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Background: Progesterone has been associated with robust positive effects in animal models of traumatic brain injury (TBI) and with clinical benefits in two phase 2 randomized, controlled trials. We investigated the efficacy and safety of progesterone in a large, prospective, phase 3 randomized clinical trial., Methods: We conducted a multinational placebo-controlled trial, in which 1195 patients, 16 to 70 years of age, with severe TBI (Glasgow Coma Scale score, ≤8 [on a scale of 3 to 15, with lower scores indicating a reduced level of consciousness] and at least one reactive pupil) were randomly assigned to receive progesterone or placebo. Dosing began within 8 hours after injury and continued for 120 hours. The primary efficacy end point was the Glasgow Outcome Scale score at 6 months after the injury., Results: Proportional-odds analysis with covariate adjustment showed no treatment effect of progesterone as compared with placebo (odds ratio, 0.96; confidence interval, 0.77 to 1.18). The proportion of patients with a favorable outcome on the Glasgow Outcome Scale (good recovery or moderate disability) was 50.4% with progesterone, as compared with 50.5% with placebo. Mortality was similar in the two groups. No relevant safety differences were noted between progesterone and placebo., Conclusions: Primary and secondary efficacy analyses showed no clinical benefit of progesterone in patients with severe TBI. These data stand in contrast to the robust preclinical data and results of early single-center trials that provided the impetus to initiate phase 3 trials. (Funded by BHR Pharma; SYNAPSE ClinicalTrials.gov number, NCT01143064.).

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: 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 micromol/L). Sustained high ICP and poor outcome were significantly correlated to high levels of EAAs (glutamate > 20 micromol/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.

Background: The ideal method for monitoring the acutely injured brain would measure substrate delivery and brain function continuously, quantitatively, and sensitively. We have tested the hypothesis that brain PO2, pCO2, and pH, which can now be measured continuously using a single sensor, are valid indicators of regional cerebral blood flow (CBF) and oxidative metabolism, by measuring its product, brain pCO2., Methods: Twenty-five patients (Glasgow Coma Score < or = 8) were studied. A Clark electrode, combined with a fiber optic system (Paratrend 7, Biomedical Sensors, Malvern, PA) was used to measure intraparenchymal brain PO2, pCO2, and pH. Data were averaged over a 1-h period before and after CBF studies. Regional CBF was measured around the probe, using stable xenon computed tomography. Regression analyses and Spearman Rank tests were used for data analysis., Results: Regional CBF and mean brain PO2 were strongly correlated (r=0.74, p=0.0001). CBF values < 18 mL/100 g/min were all accompanied by brain PO2 < or = 26 mm Hg. The four patients with a brain PO2 < 18 mm Hg died. Brain pCO2 and pH, however, were not correlated with CBF (r=0.36, p=0.24 and r=0.30, p=0.43, respectively)., Conclusions: Until recently, substrate supply to the severely injured brain could only be intermittently estimated by measuring CBF. The excellent intra-regional correlation between CBF and brain pO2, suggests that this method does allow continuous monitoring of true substrate delivery, and offers the prospect that measures to increase O2 delivery (e.g., increasing CBF, CPP, perfluorocarbons etc.) can be reliably tested by brain PO2 monitoring.

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 < or = 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 three-dimensional 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 3 (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 investigators undertook a retrospective analysis of ventriculostomy infections to evaluate their relationship to monitoring duration and prophylactic catheter exchange. In 1984, the results of an epidemiological study of ventriculostomy-related infection were published. One of the conclusions of the paper was that the incidence of ventriculostomy-related infections rose after 5 days of monitoring. This led to the recommendation that catheters be prophylactically changed at 5-day intervals if prolonged monitoring was required. A recent randomized prospective study on central venous catheters showed no reduction in infection with prophylactic catheter exchanges. This has led the authors to reexamine their experience with ventriculostomy infections. Data on 584 severely head injured patients with ventriculostomies were prospectively collected in two data banks, The Traumatic Coma Data Bank and The Medical College of Virginia Neurocore Data Bank. These data were retrospectively analyzed for factors associated with ventriculostomy related infections. It was found that there is a relationship of ventriculitis to monitoring duration but it is not simple or linear. There is a rising risk of infection over the first 10 days, but infection then becomes very unlikely despite a population that continues to be at risk. Patients in whom catheters were replaced prior to 5 days did not have a lower infection rate than those whose catheters were exchanged at more than 5-day intervals. Based on these data, it is recommended that ventriculostomy catheters for intracranial pressure monitoring be removed as quickly as possible, and in circumstances in which prolonged monitoring is required, there appears to be no benefit from catheter exchange.

