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Severe head injury remains a major problem despite advances in recent years. The mortality of patients with a coma score of eight or less is still between 45–55% (Miller et al. 1981). In an attempt to improve outcome in a significant number of these patients, we have directed our efforts toward therapeutically influencing the brain and its environment after a severe head injury. Severe mechanical brain injury initiates a series of complex events in the brain which are thought to secondarily influence the ultimate outcome of the patient. One of these proposed secondary events is cerebral acidosis. The presence of cerebral acidosis has been inferred by the presence of lactate in ·the CSF of patients sustaining a severe mechanical brain injury (Cold et al. 1975, Enevoldsen et al. 1977, Sood et al. 1980). In addition, prognostic significance has been attached to high levels of lactate in the CSF after a severe brain injury (Crockard et al. 1972; Seitz and Ocker 1977). Furthermore, it has been shown that acidosis itself, when present as the result of any pathologic process, is harmful to the brain (Pulsinelli and Petito 1983). It was felt therefore that outcome from severe head injury might be improved if cerebral acidosis present after a head injury was treated.

CT-scanning has made it possible to separate the high attenuation of a hematoma from the low attenuation of localized edema. A contusion is usually recognized as scattered areas of high attenuation (blood) within areas of normal or even low attenuation, i.e. so-called mixed density areas, it is difficult, however, to delineate a contusion exactly.

Our studies of intracranial pressure dynamics have shown that the volume extensibility, or compliance, in combination with the resistance to drainage of CSF are major parameters which affect the rate of change and resting level of the ICP. The objective of this investigation was to examine how these parameters were distributed between cranial and spinal compartments. We hypothesized that in the cranial compartment, a shift of cerebral blood volume offers the only means of rapid compensation to sudden changes in CSF volume. A second objective, then, was to examine to what extent the compliance which would be affected by the degree of this vascular compensation, is influenced by changes in mean systemic blood pressure.

✓ Fluid percussion models produce brain injury by rapidly injecting fluid volumes into the cranial cavity. The authors have systematically examined the effects of varying magnitudes of fluid percussion injury in the rat on neurological, systemic physiological, and histopathological changes. Acute neurological experiments showed that fluid percussion injury in 53 rats produced either irreversible apnea and death or transient apnea (lasting 54 seconds or less) and reversible suppression of postural and nonpostural function (lasting 60 minutes or less). As the magnitude if injury increased, the mortality rate and the duration of suppression of somatomotor reflexes increased. Unlike other rat models in which concussive brain injury is produced by impact, convulsions were observed in only 13% of survivors. Transient apnea was probably not associated with a significant hypoxic insult to animals that survived. Ten rats that sustained a moderate magnitude of injury (2.9 atm) exhibited chronic locomotor deficits that persisted for 4 to 8 days. Systemic physiological experiments in 20 rats demonstrated that all levels of injury studied produced acute systemic hypertension, bradycardia, and increased plasma glucose levels. Hypertension with subsequent hypotension resulted from higher magnitudes of injury. The durations of hypertension and suppression of amplitude on electroencephalography were related to the magnitudes of injury. While low levels of injury produced no significant histopathological alterations, higher magnitudes produced subarachnoid and intraparenchymal hemorrhage and, with increasing survival, necrotic change and cavitation. These data demonstrate that fluid percussion injury in the rat reproduces many of the features of head injury observed in other models and species. Thus, this animal model could represent a useful experimental approach to studies of pathological changes similar to those seen in human head injury.

There is evidence to suggest that severe head injury can cause disturbances of cerebral energy metabolism which can result in tissue acidosis and decreased energy production [2]. One objective of this study was to determine if fluid percussion brain injury affects cerebral energy metabolism. Additionally, since post-traumatic respiratory distress is a major complicating factor in head injury [5], another goal was to analyze the effect of hypoventilation immediately following trauma on cerebral energy metabolism.

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.

The effect of mannitol in reducing brain water has been under considerable scrutiny since the work of Takagi et al. (1983) who reported that mannitol reduced ICP but did not reduce tissue water measured gravimetrically. These results directly contradicted earlier findings by other workers. Further controversy arose with the reports by Muizelaar et al. (1983) which showed that the pressure reducing properties of mannitol act primarily through a vasoconstrictive effect and not by water reduction. This study was designed to document the acute and chronic effects of mannitol in reducing ICP, measuring tissue water by MRI and specific gravity methods.

