals were separated into three subgroups: 10 received a 1-m weight drop, 58 received a 2-m weight drop, and 13 served as controls; all were allowed to breathe spontaneously. Group 2 animals were separated into the same subgroups: four received a 1-m weight drop, six received a 2-m weight drop, and four served as controls; all of these were mechanically ventilated during the procedure. In Group 1, morphological studies using light and electron microscopy were performed at 1, 6, 24, or 72 hours, or 10 days after insult; all Group 2 rats were studied at 24 hours after injury.Results from Group 1 animals showed that no mortality occurred with the 1-m level injury, while 59% mortality was seen with the 2-m level injury. On the other hand, no mortality occurred in Group 2 animals regardless of the level of trauma induced. However, the morphological changes observed in both groups were similar. Gross pathological examination did not reveal any supratentorial focal brain lesion regardless of the severity of the trauma. Petechial hemorrhages were noticed in the brain stem at the 2-m level injury. Microscopically, the model produced a graded widespread injury of the neurons, axons, and microvasculature. Neuronal injury was mainly observed bilaterally in the cerebral cortex. Brain edema, in the form of pericapillary astrocytic swelling, was also noted in these areas of the cerebral cortex and in the brain stem. Most importantly, the trauma resulted in a massive diffuse axonal injury that primarily involved the corpus callosum, internal capsule, optic tracts, cerebral and cerebellar peduncles, and the long tracts in the brain stem. It is concluded that this model would be suitable for studying neuronal, axonal, and vascular changes associated with diffuse brain injury.

✓ Although mortality and morbidity rates from head injury have been reduced substantially by improved prehospital interventions, intensive care, and aggressive management of intracranial pressure (ICP), successful treatment of the primary brain injury has been elusive. In experimental models, tromethamine (THAM) has been effective in treating head injury; this drug acts by entering the cerebrospinal fluid compartment, reducing cerebral acidosis and ICP, and reversing the adverse effects of prophylactic hyperventilation on early recovery. In this randomized prospective clinical trial, THAM was studied to determine if it had beneficial effects in the early management of severe head injuries and if the adverse effects of hyperventilation could be prevented. A total of 149 patients with severe head injury (Glasgow Coma Scale scores of ≤ 8) were randomly assigned to either a control or a THAM group. Both groups of patients matched in terms of clinical parameters, including age, sex, number of surgical mass lesions, number in each Glasgow Coma Scale stratum, and first ICP measurement. All patients were treated by a standard management protocol, intubated, mechanically ventilated, and maintained in the pCO2 range of 32 to 35 mm Hg for 5 days. Tromethamine was administered as a 0.3-M solution in an initial loading dose (body weight × blood acidity deficit, average 4.27 cc/kg/hr) given over 2 hours, followed by a constant infusion of 1 ml/kg/hr for 5 days. Outcome was measured at 3, 6, and 12 months postinjury. Although analysis indicated no significant difference in outcome between these two groups at 3 months, 6 months, and 1 year, there was a difference regarding ICP. The time that ICP was above 20 mm Hg in the first 48 hours postinjury was less in patients treated with THAM (p < 0.05). Also, the number of patients requiring barbiturate coma was significantly less in the THAM group (5.48% vs. 18.4%, p < 0.05). The authors conclude that THAM ameliorates the deleterious effect of prolonged hyperventilation, may be beneficial in ICP control, and warrants further study as to the dosage and timing of administration.

✓ In order to define the role of intracranial and extracranial complications in determining outcome from severe head injury, 734 patients from the Traumatic Coma Data Bank were analyzed. Nine classes of intracranial and 13 classes of extracranial complications occurring within the first 14 days after admission were analyzed, while controlling for age, admission Glasgow Coma Scale motor score, early hypoxia or hypotension, and severe extracranial trauma. Outcome for survivors was based on the last recorded Glasgow Outcome Scale score, obtained a median of 521 days after injury. Intracranial complications did not significantly alter outcome for the study group. Of the extracranial complications, pulmonary, cardiovascular, coagulation, and electrolyte disorders occurred most frequently at 2 to 4 days. Infections developed later, peaking at 5 to 11 days. Gastrointestinal, renal, and hepatic complications followed no specific time course. Electrolyte abnormalities were the most frequent occurrence (59% of patients) but did not alter outcome. Pulmonary infections (41%), shock (29%, systemic blood pressure ≤ 90 mm Hg for 30 minutes or more), coagulopathy (19%), and septicemia (10%) were significant independent predictors of an unfavorable outcome. Backward-elimination, stepwise logistic regression modeling indicated that the estimated reduction of unfavorable outcome was 2.9% for the elimination of pneumonia, 3.1% for coagulation disturbances, 1.5% for septicemia, and 9.3% for shock. These data suggest that extracranial complications are highly influential in determining the outcome from severe head injury and that significant improvements in outcome in a sizeable proportion of patients could be accomplished by improving the ability to prevent or reverse pneumonia, hypotension, coagulopathy, and sepsis.

