The aim of the present study was to determine the effects of a hyperosmotic agent, 10% glycerol, on both brain energy metabolism and intracellular pH (pHi) in experimental vasogenic brain edema. Vasogenic brain edema was induced by cold injury applied to bilateral parietal portions in 13 mongrel dogs (7 glycerol, 6 control) while, 3 dogs were used as control. Before and at 24 hours after the injury, sequential phosphorous-31 magnetic resonance spectroscopy (31P-MRS) was performed for 2 hours in order to determine phosphocreatine (PCr), β-adenosine triphosphate (β-ATP), inorganic phosphate (Pi) levels and pHi. At 24 hours following cold injury, both PCr/Pi and ATP/Pi ratios significantly decreased from 7.75 to 3.97 and from 2.26 to 1.25, respectively. Furthermore, a moderate decrease in pHi of 7.16 to 7.01 was significantly demonstrated during the same experimental period. Administration of glycerol for 30 minutes significantly increased PCr/Pi from 3.97 to 5.06 and ATP/Pi from 1.25 to 1.72, respectively. Also, glycerol administration caused a significant increase in pHi from 7.01 to 7.11. This study indicates that cryogenic injury, in which formation and expansion of vasogenic brain edema a known to occur, results in disturbed brain energy metabolism and in intracellular acidosis; moreover, the administration of glycerol can ameliorate either or both of these derangements.
The potential exists for increasing the sensitivity of magnetic resonance imaging (MRI) to white matter (WM) pathologies by identifying compartments of tissue water. We have found the physical equivalents of myelin-associated biological water compartments in normal and pathologic states by using multiexponential analysis of T2 relaxation. In addition, we have applied this multiparametric technique for the definition of various types of white matter edemas. We were able to identify some changes in physical compartments visible by MRI with simultaneous changes in biological compartments. We conclude that MRI is a very sensitive method to quantify abnormal accumulation of intracerebral water; however, it is a somewhat limited probe for identifying the biologic compartmentation of edema among the various biological compartments of the brain.
In 16 patients with 21 metastastic brain tumors and 9 patients with a malignant glioma, tumor volume, volume of the edematous tissue, edema production, speed of edema propagation and edema resolution were examined by using the CT. Edema production was determined according to a technique described previously3 and ranged between 0.09 and 1.63 ml/h in metastases and between 0.42 and 3.49 ml/h in gliomas. The speed of edema propagation ranged from 0.2– 2.2 mm/h. Edema resolution can take place within the tissue (i.e. reabsorption into blood) as well by drainage into the entricular or subarachnoid CSF. In a few small metastases with a small perifocal edema (without contact to the ventricule or the subarahnoid space) the amount of edema resolution within the tissue could be determined and averaged 0.0086 ml/h/cm3. This probably represents the reabsorption of edema fluid into capillaries within the edematous tissue. If this value is used to calculate the edema reabsorption in larger tumors, the resulting data are considerable lower than the respective edema production rate of that tumor. This indicates, that in larger tumors the main fraction of the edema fluid is draining into the ventricular and/or subarachnoid CSF.
The effects of histamine on the cerebral endothelial cells were studied. To determine if the extent of brain oedema formation could be reduced with histamine receptor antagonists, mepyramine (Hi-receptor blocker), metiamide, cimetidine and ranitidine (H2receptor antagonists) were administered at a dose of 5 mg/kg body weight 4, 2 and 0 h before the onset of experimental pneumothorax induced in newborn piglets. Mepyramine and ranitidine given 2 h before the induction of EBP prevented the accumulation of water, sodium and albumin in samples taken from the parietal cortex. In other experiments, carried out on Sprague-Dawley rats of CFY strain after permanent bilateral common carotid ligation (BCCL), the accumulation of water and sodium in the ischemic brain tissue could also be prevented in a dose dependent manner by intraperitoneal injections of ranitidine given 30 min before the surgery. Taken together, these results provide pharmacological evidence for the involvement of histamine receptors in the pathogenesis of brain oedema. Consequently, the use of histamine receptor blockers both in the prevention and in the treatment of brain oedema can be recommended.
