Gravimetric measurements of cerebral edema in a rabbit brain tumor model.

The development of tumor-induced cerebral edema was studied in rabbits to establish a data base for future work using this brain tumor model to correlate the degree of edema with other functional and morphological parameters. The VX-2 carcinoma was implanted into the brains of New Zealand White rabbits. Animals were killed 9 and 13 days later, and gravimetric analysis was used to measure the specific gravity of gray and white matter in both the tumor-bearing implanted and contralateral nonimplanted hemispheres. Studies were conducted in untreated tumor-bearing rabbits as well as in those receiving dexamethasone daily for 4 days before death. Tumor tissue and peritumoral gray and white matter and contralateral gray and white matter were analyzed. In all cases, at both 9 and 13 days after tumor cell implantation, tumor tissue exhibited extremely high specific gravity values exceeding the range detectable by the assay procedure. Compared with controls, specific gravity values in tumor-bearing animals generally increased in gray matter and decreased in white matter as a function of tumor growth. This trend was seen in both peritumoral gray and white matter as well as in contralateral gray and white matter areas. However, in most cases, the changes in specific gravity values as compared with controls were not statistically significantly different. The primary exception to this was in peritumoral white matter, in which mean specific gravity values at both 9 and 13 days after implantation were statistically significantly lower than for the corresponding site in control non-tumor-bearing animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ischemic cerebral edema in primates: effects of acetazolamide, phenytoin, sorbitol, dexamethasone, and methylprednisolone on brain water and electrolytes

Brain edema was induced in primates (Macaca mulatta) after regional cerebral ischemia produced by selective embolization of the internal carotid artery bifurcation. Details of the alterations in the distribution of water and electrolytes in the brain during the evolution of ischemic cerebral edema have been described elsewhere. The effects of five theoretically useful pharmacological agents were studied. Acetazolamide failed to improve ischemic edema and, rather, increased mortality. Phenytoin definitely prevented both edema and infarction in only the cerebral cortex. Sorbitol was effective to induce dehydration of the affected cortex and the normal brain tissue, with obvious reduction of the brain bulk. High dose steroids showed an ability to modify edema in the cortex, putamen, and white matter. However, animals treated with methylprednisolone rather than dexamethasone showed a better neurological recovery and smaller infarcts.     

Evidence against leukotrienes as mediators of brain edema

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 microM) 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-microM 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.(ABSTRACT TRUNCATED AT 400 WORDS)     

The effect of intravenous lidocaine on experimental brain edema and neural activities

A series of experiments was conducted to clarify the effect of intravenous administration of lidocaine on brain water content, local cerebral blood flow (lCBF), and neural recovery in brain injury induced by exposure of the cat's cerebral surface to the air. The injury produced ischemia and edema in the cortex and white matter without direct damage of the cortex. Lidocaine (3.0 mg/kg) was given intravenously for 30 minutes immediately after air exposure and thereafter at the rate of 2 mg/kg/hour. Twelve hours after exposure, lidocaine significantly suppressed cortical ischemia and edema; however, it had no effects in the white matter. The electrophysiologic activities of the cortex and white matter which were assessed by the direct cortical response and somatosensory evoked response were significantly preserved by lidocaine compared with nontreated animals. The results of this experiment demonstrate that intravenous lidocaine has a significant beneficial effect on cortical ischemia and electrophysiologic activities of the cortex and white matter in injured brain.     

Effect of dexamethasone on cerebral edema from cranial impact in the cat

A Remington humane stunner was used to deliver blows to the skulls of anesthetized cats. Alternate animals were post-treated with either dexamethasone (4 mg/kg/day) or a comparable volume of saline. Each animal was tested for cerebral edema 48 hours after impact by measurement of the change in density of white matter from normal values. Dexamethasone therapy did not reduce the change in density of hemispheres with contusions involving both cortex and underlying white matter. For hemispheres with contusions limited to cerebral cortex, there was minimal edema of the white matter, which was reduced a slight amount by dexamethasone.     