We performed a series of five baboon experiments to compare cerebral blood flow measured with an improved stable xenon/CT method and the radiolabelled microsphere technique at a PaCO2 of 40 mm Hg. The xenon/CT method was implemented by fitting the arterial xenon uptake with a double exponential function, by measuring the oxygen and carbon dioxide concentrations continuously during each breath and by taking into account the lung-to-brain transit time of xenon. The time of xenon inhalation was extended to 30 minutes to obtain more reliable estimates of CBF in white matter regions. The results indicate an overall correlation coefficient of 0.92 between the two methods and good numeric agreement.

✓ A mathematical model of the cerebrospinal fluid (CSF) system was developed to help clarify the kinetics of the intracranial pressure (ICP). A general equation predicting the time course of pressure was derived in terms of four parameters: the intracranial compliance, dural sinus pressure, resistance to absorption, and CSF formation. These parameters were measured in the adult cat, and the equation was tested by comparing experimental and calculated values of the time course of pressure in response to volume changes. The theoretical and experimental results were in close agreement, and the role of each parameter in governing the dynamic equilibrium of the ICP was determined. From this analysis, dynamic tests were developed for rapid measurement of CSF formation, absorption resistance, and the bulk intracranial compliance. These techniques are applicable to clinical settings, providing data that are useful in characterizing the physiological mechanisms responsible for raised ICP and assessing changes induced by therapy.

The intracranial compliance as measured by the PVI has been considered an important parameter in dynamical analysis of the ICP. The importance of compliance measures in the clinical setting has been emphasized by several investigators; however, the number f clinical investigations focused on biomechanical indices associates with head injury have been relatively few. The aim of this investigation was to study the temporal relationship between intracranial compliance and ICP in a group of severely head injured patients. Our objectives were to characterize the biomedical profile of the head injured patient immediately upon stabilization in the ICU setting and to follow the temporal course of ICP and PVI during the five days post injury.

✓ Significant errors are introduced into the measurement of brain tissue water by the specific gravity technique when the edema fluid contains protein. Protein adds to the tissue solids, increasing the density of the tissue, and masks the proportional increase of brain water. Existing equations relating measured specific gravity and tissue water are not applicable, and a new formula was developed that compensates for the protein component of edema and reduces the experimental error. The new method was applied to the measurement of tissue water in cat brain made edematous by direct infusion of fluids of known composition and volume to test the theory. This technique for improving the gravimetric assessment of brain edema is presented.

Brain compliance is the ability of the cranial contents to accommodate an extra amount of volume (e.g., hematoma, CSF, increased cerebral blood volume, CBV) without much increase in ICP. PVI is a measure of brain compliance and is the calculated volume (in milliliters) required to raise ICP by a factor of 10 (Marmarou et al. 1978). It is thought to be a reflection of the vascular component of the intracranial compartment (Lofgren et al. 1973; Shapiro et al. 1980), also after head injury (Marmarou et al. 1973). Changes in blood pressure or CPP have a major influence upon the intracranial blood vessels, particularly arterioles, the extent and the direction of this influence being in turn dependent on whether autoregulation is (still) operative or not. Thus, several authors, using pentobarbit-alanesthetized animals, found that PVI or some other measure of brain compliance did not change with changes in CPP within the range of autoregulation (Avezaath et al. 1980; Leech and Miller 1974; Takagi et al. 1980). Outside the range of autoregulation, brain compliance or PVI became inversely related to changes in CPP in these and other studies (Avezaath et al. 1980; Gray and Rosner 1987; Leech and Miller 1974). However, Gray and Rosner found that within the limits of autoregulation PVI and CPP were related in a linear fashion, with increasing blood pressure being reflected by a rise in PVI (Gray and Rosner 1987). But, this relationship was marked only in cats anesthetized with methohexital and hardly present with pentobarbital anesthesia. They concluded that pentobarbital, because of its own major vasoconstrictory effect, blunted the responses of cerebral blood vessels to changes in CPP and therefore obscured the relationship between PVI and CPP (Gray and Rosner 1987). In the present paper responses of ICP and PVI to changes in blood pressure were investigated in severely head injured patients in whom anesthesia is not necessary at all. Moreover, in some of these patients autoregulation is intact, while in others it is absent (though, for unknown reasons) (Muizelaar et al. 1984).