A model of occlusive stroke in the aging brain has been developed and used to evaluate the effects of age upon cerebral infarction, cerebral oedema and neuroprotective potential. Focal ischaemia following left middle cerebral artery occlusion has been compared in aged (30 month) and adult (< 17 month) rats, with histological assessment of infarct volume and analysis of specific gravity as an index of cerebral oedema. Aging was associated with a significant increase in cerebral infarct size. The mean infarct volume in aged rats was 40.5% +/- 2.6% of the hemisphere volume, compared to 30.9% +/- 0.7% in adults (p < 0.01). Pre-treatment with the competitive N-Methyl-D-Aspartate (NMDA) receptor antagonist 3-(2-Carboxy Piperazin-4-yl)Propyl-l-Phosphonate (D-CPP-ene) reduced infarct volumes in both age groups to 33.0% +/- 1.8% and 20.7% +/- 3.2% in aged and adult animals, respectively (p < 0.05). There was significantly less oedema of the cerebral cortex in D-CPP-ene pre-treated rats; mean cortical specific gravity 4 hours post-infarction was 1.0381 +/- 0.0013 in untreated aged rats and 1.0391 +/- 0.0014 in untreated adults, compared to 1.0458 +/- 0.0031 in treated aged rats and 1.0442 +/- 0.0014 in treated adults (p < 0.05). At 24 hours post-infarction, D-CPP-ene pre-treated aged rats had a mean cortical specific gravity of 1.0403 +/- 0.0006 compared to 1.0361 +/- 0.0014 in untreated aged animals (p < 0.05). This study has demonstrated an age-related increase in cerebral infarct size, but has shown that the aging brain is amenable to neuroprotection by NMDA receptor antagonism.
A study was conducted to examine whether swelling of the brain due to vasogenic-type and cytotoxic-type edema is isotropic or anisotropic. Vasogenic edema was induced by cryogenic injury in cats, and coronal sections of the brain were examined at 4-5 h after injury. The swelling of the edematous white matter longitudinal to and transverse to the subcortical neuronal fibers was 2.3% and 91.1%, respectively. Ischemic edema was examined using cortical tissue specimens of cat brain subjected to either middle cerebral artery occlusion for 3 h or immersion in saline after decapitation for 3 h. The swelling parallel to the left-right axis, caudo-rostral axis and antero-posterior axis was 9.6%, 10.1% and 8.5%, respectively. Neuroglial cell swelling was prominent in the ischemic cortex. Thus swelling of the white matter in vasogenic-type edema was anisotropic, whereas that of gray matter in cytotoxic-type (ischemic) edema was isotropic. This observed difference in the biomechanical properties of brain tissue should be taken into account when the etiology of edema-mediated tissue injury, such as herniation, secondary bleeding or ischemia is investigated.
In order to study the possible role of C kinase (PKC) on sodium pump of cerebral vessels, we used diacylglycerol (diC8: sn-1,2-dioctanoylglycerol) and phorbol esters (PMA: phorbol 12-myr-istate 13-acetate; PDA: phorbol 12,13-diacetate; 4 oc-P: 4-alpha phorbol) as PKC activators, and examined their effects on Na, KATPase activity in rat brain microvessels (MVs). Rats were divided into non-treated (control; n = 9), four-vessel occlusion (4VO; 30-30 minutes ischemia and recirculation, n = 5), and middle cerebral artery occlusion (MCAO, n = 3) groups. MVs were passed through nylon meshes and were obtained by ultracentrifuge at 58000 g. Na,K-ATPase activity in MVs was determined by the phosphomolybdate method. DiC8 enhanced Na,K-ATPase activity at 10-4M in the control group, the 4VO group and the contralateral hemispheres of the MCAO group (139% ± 0.06**, 135% ± 0.2*, 133% ± 0.18, mean ± SE, * p < 0.05, ** p < 0.01, Wilcoxon rank sum) respectively, but had no effects on MVs in the ipsilateral hemispheres of MCAO group (-74% ± 0.04). This activation by diC8 was inhibited by PKC inhibitors, staurosporine (3 x 10-8M) and H7 (l0-6M) in the control MVs. By contrast, PMA suppressed Na, KATPase at 10-5M in the control group (-25% ±0.07*), but it tended to activate Na,K-ATPase activity in the ipsilateral hemispheres of the MCAO groups (33% ± 0.09). PDA and 4 α-P did not have any consistent effects at the concentration examined. The cause of difference between the effects of diC8 and PMA is unclear at present, but it may stem from the mode of lipid-membrane interaction in these agents and the difference in the condition of cells as well.
Thermal clearance has been used as a measure of tissue blood flow for over 60 years. We have developed a probe which can be used to monitor cerebral cortical thermal clearance in patients suffering from acute neurosurgical disorders. Despite its limitations of size, invasiveness, small sample volume, and difficult quantification it has proved a reliable method, showing a good correlation between measured thermal clearance and the onset of clinical signs of ischaemia.
This paper is a review and synthesis of work done in our laboratory by many investigators over roughly 18 years dealing with the microcirculation in a zone of acute ischemic injury. The work has been guided by a hypothesis that blood flowing through the microcirculation of an acute injury zone is capable of undergoing a multifactorial interaction at the blood-endothelial interface that can progressively impair microvascular perfusion and contribute locally to the evolution of cellular damage and death. Our work has implicated Factor VIII/von Willebrand factor, prostanoids, leukocytes, platelets, platelet-activating factor, leukotrienes, adhesion receptors, monocytes/macrophages, and cytokines in this interaction.