Measurement of changes in brain water in man by magnetic resonance imaging

John Hunter was undoubtedly aware of the water content of normal brain tissue, and described cerebral oedema. The advent of nuclear magnetic resonance (NMR) shed new light on brain water, and the derivation of spatial information and hence images from NMR signals, has permitted studies of regional brain water in man in vivo. The initial study described here tested whether NMR longitudinal relaxation time (T1) correlates with brain water content in the cerebral cortex and white matter in man, and significant relationships have been demonstrated in cortex (r = 0.65, P less than 0.002) and white matter (r = 0.94, P less than 0.0001), the latter having narrow 95% confidence limits. The residual variance allows the prediction of water content from the T1 of white matter, measured from the image of a single patient, with an accuracy of +/- 4% of total tissue water with 95% confidence. In the further study described, the effects of dexamethasone and an infusion of 20% mannitol on brain water content has been assessed in patients with intrinsic cerebral tumours. Dexamethasone had no significant effect on the T1 of normal brain, oedematous peritumoural white matter, or tumour tissue. It must be concluded that the water content of these tissues is not changed by dexamethasone and that the clinical improvement seen in patients with cerebral tumours immediately after dexamethasone has to be explained by some mechanism other than a reduction in cerebral oedema. Mannitol did reduce the T1 of oedematous peritumoural white matter, and the T1 of tumour tissue, but did not change the T1 of normal brain significantly.(ABSTRACT TRUNCATED AT 250 WORDS)     

Peritumoral brain edema associated with meningioma--histological study of the tumor margin and surrounding brain.

Thirty-nine cases of intracranial meningiomas were analyzed to identify factors causing brain edema. Edema was significantly correlated with tumor size and the destruction of the leptomeninges and cortex. Meningotheliomatous meningioma tended to have more peritumoral edema. There was no correlation between the presence of edema and location of the tumor or histological features including lymphocytic infiltration and the presence of glial fibrillary acidic protein-positive cells in the tumor tissue. Larger tumors destroy the leptomeninges and cerebral cortex, allowing direct transmission of humoral edema-promoting factor or edema fluid into the white matter, resulting in vasogenic edema.     

Experimental carbon dioxide laser brain lesions and intracranial dynamics: Part 2. Effect on brain water content and its response to acute therapy

Experimental brain lesions were created over the left parietooccipital cortex of the albino rabbit through the intact dura mater with high radiating carbon dioxide laser energy (40-W impact, 0.5-second duration, for a total time of 4 seconds on a 12.5-mm surface). The brain water content was studied 2, 6, and 24 hours after the insult. Another two groups of animals received acute therapy with either dexamethasone (1 mg/kg) or furosemide (1 mg/kg). In all groups, Evans blue extravasation uniformly extended from the impact crater into the surrounding white matter. The brain water content in the gray matter was elevated from the control value by 2 hours after impact (P less than 0.005) and remained elevated at 6 and 24 hours. The white matter brain water content did not increase until 6 hours after impact and remained elevated in the 24-hour group (P less than 0.005). After dexamethasone treatment, there was a significant decrease of water in the gray matter (P less than 0.01), but not in the white matter. With furosemide therapy, there was no reduction of gray or white matter brain water.     

Acute changes in regional cerebral metabolite values following experimental blunt head trauma

A Remington humane stunner was used to deliver a blow to the left side of the surgically-exposed skull in ketamine-anesthetized cats. At 15 minutes after the trauma, brain tissue was frozen in situ. In animals without visible tissue hemorrhage (Grade 0) and in those with unilateral cerebral contusions involving the cerebral cortex and white matter (Grade 2), regional cerebral metabolite concentrations were measured by enzymatic-fluorometric techniques and edema was tested with an organic gradient. No substantial changes in cerebral metabolite concentrations were observed in head-injured animals without cerebral contusions. In animals with unilateral contusions, the white matter neighboring the tissue hemorrhage had an increase in lactic acid and a decrease in phosphocreatine as compared to values from corresponding areas on the contralateral side, and in control and Grade 0 animals. The cerebral cortex adjacent to tissue hemorrhage had a variable response that ranged from metabolite concentrations within normal ranges to marked decreases in high-energy phosphates and increases in lactic acid. Metabolites of the cortex and white matter contralateral as well as distant to contusion were not statistically different from values of control animals. Changes in several metabolites correlated well with the magnitude of edema. It is concluded that focal metabolic alterations can occur shortly after severe blunt head injury, and that these events may contribute to acute traumatic cerebral edema.     