✓ The literature suggests that in children with severe head injury, cerebral hyperemia is common and related to high intracranial pressure (ICP). However, there are very few data on cerebral blood flow (CBF) after severe head injury in children. This paper presents 72 measurements of cerebral blood flow (“CBF15”), using the 133Xe inhalation method, with multiple detectors over both hemispheres in 32 children aged 3 to 18 years (mean 13.6 years) with severe closed head injury (average Glasgow Coma Scale (GCS) score 5.4). In 25 of the children, these were combined with measurements of arteriojugular venous oxygen difference (AVDO2) and of cerebral metabolic rate of oxygen (CMRO2). In 30 patients, the first measurement was taken approximately 12 hours postinjury. In 18 patients, an indication of brain stiffness was obtained by withdrawal and injection of ventricular cerebrospinal fluid and calculation of the pressure-volume index (PVI) of Marmarou. The CBF and CMRO2 data were correlated with the GCS score, outcome, ICP, and PVI. Early after injury, CBF tended to be lower with lower GCS scores, but this was not statistically significant. This trend was reversed 24 hours postinjury, as significantly more hyperemic values were recorded the lower the GCS score, with the exception of the most severely injured patients (GCS score 3). In contrast, mean CMRO2 correlated positively with the GCS score and outcome throughout the course, but large standard deviations preclude making predictions based on CMRO2 measurements in individual patients. Early after injury, there was mild uncoupling between CBF and CMRO2 (CBF above metabolic demands, low AVDO2) and, after 24 hours, flow and metabolism were completely uncoupled with an extremely low AVDO2. Consistently reduced flow was found in only four patients; 28 patients (88%) showed hyperemia at some point in their course. This very high percentage of patients with hyperemia, combined with the lowest values of AVDO2 found in the literature, indicates that hyperemia or luxury perfusion is more prevalent in this group of patients. The three patients with consistently the highest CBF had consistently the lowest PVI: thus, the patients with the most severe hyperemia also had the stiffest brains. Nevertheless, and in contrast to previous reports, no correlation could be established between the course of ICP or PVI and the occurrence of hyperemia, nor was there a correlation between the levels of CBF and ICP at the time of the measurements. The authors argue that this lack of correlation is due to: 1) a definition of hyperemia that is too generous, and 2) the lack of a systematic relationship between CBF and cerebral blood volume. The implications of these findings for therapeutic modes of controlling ICP in children, such as hyperventilation and the use of mannitol, are discussed.

Although advances have been made in the treatment of patients with severe head injury, certain patients will go on to die, some from medical coma and some from uncontrolled intracranial hypertension (Miller et al. 1981). In an attempt to improve outcome in these patients, certain investigators have advocated the use of barbiturates in high doses (Marshall et al. 1979; Rockoff et al. 1979).

The progressive increase in brain volume following severe mechanical injury ultimately leads to intracranial ischemia and hypertension. The severity of the problem is in part reflected in the statistic that 50% of patients who succumb to head injury die of excessively high intracranial pressure [1, 2]. The objective of the present research is to identify the role that brain edema plays in this swelling process and to determine in a well-defined model of brain injury how edema affects cerebral blood flow.

✓ The pressure-volume index (PVI) technique of bolus manipulation of cerebrospinal fluid (CSF) was used to measure neural axis volume-buffering capacity and resistance to the absorption of CSF in 16 hydrocephalic infants prior to shunting. The mean steady-state intracranial pressure (ICP) was 11.7 ± 5.7 mm Hg (± standard deviation (SD)), representing a modest elevation of ICP in infants. The mean measured PVI was 28.1 ± 1.5 ml (± standard error of the mean (SEM)) compared to the predicted normal level for these infants of 12.1 ± 2.7 ml (± SD) (p < 0.001). This resulted from an enhanced volume storage capacity in the hydrocephalic infants. The PVI was not related to ventricular size in these hydrocephalic infants. Although absorption of the additional bolus of fluid did not occur at steady-state ICP, it was readily absorbed once ICP was raised above a mean threshold pressure of 16.0 ± 5.0 mm Hg (± SD) in 13 of the 16 infants. Above this pressure, the mean CSF absorption resistance was 7.2 ± 1.3 mm Hg/ml/min (± SEM) which is twice the normal values as measured by the bolus injection technique. The biomechanical profile of infantile hydrocephalus described in this study indicates that two factors are required for progression of ventricular volume. While an absorptive defect may initiate the hydrocephalic process, progressive volume storage requires an alteration in the mechanical properties of the intracranial compartment.

