Blood-brain barrier pathophysiology and ischaemic brain oedema

Cerebral oedema is a potentially lethal complication of brain infarction. Ischemia, by altering membrane ionic pump function, induces cell swelling and cytotoxic oedema. It also initiates early oxidative and inflammatory cascades leading to blood-brain barrier disruption, vasogenic oedema and haemorrhagic transformation. The mechanisms of blood-brain barrier disruption involve endothelial cell activation and endothelial basal membrane degradation by matrix metalloproteinases. Reperfusion by tissue plasminogen activators is the only treatment improving stroke prognosis. This treatment also increases vasogenic oedema and the risk of symptomatic haemorrhagic transformation, reducing the benefit of reperfusion. Experimental studies suggest that the inhibition of blood-brain barrier proteolysis reduces vasogenic oedema and the risk of haemorrhage. This recent progress in the understanding of blood-brain barrier disruption during ischaemia brings forward new therapeutic strategies using agents capable of interfering with the ischaemic cascade in order to increase the therapeutic window between the onset of ischaemia and thrombolytic reperfusion.     

Regional cerebral blood flow and cerebral perfusion pressure in global brain oedema induced by water intoxication

Summary Global brain oedema was induced by water intoxication with 50, 100, 150 and 200 ml Aqua dest./kg body weight in cats. In moderate brain oedema (following a water load of 100–150 ml/kg body weight) rCBF decreased independently of CPP but in close correlation to the increase of tissue water content. In severe brain oedema (following a water load of 150–200 ml/kg body weight) rCBF dropped progressively to very low values close to zero flow. This was paralleled by a sharp CSFP increase accompanied by an extreme CPP decrease to about 20 mm Hg and a further but less steep increase of tissue water content.The reason for the CPP-independent rCBF decrease in moderate brain oedema seems to be a diminution of capillary diameter as a consequence of astroglia swelling both in the vicinity of and at distance from the vessels. Moreover an increase of tissue pressure also causes an increase of cerebrovascular resistance. In severe brain oedema additional extreme ICP increase and CPP decrease finally supervene causing blood flow to stop.These results are discussed with relation to the clinical conditions of increased intracranial pressure due to brain oedema, hydrocephalus, or an intracranial expanding mass. It can be concluded that the effect of increased ICP on rCBF is different in these situations.This investigation was supported by a grant from the Deutsche Forschungsgemeinschaft.     

The effect of neodymium yttrium aluminum garment laser on the cerebral blood vessel and blood brain barrier

The effect of the laser energy to the cerebral vascular reactivity and the blood brain barrier. A Nd:YAG laser with 20 watt impacts of 0.5, 1.0, 2.5 and 5.0 seconds duration time were irradiated through the cranial window made at the parietal regions of anesthetized adult cats. The disruption of the blood brain barrier was examined by checking the degree of the extravasation of Evans blue dye administrated in the vein. The cortical vessel reactivity was observed through the cranial window and evaluated using an intravital microscope and a videoangiometer. The extravasation of Evans blue dye was seen uniformly extending from the histologically changed area into the surrounding tissue in all experiments. The extent of the extravasation of dye was 1 to 1.5 mm larger than the extent of the histologically changed area produced by laser irradiation. Pial arteries in the area with histological changes dilated markedly and some of them lost their blood stream. Pial arteries in the area of Evans blue extravasation, but outside it histological changes also dilated markedly. Furthermore, pial arteries within a distance of 200 to 400 microns from the edge of the Evans blue extravasation area also dilated moderately. A statistical estimation showed that the degree of dilatation of arteries in the area outside the histological change improved significantly in the time course of five minutes.     

Brain oedema,intracranial pressure and cerebral blood flow

Brain oedema leads to pathological changes in intracranial pressure (ICP) and cerebral blood flow in a wide range of clinical scenarios, because the brain produces oedema in response to many diseases. Clinical management often focuses on minimizing elevations of ICP and maintaining adequate cerebral blood flow. A working knowledge of physiological principles linking brain oedema, ICP and blood flow is essential for clinicians facing these clinical problems. These principles are explained here, and also some insights are provided concerning the mechanisms of disease on the cellular level. This is then applied to the clinical problem of traumatic brain injury illustrating physiological principles in clinical practice.     