Time course and spatial distribution of neodymium: yttrium-aluminum-garnet (Nd:YAG) laser-induced lesions in the rat brain

Cerebral lesions made by focal neodymium:yttrium-aluminum-garnet (Nd:YAG) laser irradiation of the rat forebrain were studied in adult Wistar rats. For the analysis of time-dependent changes, the brains of 28 animals were irradiated with a constant energy density of 461 J/cm2. In this series, survival time ranged from 0.5 hours to 80 days. Immediately after irradiation, a circular lesion appeared on the surface of the brain. This lesion was surrounded by an edematous area intensively stained with Evans blue. At energy levels higher than 30 J, this circular edema contained numerous thrombosed vessels. Histopathologically, the lesion consisted of three distinct zones: the central coagulation necrosis was surrounded by a zone of delayed colliquation necrosis and by perifocal edema. At approximately 80 days after irradiation, the resulting cortical defect was covered by a pial membrane. Edematous changes of the brain cortex and the adjacent white matter were observed as early as 1 hour after irradiation. Within 16 hours, the perifocal edema spread over the white matter of both hemispheres, and it had disappeared by the 5th day after irradiation. In a second experiment, the energy density varied from 231 to 3077 J/cm2. This series consisted of 84 animals that were allowed to survive 48 hours. The size of the lesion depended on the level of energy applied, but the depth of the lesion varied less than the diameter at the brain surface.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cerebral edema associated with meningiomas

The cerebral edema, as judged by computed tomographic scan, associated with supratentorial meningiomas was assessed in 55 cases. No relationship to the occurrence or the degree of edema could be established with respect to meningioma location, histological type, tumor vascularity, cellularity, number of mitotic figures, necrosis, calcification, or cortical invasion. The larger the meningioma, the more likely the presence of and the severity of cerebral edema. The edema is a significant factor in the occurrence of clinical signs and symptoms. A biopsy of cerebral cortex and white matter underlying a transitional meningioma in a patient with associated cerebral edema demonstrated perivascular astrocytic end-feet swelling in the cortex and considerable extracellular fluid in the white matter. The ultrastructural appearance is similar to that seen with primary and metastatic brain tumors and with experimental vasogenic cerebral edema.     

Effect of furosemide on experimental traumatic cerebral edema.

The present study was designed to test the effectiveness of furosemide in reducing cerebral edema due to closed head trauma. A Remington Humane Stunner was used to deliver blows to the heads of anesthetized cats. Impacted animals were divided into three groups: (a) trauma, no drug, and ad lib. fluid intake after head injury; (b) trauma, no drug, and standardized fluid intake (0.9% NaCl; 10 ml/lb/day); and (c) trauma, furosemide (3 mg/lb/day), and standardized fluid intake. For the treated cats, we began furosemide therapy 1 hour after head injury and used three intramuscular injections/day. The animals were killed 48 hours after head trauma. From animals with unilateral contusion, we took bilateral white matter samples from five points along the centrum semiovale and tested for edema using density determinations with an organic density gradient. Serum electrolytes, blood urea nitrogen, and weight were determined before the cats were impacted and before they were killed. All impacted animals demonstrated weight loss. Density data showed a normal water content for white matter in the uncontused hemispheres of all impacted cats. Contused hemispheres showed a significant decrease in density (increase in brain water content) for both treated and untreated cats. In the furosemide-treated animals, however, the brain edema was significantly less than that found in the untreated groups. Analysis of data from individual brain sections of furosemide-treated animals suggested a reduction in the spread of edema fluid 48 hours after head injury.     