The association of changes in the metabolic pathway of monoamines (dopamine and 5-hydroxytryptamine) with mitochondrial enzymatic systems which are involved in the production and removal of free radicals formed during dopamine metabolism and formation of edema was investigated in bilateral brain ischemia in gerbils. The results suggest that the involvement of DA-derived free radicals in brain edema is unlikely in early reflow, because disbalance between H2O2-producing reactions of DA-metabolism, and mitochondrial antioxidative capacity does not occur prior to 1 hour reflow after 15 min bilateral ischemia in gerbils. However, the findings of this study reinforce the participation of 5-HT in the formation of ischemic brain edema.
The evolution of brain edema research is outlined from early experimental studies to the development of present concepts and interpretations, as well as the establishment of criteria for the two main types of edema, cytotoxic and vasogenic.
The vasoactive peptide endothelin-1 (ET-1) dose-dependently increased release of 51Cr from human cerebromicrovascular endothelial cells (HBEC), without affecting cell viability as assessed by lactate dehydrogenase release. ET-1 also induced transient accumulation of inositol triphosphate (IP3) and release of [3H] arachidonic acid (AA) from HBEC. The ET-1-induced 51Cr release, formation of IP3, and AA release from HBEC were competitively inhibited by selective ETA subtype receptor antagonist BQ-123. ET-1-stimulated 51Cr- and AA release from HBEC were potentiated by proteinkinase C (PKC) activator phorbol-myristate ester, and abolished by H7, an inhibitor of PKC. Dexamethasone, indomethacin, acetylsalicylic acid, imidazole, as well as the inhibitor of protein kinase A, H8, had no effect on 51Cr release. The results suggest that ETA-receptor mediated activation of PKC and increase in the HBEC 'permeability' for low molecular weight molecules in response to excessive release of endothelins from either HBEC or surrounding tissues during pathologic conditions may contribute to the formation of cerebral edema.
In 77 head-injured and transfused patients, the amount of blood volume replacement (BVR) and patient outcome were retrospectively analyzed. They were divided into four groups of intracranial lesion by initial CT; acute subdural hematoma (SDH) with or without other lesions, traumatic subarachnoid hemorrhage only, epidural hematoma only and all other lesions. Result shows SDH is the most vulnerable to massive transfusion and BVR more than 5000 ml was fatal. Patients with other lesions have high possibility of survival even if BVR amounts to 7000ml. It is concluded, for patients resuscitated with excessive amount of transfusion (> 5000 ml), follow up CT and some vigorous treatment such as administration of hypertonic solutions should be scheduled.
The progression of brain edema in seven patients with hypertensive intracerebral hemorrhage (ICH) was evaluated. Five were of putaminal and two were of thalamic hemorrhage. The hematoma volume in the patients was 4 approximately 40 ml (18.9 +/- 8.0 ml). Sequential MRI (SE: 2000/40) was performed at one, two and four weeks after onset. The edema volume (EV) was calculated as 1/2.(long diameter).(short diameter).(thickness) of the high intensity area (HIA) on MRI. In comparison with the EV at one week after onset, the EV at two weeks was increased and the EV at four weeks returned to the same level of that at one week (132.3 +/- 26.1%, 100 +/- 10.6%, respectively). In contrast, the consciousness level and motor weakness of the patients had already improved at two weeks after onset. Our results demonstrate that progression of brain edema after small or medium size ICH may not bring about a deterioration of the clinical course. Moreover, progression of brain edema to the cerebral cortex and ventricle as indicated by MRI suggested an absorption pathway for the edema fluid, and implying that brain edema following ICH could play a part in the healing process after ICH.
Brain edema caused by glutamate excitotoxicity was studied in well oxygenated neonatal cerebrocortical brain slices (350 μthick). Slices exposed to 60 minutes of 2 mM glutamate, with or without glutamate antagonists (dizocilpine, kynurenate, or NBQX), were allowed to recover for 60 minutes. The protocol was identical to that in noninvasive multinuclear NMR spectroscopy studies (31P/1H/19F) of live slices. Percent water and swelling were determined invasively in isolated slices by wet and dry weight measurements before and after glutamate exposure. Edema was detectable within minutes in all experiments with glutamate exposures, but not in untreated control slices. Dizocilpine, kynurenate, and NBQX differently aftected swelling, which correlated with PCr and ATP loss in separate NMR studies. Synaptic glutamate receptor activation appears to initiate events causing both edema and energy failure. Multiple glutamate receptor types seem to be involved. No glutamate antagonist provided greater protection against both edema and energy loss than dizocilpine. Dizocilpine might also block voltage-dependent Na+ channels, and provide protection via mechanisms other than NMDA-receptor dependent channel antagonism.