Plasma osmolarity and cerebral volume

Under normal physiological conditions, the osmolarity of extracellular fluids (ECFs) and natremia are controlled by two regulatory mechanisms modulating the water balance and sodium outflow from information collected by the osmoreceptors and baroreceptors, respectively. As well, under normal physiological conditions, water and electrolytes of brain ECFs are secreted by the endothelial cells of brain capillaries. Furthermore, isotonicity is present on both sides of the blood-brain barrier. In the event of systemic osmolarity disorders, water transport subject to osmosis laws occurs at the level of the blood-brain barrier. In the case of plasmatic hyperosmolarity cerebral dehydration is observed, while cerebral edema occurs in the contrary case. However, plasmatic osmolarity disorders have less effect on the cerebral volume when their introduction is slow. Experimentation in acute conditions shows that measured variations of the cerebral water content are lower than calculated variations, thus suggesting the existence of an adaptive mechanism, that is, the cerebral osmoregulation which limits the variation of the volume of brain cells by modulating their osmoactive molecule content. These osmoactive molecules are, on the one hand, the electrolytes, which are early and rapidly mobilized, and, on the other hand, the organic osmoles (amino acids, etc.), whose secretion is slower and delayed. This phenomenon should be taken into account in the treatment of osmolarity disorders. Thus, the related-risk of treatment for natremia disorders is therapeutic reversal of the osmotic gradient at the level of the blood-brain barrier. This reversal, which corresponds to a second osmotic stress, requires the implementation of a new procedure of cerebral osmoregulation in the opposite direction of the preceding one. As successive osmotic stresses decrease the effectiveness of brain osmoregulation, the risk for cerebral dehydration and pontine myelinolysis increases when the treatment of chronic hyponatremia is too aggressive. Finally, the choices for infusion solutions in neurosurgery and treatment for osmolarity disorders are also based on the relationships that exist between plasmatic osmolarity and the brain.     

Disturbances in the blood-brain barrier and cerebral blood flow after rapid brain decompression in the cat

Summary The effect of sudden decompression of the brain on the blood-brain barrier and cerebral blood flow was studied in cats. The decompression experiments were performed on 9 cats which had been subjected to two hours of compression with an epidural balloon and on 10 cats subjected to four hours of balloon compression. In both experimental groups one could observe haemorrhages and disturbances in the blood-brain barrier in the cortex of the previously compressed hemisphere and in the basal nuclei. The extent of these changes depended on the duration of the epidural compression. At the same time, a decrease in cerebral blood flow, mainly in the brain cortex, was observed in both experimental groups.This study was supported in part by a grant from the Polish Academy of Sciences.We should like to thank Mr. A. Budny for technical assistance.     

The role of cerebral blood volume changes in brain specific-gravity measurements

Cerebral blood volume (CBV) was calculated in gerbils from specific-gravity (SG) changes between normal and saline-perfused brains. Furthermore, changes in CBV were investigated during ischemia using carbon-14-labeled dextran (MW 70,000) as an intravascular marker. Both data were used to evaluate the possible error due to a change in CBV on the measurement of ischemic brain edema by the SG method. The methodological error found was 0.0004 for a 100% CBV change. This error is insignificant, being less than the standard deviation in the SG measured for the gerbil cortex (SG 1.0494 +/- 0.0006). Thus, CBV changes are not responsible for the SG variations observed during the first phase of ischemia. These variations are better explained as an increase of brain water content during ischemia.     

Measurement of brain tissue pressure in cold induced cerebral oedema

Summary The clinical course preceding brain death was observed in 62 patients by frequent clinical examinations; in 44 of them the intracranial pressure was recorded continuously. In 53 patients the diagnosis of brain death was confirmed by demonstration of cessation of the brain circulation using four-vessel cerebral angiography. Sudden and gradual deterioration was found as the intracranial pressure rose to the level of the arterial blood pressure. After arteriographic documentation of brain death spinal reflexes were present in 80 per cent of the patients.Supported by grants from Danish Medical Research Council and F. L. Schmidt & Co's jubeleumsfond.     