✓ The pressure-volume index (PVI) technique of assessing neural axis pressure-volume relationships was used as an adjunct to managing 22 children with severe head injuries and a Glasgow Coma Scale score of 8 or less. Ventricular cannulation was used to continuously monitor intracranial pressure (ICP). Actual PVI was measured by bolus injection of fluid and compared with predicted values determined from head circumference and spinal axis length in each patient. In 55% of the children, ICP was below 20 mm Hg at initial monitoring. During the course of monitoring, 86% of the children had ICP's exceeding 20 mm Hg. Reduced PVI (less than 80% of predicted normal) proved to be an accurate indicator of impending intracranial hypertension. The PVI proved to be a useful test for assessing the response to therapies for lowering ICP. This study demonstrates that reduced neural axis compliance accompanies intracranial hypertension following severe head injury in children, and that treatment of reduced neural axis compliance may prevent refractory intracranial hypertension.

✓ Autoregulation of cerebral blood flow (“CBF15”) was tested in a series of 26 pediatric patients (mean age 13.2 years) with severe head injury (average Glasgow Coma Scale (GCS) score 5.5) in the acute stage. A baseline 133Xe CBF measurement was performed and then repeated, after blood pressure was increased by 29% with intravenous phenylephrine or decreased by 26% with intravenous trimethaphan camsylate. Correlations were made between CBF and clinical condition, outcome, time after injury, intracranial pressure (ICP), and pressure-volume index (PVI) changes, and the site of injury (hemispheres, diencephalon, or brain stem). The site of injury was determined with multimodality evoked potential measurements. Autoregulation was intact in 22 (59%) of 37 measurements. There was no correlation with GCS score, outcome, time after injury, site of injury, or way of testing (decreasing or increasing blood pressure). Autoregulation was statistically significantly more often impaired when CBF was either below normal −2 standard deviations (SD) (reduced flow) or above normal +2 SD (absolute hyperemia). In cases with intact autoregulation, mean ICP decreased from 17.5 to 15.0 mm Hg with higher blood pressure and increased from 19.0 to 21.3 mm Hg with lower blood pressure. When PVI was measured during the blood pressure manipulations, it was found to change in a direction opposite to the ICP change. The consequences of these findings in the management of ICP problems with blood pressure control are discussed.

The effect of mild closed head trauma, induced by the weight-drop method (450 g from a 1-m height), on lipid peroxidation and energy metabolism of brain tissue was determined at various times after cerebral injury in spontaneously breathing rats (1, 10, 30 minutes and 2, 6, 15, 24, 48, and 120 hours). Animals were continuously monitored for the evaluation of blood pressure, blood gases, heart rate, and intracranial pressure. Analysis of malondialdehyde (MDA) as an index of lipid peroxidation, ascorbic acid, high-energy phosphates, nicotinic coenzymes, oxypurines, and nucleosides was performed by high-performance liquid chromatography (HPLC) on neutralized perchloric acid extract of the whole brain. Data showed that MDA, undetectable in control, sham-operated rats, was already present within 1 minute of trauma (1.77 nmol/g wet weight; SD = 0.29) and reached maximal values by 2 hours (72.26 nmol/g w.w.; SD = 11.26), showing a progressive slow decrease thereafter. In contrast, ATP, GTP, and nicotinic coenzyme (NAD and NADP) concentrations showed significant reduction only by the second hour postinjury. Maximal decrease of the ATP and GTP concentrations were seen at 6 hours postinjury, whereas NAD and NADP concentrations showed maximum decline by 15 hours. Values recorded in mechanically ventilated rats did not differ significantly from those obtained in spontaneously breathing animals. These findings, supported by the absence of blood gas and blood pressure changes in the spontaneously breathing rats, strongly support the premise that biochemical changes (primarily lipid peroxidation) are not caused by secondary ischemic-hypoxic phenomena but rather are triggered by these forces acting on the brain at the time of impact. In addition, these results suggest that depression of energy metabolism might be caused by peroxidation of the mitochondrial membrane with a consequent alteration of the main mitochondrial function-that is, the energy supply.