We investigated whether prolonged high colloid oncotic therapy for two weeks can suppress contusional brain edema. Eighteen patients with cerebral contusion were randomly divided into two groups of patients receiving high oncotic pressure (HOP; 26–30 mmHg) treatment and those receiving normal oncotic pressure (NOP; 22–26 mmHg) treatment. Oncotic pressure was maintained for two weeks with administration of a 25% albumin solution with additional use of furosemide. Edema volume was calculated by summation of all measured low-density areas in each CT slice multiplied by 1.0 cm of slice of thickness. We expressed contusional brain edema volume as a percent increase based on each patient’ s initial CT. The mean percent increase of contusional brain edema in the NOP group was significantly higher than that in the HOP group at 9–15 days (208.9% and 14.0%, respectively) and 16–25 days (188.8% and 10.0%, respectively). There were no complications such as heart failure or renal failure during treatment. All the patients in the HOP group recovered with minimal or no neurological deficit. On the other hand, 30% of patients in the NOP group remained in poor condition. With frequent measurement of oncotic pressure and adjustment of fluids and electrolytes, continuous oncotic therapy for two weeks effectively and safely reduced contusional brain edema.
Acute subdural hematoma (ASDH) gives rise to a mass effect not only by itself but also through unilateral hemispheric swelling, The present study tested the hypothesis that hemispheric swelling is mediated by mechanisms which involve excitatory amino acids (EAAs). After removal of the subdural clot, introduced by homologous blood (0.1-0.2 ml), the % brain water was determined from the formula: ((wet weight - dry weight) / wet weight) x 100. The % brain water of the left hemisphere was significantly greater than that of the right hemisphere during the initial 6 hours after induction of ASDH in animals injected with 0.2 ml blood. A less marked but significant increase was observed in the animals injected with 0.1 ml blood. Systemic pretreatment with kynurenic acid (KYN; 800 mg/kg, i.p.), a broad-spectrum EAA antagonist, attenuated the increase in % brain water in the animals injected with 0.2 ml blood. In order to determine the changes in cerebral metabolism induced by the model of ASDH employed in the present study, we measured the cortical cytochrome oxidase (CYO) activity, a marker of mitochondrial respiration, in a separate group of animals. The CYO activity estimated densitometrically from the histochemical staining was not significantly altered in the animals injected with either 0.1 or 0.2 ml blood, suggesting absence of ischemia. These results indicated that the hemispheric swelling associated with thin ASDHs may be partially mediated by mechanisms other than ischemia, in which EAAs appear to be involved.
We will report our accumulated experience in monitoring of brain temperatures in neurosurgical patients. The intraventricular temperature was monitored with a thermocouple designed for the purpose. This thermocouple was introduced through a plastic catheter, which was also used for monitoring intracranial pressure. The rectal and epidural temperature was simultaneously measured, with commercially available thermocouples. Human brain temperature is higher than the central core temperature, and there is also a temperature gradient within the brain, with the central parts being warmer than the surface. The relationship between rectal, epidural and intraventricular temperatures is maintained during anaesthesia. We have also shown that it is possible to lower the temperature of the human brain.
Brain edema was induced in adult rats by intraperitoneal injection of distilled water equivalent to 15% of the animal's body weight. Mean +/- SEM serum osmolality fell from 291 +/- 3 mOsm to 253 +/- 4 mOsm during the next hour while cerebral gray matter water content increased from 79.5 +/- 0.2% to 80.9 +/- 0.2%. Gray matter content of sodium, potassium, taurine, glycine, glutamine, and glutamate were unchanged. However, the blood-brain barrier permeability/surface area product for water decreased by 40%. This alteration in water permeability may represent a response to limit water influx during the first hour of hypoosmotic brain edema.
An endogenous ouabain-like factor (EOLF) was measured in brain tissue of cats 12 and 24 hrs after cold injury-induced edema. EOLF was assayed via its inhibition of 86Rb+uptake in human red blood cells in a fraction which was obtained from brain tissue by methanol extraction, chloroform treatment and purification of the water phase by C-18 HPLC. As compared to the contralateral hemispheres with an EOLF concentration of 605 ±71 pmol ouabain equivalents per g wet weight, the edematous hemisphere had significantly higher concentrations: 12 hours after cold injury it was 2600 ± 1762 pmol (p < 0.03) and fell to 857 ± 160 pmol ouabain equivalents/g wet weight after 24 hrs. Similar kinetics were evident for the EOLF concentrations in cerebrospinal fluid. It is suggested that the increase of EOLF in the edematous brain hemisphere may participate as a mediator in the development of vasogenic brain edema in the disturbance of the sodium metabolism.