Objective: To determine the effect of continuous rotational therapy on the dynamics of intracranial pressure., Design: A controlled, prospective evaluation of intracranial pressure during continuous rotation therapy., Setting: Neuroscience intensive care unit in a university hospital., Patients: A total of 58 severely brain-injured patients (Glasgow Coma Score of < or = 9) ranging in age from 14 to 81 yrs., Interventions: All patients had intraventricular catheters placed to continuously monitor intracranial pressure and all patients were placed on continuous rotational therapy once stabilized., Measurements and Main Results: Intracranial pressure data were measured in each patient during nonrotation and these data were compared with intracranial pressure data during rotation, thus allowing each patient to serve as their own control. In addition, the intracranial pressure during rotation (40 degrees from center) was further analyzed to determine the effect of angulation on the intracranial pressure. Analysis of computer-recorded intracranial pressure data showed no significant difference in intracranial pressure measured during rotation and nonrotation over the first 5 days postinjury. Minimal differences in intracranial pressure (< 1 to 2 mm Hg) were noted in right/center/left positions. It was also determined that intracranial pressure increased up to 6.5 mm Hg (p = .12) in patients who presented with a unilateral lesion on admission computed tomography when they rotated to the side of the lesion. However, these fluctuations did not promote additional intracranial pressure management., Conclusions: We conclude that the systemic benefits known to be derived from the use of continuous rotation therapy in the severely head-injured patient can be sustained without any deleterious effects on the intracranial pressure.

The care of the patient begins at the moment of injury, and thus, prehospital care is crucial in the overall treatment of the patient. This article discusses the basic principals involved in prehospital care, including the importance of timing, emergency medical training, and resuscitation at the scene. It discusses how the patient is evaluated, the types of transportation available, and the appropriate destination for the patient depending on his or her injuries.

In the belief that secondary cerebral compression, hypoxia, and ischemia materially influence the outcome from severe head injury, a standardized protocol was followed in 160 patients, with emphasis on early diagnosis and evacuation of intracranial mass lesions by craniotomy, artificial ventilation, control of increased intracranial pressure, and aggressive medical therapy. Of these patients, 36% made a good recovery, 24% were moderately disabled, 8% were severely disabled, 2% were vegetative, and 30% died. The mortality rate compares favorably with outcomes in similar patients reported from other centers and there has been no increase in the numbers of severely disabled or vegetative patients. It is proposed that vigorous surgical and medical therapy, by preventing or reversing secondary cerebral insults, enables some patients who would have died to make a good recovery without increasing the proportion of severely disabled patients.

The objectives of the present study were to evaluate the relationship between the fractional amplitudes of the EEG derived from power spectral analysis (PSA) of the electroencephalogram (EEG) and depth of coma measured clinically with the Glasgow Coma Score, and to assess the accuracy of PSA in predicting long-term outcome. Thirty-two patients rendered unconscious by blunt head injury (mean (GCS = 7) had intermittent EEG recordings daily from 1-10 days post injury. There was a significant correlation between fractional amplitude of the EEG and the GCS. The rate and magnitude of change in the EEG and GCS were also correlated. There were significant differences in PSA parameters between improved and deteriorated patient groups at the termination of monitoring (p = .02) and in the change of PSA parameters over time (p = .02). Using linear discriminant analysis of PSA parameters, the accuracy of outcome prognostication based on the six month outcome was approximately 75%. Accurate classification of outcome was possible in a number of patients in whom there was little or no change in the GCS during the period of monitoring.