✓ The transit routes of fluid and particulate matter through brain tissue remain unclear. The object of this study was to examine the movement of macromolecules through brain tissue to further clarify the clearance pathways of edema proteins as they migrate toward the cortex. For this purpose, albumin solution (20 µl rat albumin diluted to 65 mg/ml with mock cerebrospinal fluid (CSF)) was intracerebrally infused into the caudate putamen, and the migration through brain tissue as well as through the ultrastructure of the cortical surfaces was explored using an immunocytochemical technique. The authors observed immunoreactive product on the glial limitans and pial lining as well as in the extracellular space of the cortical neuropil at 24 hours postinfusion, confirming that the protein had reached the cortical surface. To confirm the efflux of macromolecules into the subarachnoid CSF, 71,200 D fluorescein isothiocyanatedextran (FITC-dextran 71,200) was infused; cortical surfaces of brains removed en bloc as well as coronal sections were macroscopically observed under ultraviolet illumination at 15 minutes and 24 hours postinfusion. It was observed that infused FITC-dextran 71,200 mainly localized in the cortical white matter and caudate putamen of the infusion site at 15 minutes postinfusion and by 24 hours was distributed in the entire cortex of the infused hemisphere. However, the dynamics of lower-molecular-weight substances was completely different. The spatial distribution of FITC-dextran 4400 diverged upward toward the cortical surface and spread more extensively than FITC-dextran 71,200. These observations were consistent with a diffusion process as the spread of the tracer was dependent upon molecular size. These studies provide compelling evidence that a process other than bulk flow was involved in the spread of macromolecules through the extracellular space of the normal cortical neuropil to sink into the subarachnoid space. It was concluded that the CSF pathway via the extracellular space of the cortical neuropil is a primary route for clearance of extracellular edema proteins to the subarachnoid space and that diffusion is involved in this process.

✓ In this study, data were prospectively collected from 753 patients (111 children and 642 adults) with severe head injury and examined for evidence of diffuse brain swelling and its association with outcome. Diffuse brain swelling occurred approximately twice as often in children (aged 16 years or younger) as in adults. A high mortality rate (53%) was found in these children, which was three times that of the children without diffuse brain swelling (16%). Adults with diffuse brain swelling had a mortality rate (46%) similar to that of children, but only slightly higher than that for adults without diffuse brain swelling (39%). When the diagnosis of diffuse brain swelling was expanded to include patients with diffuse brain swelling plus small parenchymal hemorrhages (< 15 cu cm), these mortality rates were virtually unchanged.

✓ Leukotrienes are powerful metabolites of arachidonic acid which are known to increase the permeability of peripheral blood vessels. These substances are found in brain tissue in association with cerebral ischemia, and in brain tumors. Therefore, it has been proposed that leukotrienes have a mediator function in brain edema. This hypothesis was subjected to further experimental analysis in this study, in which the authors investigated whether: 1) superfusion of the exposed brain surface with leukotrienes increases the permeability of extraparenchymal blood vessels in vivo; 2) intraparenchymal infusion of leukotrienes induces brain edema; and 3) pharmacological inhibition of leukotriene formation by BW755C, an inhibitor of leukotriene synthesis, reduces formation of brain edema from a standardized traumatic insult. The pial vessels of the parietal cortex of cats were examined by fluorescence microscopy during cerebral superfusion with the leukotrienes C4 (LTC4), D4 (LTD4), or E4 (LTE4) by using an open cranial window preparation. Intravenous Na+-fluorescein served as an in vivo blood-brain barrier (BBB) indicator. Superfusion of the pia with leukotrienes (up to 2 µM) did not open the barrier to fluorescein, but was associated with a significant constriction (up to 25%) of arterial and venous vessels. In experiments with slow infusion of leukotriene B4 (LTB4) or LTC4 into the white matter of feline brain, the tissue water content was subsequently determined in serial brain slices using the specific gravity method. Tissue water profiles obtained after a 15- µM infusion of either LTB4 or LTC4 were virtually identical with those of control animals infused with mock cerebrospinal fluid. Thus, neither LTB4 nor LTC4 led to an augmentation of infusion-induced brain edema. In a final series, a cold lesion of the left parietal cortex was induced in rabbits. Twenty-four hours later, swelling of the exposed hemisphere was quantified by gravimetrical comparison of its weight with that of the contralateral nontraumatized hemisphere. Eight animals received BW755C intravenously prior to and after trauma to inhibit formation of leukotrienes. Seven rabbits were infused with an equivalent volume of saline as a control study. The resulting hemispheric swelling was 7.7% ± 0.6% (mean ± standard error of the mean) 24 hours later in animals receiving BW755C and 7.8% ± 1.2% in the control group, indicating that inhibition of leukotrienes was ineffective in preventing formation of vasogenic brain edema. The findings demonstrate that leukotrienes administered to the brain in concentrations occurring under pathological conditions do not open the BBB nor do they induce brain edema. Moreover, formation of brain edema from a standard insult was not therapeutically influenced by inhibition of leukotriene synthesis. Thus, the current findings taken together do not support a role of leukotrienes as mediators in brain edema.