Experimental studies of brain edema by infusion edema model-- biophysical changes of edema fluid in white matter of the brain

The important changes in the area of brain edema are the accumulation and the spreading of edema fluid through the extracellular space in white matter of the brain. In this study, we described the changes of tissue resistance and compliance as the increment of accumulated volume of fluid produced by the slow infusion of normal saline or plasma into white matter of the cat brain. Adult cats (22) were tracheotomized, paralyzed with Galamine (2 mg/kg) and maintained normocapnic, normotensive under nitrous oxide anesthesia. Normal saline or plasma of their own was infused slowly through 25 gauge needle implanted into left frontal white matter by stereotaxic technique. A low compliance pressure gauge transducer was connected to the line for the measurement of inflow pressure. Tissue resistance and compliance for the movement of infused fluid into white matter were delivered from the changes of inflow pressure by adding the 3 microlitter per minutes on top of the resting steady state pressure. Values of tissue resistance in normal white matter, determined at the accumulated volume of 0.05 ml was very high (normal saline infusion: 6.42 +/- 0.61 X 10(3) mmHg/ml/min, plasma infusion: 5.47 +/- 1.43 X 10(3) mmHg/ml/min). But it decreased rapidly followed by more gradual decrease of tissue resistance became more edematous, reaching a plateau of one sixth of initial value at an infused volume of 0.5 ml. Tissue compliance changed by an opposite pattern of rapid increase and plateau to the changes of tissue resistance.     

Passage of mannitol into the brain around gliomas: a potential cause of rebound phenomenon. A study on 21 patients

AIM: Widespread use of mannitol to reduce brain edema and lower elevated ICP in brain tumor patients continues to be afflicted by the so-called rebound phenomenon. Leakage of mannitol into the brain parenchyma through an altered BBB and secondary reversal of osmotic gradient is considered the major cause of rebound . This has only been demonstrated experimentally in animals. As a contribution to this issue we decided to research the possible passage of mannitol into the brain after administration to 21 brain tumor patients. METHODS: Mannitol (18% solution; 1 g/kg) was administered as a bolus to patients (ten had malignant glioma, seven brain metastases and four meningioma) about 30 minutes before craniotomy. During resection, a sample of the surrounding edematous white matter was taken at the same time as a 10 ml venous blood sample. Mannitol concentrations were measured in plasma and white matter by a modified version of the enzyme assay of Blonquist et al. RESULTS: In most glioma patients, mannitol concentrations in white matter were 2 to 6 times higher than in plasma (mean 3.5 times). In meningioma and metastases patients plasma concentrations of mannitol were higher than white matter concentrations except in three cases with infiltration by neoplastic cells. CONCLUSIONS: The results of our study show that even after a single bolus, mannitol may leak through the altered BBB near gliomas, reversing the initial plasma-to-blood osmotic gradient, aggravating peritumoral edema and promoting rebound of ICP.     

Effects of tromethamine and hyperventilation on brain injury in the cat

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.     

Neurotransmitter amines in brain edema of a rat glioma model

The effect of vasogenic brain edema on amine neurotransmitter concentrations was studied in rats bearing transplanted glioma C6 brain tumors. In comparison with sham-operated and nonoperated controls, the tumor-implanted animals showed significant decreases in both dopamine (DA) and norepinephrine (NE) in the hypothalamus, cortex, and striatum. Treatment with dexamethasone (DEX) tended to restore these monoamines to the levels measured in sham-operated controls. In the nonoperated controls, DEX significantly increased NE but not DA. In tumor-bearing rats there was no increase in hypothalamic or striatal water content, and DEX had no effect on the water content of these structures. However, there was a significant increase in the cortical water content, which was reduced by DEX to the control levels. The water content within the tumor was also significantly decreased by DEX. In the nonoperated controls, there was no difference in water content between DEX-treated and nontreated animals. These findings suggest that tumor-induced brain edema reduces noradrenergic and dopaminergic activities. DEX administration resulted in normalization of the water content in edematous regions and of the DA and NE concentrations, and brought about marked symptomatic improvement.     

Regional metabolism in experimental brain tumors in cats: relationship with acid/base, water, and electrolyte homeostasis.