To discover which factors contributed to recovery after surgical intracranial decompression, we reviewed the records of 82 consecutive comatose patients with traumatic acute subdural hematoma (ASDH) who were treated in a single center under a uniform protocol. The delay from injury to operation was the factor of greatest therapeutic importance. Patients who underwent surgery within the first four hours had a 30 per cent mortality rate, as compared with 90 percent in those who had surgery after four hours (P less than 0.0001). Other important prognostic variables included results of the initial neurologic examination, sex, multimodality-evoked potentials, and postoperative intracranial pressure (ICP). If all patients with traumatic ASDH were taken directly to hospitals equipped to diagnose and remove the hematoma within four hours of injury, mortality rates could be reduced considerably.

Measurements of intracranial pressure (ICP) were begun within hours of injury in 160 patients with severe brain trauma, and continued in the intensive care unit. Some degree of increased ICP (greater than 10 mm Hg) was present on admission in most cases (82%), and in all but two of the 62 patients with intracranial mass lesions requiring surgical decompression; ICP was over 20 mm Hg on admission in 44% of cases, and over 40 mm Hg in 10%. In patients with mass lesions only very high ICP (greater than 40 mm Hg) on admission was significantly associated with a poor neurological picture and outcome from injury, while in patients with diffuse brain injury any increase in ICP above 10 mm Hg was associated with a poorer neurological status and a worse outcome. Despite intensive measures aimed at prevention of intracranial hypertension, ICP rose over 20 mm Hg during the monitoring period in 64 of the 160 patients (40%). Postoperative increases in ICP over 20 mm Hg (mean) were seen in 52% of the patients who had had intracranial masses evacuated, and could not be controlled by therapy in half of these cases. Even in patients without mass lesions, ICP rose above 20 mm Hg in a third of the cases, despite artificial ventilation and steroid therapy. Of the 48 patients who died, severe intracranial hypertension was the primary cause of death in nearly half and even moderately increased ICP (greater than 20 mm Hg) was associated with higher morbidity in patients with mass lesions and those with diffuse brain injury. Measurement of ICP should be included in management of patients with severe head injury.

There has been a rapid expansion of knowledge in the field of nutrition and metabolism with regard to the general surgical patient. However, only recently has there been greater appreciation of the benefits of adequate nutrition and appropriate metabolic care of the neurosurgical patient. In this review, the authors attempt to outline 1) the metabolic response to stress in general, and how it applies to the neurosurgical patient; 2) how best to provide adequate nutritional support for the neurosurgical patient; 3) the effects of nutrition on neurotransmitters; and 4) the effect of diet and nutrition on patients with malignant brain tumors.

A series of 100 patients 19 years of age or younger is presented. Age, mechanism of injury, Glasgow coma score (GCS), diagnosis, outcome, and other factors are analysed. Ninety-four per cent of the patients had ICP monitoring, 68% had a good or moderately disabled outcome; that is, they were functioning. There was a 24% mortality. There was a 25% incidence of mass lesion and these patients did worse. The major cause of death was neurologic injury.

Hypophosphatemia occurs in a variety of clinical conditions. It develops in parallel with phosphate depletion from body losses or more commonly as a sequel to the redistribution of phosphate from the extracellular to the intracellular compartment. Hypophosphatemia is a multisystem disturbance capable of involving the neurological, immunological, and muscular systems, among others. In this report, we describe five patients with severe head injury who developed marked hypophosphatemia (less than 1 mg/dl) within 24 hours of hospitalization. This fall in serum phosphate coincided with the induction of respiratory alkalosis consequent to mechanical ventilation. In four of the five patients, as acid-base parameters returned to normal, serum phosphate values rose, in all instances reaching values greater than 2.5 mg/dl. Urinary phosphorus excretion, ordinarily negligible after hypophosphatemia induced by hypocapnia, was still present in Cases 1 and 4 (greater than 600 mg/24 hours). This is unexplained by any of the known hormonal or fluid alterations that accompany head injury. These five patients developed severe, yet transient, hypophosphatemia that resolved upon correction of hyperventilation-induced acid-base abnormalities. We discuss the pathophysiology of this entity and the implications for the head trauma patient.