✓ The degree of brain-stem dysfunction associated with high-level fluid-percussion injury (3.0 to 3.8 atm) was investigated in anesthetized cats. Measurements were made of the animals' intracranial pressure (ICP), pressure-volume index (PVI), far-field brain-stem auditory evoked responses (BAER's), and cerebral blood flow (CBF). The animals were classified into two groups based on the severity of neuropathological damage to the brain stem after trauma: Group 1 had mild intraparenchymal and subarachnoid hemorrhages and Group 2 had severe intraparenchymal and subarachnoid hemorrhages. The ICP values in Group 1 were insignificantly lower than those in Group 2, while the PVI values in Group 2 were clearly lower (p < 0.05). Immediately after the injury, peaks II, III, and IV of the BAER's demonstrated a transitory and marked suppression. One Group 1 and two Group 2 animals showed the disappearance of peak V. In Group 1, the latencies of peak II, III, and IV gradually increased until 60 to 150 minutes postinjury, then returned to 95% of baseline value at 8 hours; however, the animals in Group 2 showed poor recovery of latencies. Two hours after brain injury, the CBF decreased to 40% of the preinjury measurement in both groups (p < 0.001). In contrast to Group 2, the CBF in Group 1 returned to 86.8% of the preinjury measurement by 8 hours following the injury. Changes in PVI, BAER, and CBF correlated well with the degree of brain-stem injury following severe head injury'- These data indicate that high-level fluid-percussion injury (> 3.0 atm) is predominantly a model of brain-stem injury.

✓ In this prospective multicenter study, the authors have examined data derived from the initial computerized tomography (CT) scans of 753 patients with severe head injury. When the CT findings were related to abnormal intracranial pressure and to death, the most important characteristics of the scans were: midline shift; compression or obliteration of the mesencephalic cisterns; and the presence of subarachnoid blood. Diffuse hemispheric swelling was also found to be associated with an early episode of either hypoxia or hypotension.

✓ The outcome 1 year after they had sustained a severe head injury was investigated in patients who were admitted to the neurosurgery service at one of four centers participating in the Traumatic Coma Data Bank (TCDB). Of 300 eligible survivors, the quality of recovery 1 year after injury was assessed by at least the Glasgow Outcome Scale (GOS) in 263 patients (87%), whereas complete neuropsychological assessment was performed in 127 (42%) of the eligible survivors. The capacity of the patients to undergo neuropsychological testing 1 year after injury was a criterion of recovery as reflected by a significant relationship to neurological indices of acute injury and the GOS score at the time of hospital discharge. The neurobehavioral data at 1 year after injury were generally comparable across the four samples of patients and characterized by impairment of memory and slowed information processing. In contrast, language and visuospatial ability recovered to within the normal range. The lowest postresuscitation Glasgow Coma Scale (GCS) score and pupillary reactivity were predictive of the 1-year GOS score and neuropsychological performance. The lowest GCS score was especially predictive of neuropsychological performance 1 year postinjury in patients who had at least one nonreactive pupil following resuscitation. Notwithstanding limitations related to the scope of the TCDB and attrition in follow-up material, the results indicate a characteristic pattern of neurobehavioral recovery from severe head injury and encourage the use of neurobehavioral outcome measurements in clinical trials to evaluate interventions for head-injured patients.