Experimental brain tumors were produced in cats by xenotransplantation of the rat glioma clone F98 into the white matter of the left hemisphere. One to 4 weeks after implantation, local adenosine triphosphate (ATP), glucose, lactate, and tissue pH were measured via imaging techniques in cryostat sections passing through the center of the tumor and correlated with changes in water and electrolyte content. The tumors exhibited a heterogeneous metabolic pattern, with a tendency for ATP to decrease and lactate to increase during tumor development. Tissue pH was above 7.5 in tumors with high ATP content but it sharply declined at low ATP levels. In peritumoral edema, ATP also decreased and lactate increased but, in contrast to tumor tissue, pH became more alkaline. Metabolic changes were associated with edema formation, as evidenced by the rise in water and sodium content. There was a distinct difference between tumor tissue and peritumoral edema: in tumor tissue, pH declined with increasing water content, whereas in peritumoral edema it increased. These observations are interpreted as follows: 1) in tumor tissue, "lactacidosis" and ATP depletion are attributed to disturbances in blood flow, resulting in metabolic failure and the intracellular "cytotoxic" accumulation of water; 2) in peritumoral edema, "lactalkalosis" is the result of an efflux of (alkaline) lactate salts from the tumor into the expanded extracellular compartment, and the decrease in ATP is the volumetric effect of extracellular "vasogenic" edema fluid and not the result of cellular energy failure. These findings are of importance for the interpretation of volume-selective magnetic resonance spectroscopy and may contribute to the establishment of spectroscopic criteria for the evaluation of therapeutical interventions.     

Proton magnetic resonance studies of triethyltin-induced edema during perinatal brain development in rabbits

To better understand the role of myelin-associated water in the differentiation of white and gray matter in magnetic resonance (MR) imaging, changes in MR relaxation processes were studied in rabbits during myelination and after induction of cytotoxic edema with triethyltin (TET). Normal rabbits were killed at various age intervals ranging from premature (28 days' gestation) to adult, and changes in MR relaxation times (T1 and T2) and in water and electrolyte content were determined for various areas of brain and muscle. Similar measurements were made in rabbits of comparable age exposed to TET. Light and electron microscopy and MR imaging were used to follow myelin development and morphological changes induced by TET. During the first 30 postnatal days, both T1 and T2 declined by 50% in normal rabbits, a fall that paralleled the loss in brain water and sodium that occurred during the same period. Exposure to TET prolonged T1 and T2 in white but not gray matter, reflecting the accumulation of sodium and water (edema fluid) in white matter areas. Multiexponential analysis revealed a second, longer component in T2 magnetization decay of TET-exposed white matter, presumably attributable to accumulation of non-ordered water within intramyelinic vacuoles, a supposition consistent with electron microscopic and MR imaging findings. In contrast to reports by others, changes in T1 (but not T2) closely correlated with alterations in brain water (r = 0.93, df = 39). The absence of tissue disruption in the animals in the present study may account for these differences, but further studies will be required both to resolve this question and to fully understand MR images of white matter edema in mature and immature brain.     

The kallikrein-kinin system as mediator in vasogenic brain edema. Part 1: Cerebral exposure to bradykinin and plasma

Plasma and bradykinin were perfused into the ventricular system of mongrel dogs to investigate whether either or both induce brain edema. Formation of cerebral edema was determined by measurement of cerebral water and electrolytes in periventricular white matter, cerebral cortex, and caudate nucleus. The response of cerebral tissue to exposure to bradykinin or to plasma, as a carrier of kininogens, was analyzed by assessment of the perfusate composition after ventricle passage. The authors report that cerebral administration of bradykinin induces cerebral edema. Ventricular perfusion with plasma also led to an increase of cerebral water content which was restricted to the white matter, but involved all brain tissue areas, if bradykinin was used. Ventricular perfusion with plasma was associated with consumption of the kinin precursor (kininogens) indicative of formation of kinins. Significant consumption of the precursor was found in five out of nine animals subjected to plasma perfusion of the ventricular system. In these animals a close correlation between the increase of white matter water content and kininogen-consumption as a measure of kinin-formation was obtained. Marked kinin-degrading activity was observed during ventricular perfusion with bradykinin as concluded from a considerable decrease of bradykinin concentration in the cisternal effluent compared to the inflowing perfusate concentration. Ventricular perfusion with plasma was associated with a decrease of K+ clearance capacity with continued duration, and in two animals with a release of glutamate into the plasma perfusate, suggesting an involvement of cytotoxic mechanisms. These findings provide support for the hypothesis of a mediator function of the kallikrein-kinin (KK) system in vasogenic brain edema. The next question that needs to be answered to complete the picture--does spontaneous activation of the KK system occur in conditions leading to vasogenic edema?--is studied in a subsequent report.     

Comparative observation with MRI and pathology of brain edema at the early stage of severe burn

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