The authors studied intracranial pressure (ICP) and intracranial compliance as defined by the pressure-volume index (PVI) in 34 severely head-injured patients with a Glasgow Coma Scale score of 8 or less. The objective of the research was to determine if there was a correlation between the pressure-volume status and subsequent increase in ICP. The PVI and ICP measurements were obtained serially, and the temporal course of the pressure-volume status and ICP was determined during the 5-day period following injury. Aggressiveness of ICP was quantified by a therapy intensity level scale. A clear relationship between the PVI measured soon after injury and subsequent development of ICP emerged. Following mechanical trauma the PVI is reduced, and the degree of reduction and extent of biomechanical recovery are closely related to outcome and development of raised ICP.

Data from 523 patients admitted to the Medical College of Virginia with severe head injury and known 6-month outcomes were analyzed in order to determine the optimal combination of early-available prognostic factors. Twenty-one prognostic indicators noted in the emergency room at admission were used to predict outcomes into four categories: good, moderately disabled, severely disabled, or vegetative/dead. A combination of the patient's age (in years), the best motor response (graded in the usual six-point scale), and pupillary response (in both eyes) was found to be the most accurate indicator. The model correctly predicted outcome into one of the four outcome categories in 78% of cases ("specifically accurate predictions"). If predictions into an outcome category adjacent to the actual outcome were accepted, this model was accurate in 90% of cases ("grossly accurate predictions"). A set of three simple graphs based on this model can be used for rapid early estimation of probable outcome in a severely head-injured patient at admission.

An analysis of clinical and demographic data of 264 patients with severe head injury showed that a combination of the Glasgow Coma Scale (GCS) score, oculocephalic responses, and age can provide a simple but reliable prediction of outcome in severe head injury. Addition of other clinical data, excluding intracranial pressure and evoked potentials, improved the predictability only negligibly. A simple chart, which is constructed from the application of the logistic regression model, can be used to determine the odds of a good outcome from the combination of the three factors. A method is given by which the GCS score of a patient with a missing verbal response score can be accurately approximated in order to complete the chart. Among other values, the odds of a good outcome provide the clinician with a reliable measure of the relative severity of a patient's injury. The accuracy of the chart in prediction is expected to be 80% or above.

The authors studied the relative contribution of cerebrospinal fluid (CSF) and vascular parameters to the level of intracranial pressure (ICP) in 34 severely head-injured patients with a Glasgow Coma Scale score of less than 8. This was accomplished by first characterizing the temporal course of CSF formation and outflow resistance during the 5-day period postinjury. The CSF formation and outflow resistance were obtained from pressure responses to bolus addition and removal of fluid from an indwelling ventricular catheter. The vascular contribution to the level of ICP was assessed by withdrawing fluid at its rate of formation and observing the resultant change in equilibrium ICP level. It was found that, with the exception of patients with subarachnoid hemorrhage, CSF parameters accounted for approximately one-third of the ICP rise after severe head injury, and that a vascular mechanism may be the predominant factor in elevation of ICP.

In certain subgroups of severely head-injured patients, the mortality rate remains unacceptably high. The authors describe a randomized, controlled trial of prophylactic pentobarbital therapy in a group of these patients. Pentobarbital was started as soon as possible after the head injury, regardless of the intracranial pressure (ICP), and was continued for a prescribed period of time. The study included 53 consecutive head-injured patients over the age of 12 years, who had either an acute intradural hematoma (subdural and/or intracerebral, large enough to warrant surgical decompression), or no mass lesion but whose best motor response was abnormal flexion or extension. All patients in the study were randomly assigned to a control group (26 cases) or a pentobarbital-treated group (27 cases) once the diagnosis had been made and informed consent obtained. All patients were treated with the same protocol of aggressive resuscitation, prompt diagnosis and treatment of mass lesions, and intensive care, with close follow-up monitoring. The randomization was effective in producing a close match between the control and treated groups with respect to age, sex distribution, cause of injury, neurological status, intracranial lesions, prevalence of early systemic insults, midline shift, and initial ICP. Outcome was essentially the same in each group. There was no difference between groups in the incidence of elevated ICP, the duration of ICP elevation, or the response of ICP elevations to treatment. Arterial hypotension occurred in 14 patients (54%) in the treated group and only two patients (7%) in the untreated group. Based on these data the authors cannot recommend the prophylactic use of pentobarbital coma in the treatment of patients with severe head injury. They also believe that its use is accompanied by significant side effects which can potentially worsen the condition of a patient with severe head injury.