Osmotic blood-brain barrier modification and combination chemotherapy: concurrent tumor regression in areas of barrier opening and progression in brain regions distant to barrier opening

Chemotherapeutic drug delivery can be enhanced by administering drugs into the internal carotid or vertebral artery circulation after osmotic opening of the blood-brain barrier (BBB). As evidence of the clinical implications of this technique, radiographic documentation of central nervous system (CNS) tumor regression was observed in three patients concurrent with the development of new tumor nodule(s) in portions of the brain distant from the region of osmotic blood-brain barrier opening. These three patients, one with metastatic carcinoma of the breast, one with glioblastoma, and one with primary CNS lymphoma, highlight the importance of drug delivery to CNS malignancies.     

Haemodialysis and cerebral oedema

BACKGROUND: Haemodialysis may cause neurological symptoms ranging from inconvenient feelings of disequilibrium to life-threatening neurological complications. There are animal data to suggest cerebral swelling may accompany haemodialysis and contribute symptomatically to dialysis disequilibrium. However, MR images acquired following haemodialysis often fail to demonstrate evidence of cerebral oedema. We wished to quantify any potential cerebral volume change which is caused by haemodialysis treatment. METHOD: Five renal patients and 5 control subjects had a two volumetric T1-weighted MRI scans on the same day. The patients were imaged immediately before and after haemodialysis. None were taking steroids. Precise positional matching (registration) was used to quantify cerebral volume change. RESULTS: Patients had an increase in cerebral volume following dialysis which averaged 32.8 ml (SE 7.4 ml, 3% brain volume). The change in the controls was 1.4 ml (SE 0.6 ml), p < 0.001. No patient had significant neurological symptoms. CONCLUSION: Cerebral oedema developed in the patients following dialysis. There is a good biological model for these observations. Modifications to dialysis may help. Common problems which increase cerebral volume, e.g. acute stroke, require careful appraisal in these patients. These observations need consideration when quantifying atrophy in dialysis patients.     

Regional cerebral blood flow and regional metabolism in cold induced oedema

Summary 24 hours following a cold induced oedema in cats rCBF was measured in the lesion area, the bluish stained cortex immediately adjacent to the lesion, a cortical area remote from the lesion, and in the contralateral uninjured hemisphere. Thereafter the brain was frozen and the respective tissue areas were removed and analyzed for water and electrolyte content as well as metabolite concentrations. It seems, that in the neighbourhood of a local lesion at least 3 different brain regions can be differentiated with regard to their characteristic pattern of data. In non-oedematous regions either hyperaemia or hypoaemia could be observed. In areas with local brain oedema rCBF was reduced inversely proportional to the tissue water content. It seems that the luxury perfusion syndrome represents only one of several possibilities of regional flow pattern around a local brain lesion and its occurrence is confined to non-oedematous areas.Reduction of rCBF by 20% in the remote and by 33% in the adjacent oedematous areas does not cause significant changes in the tissue concentrations of phosphocreatine, ATP and ADP, while lactate and the L/P ratio are clearly elevated. A significant drop of the high-energy compounds is found in the lesion, where the flow was reduced by about 62%. This indicates that the local tissue hypoxia occurs as a result of the diminution in local microcirculation.This investigation was supported by a grant from the Deutsche Forschungsgemeinschaft.     

Enhanced disruption of the blood brain barrier by intracarotid mannitol injection during transient cerebral hypoperfusion in rabbits

Fairly large volumes of intracarotid mannitol (20% to 25%) are required to disrupt the blood brain barrier (BBB), that is, 200 to 300 mL/30 s in humans or 10 mL/40 s in rabbits. During transient cerebral hypoperfusion blood flow to the rabbit brain is decreased to 0.2 to 0.3 mL/30 s. We therefore hypothesized that if the disruption of the BBB by intracarotid mannitol was primarily due to its osmotic effects, injection of 0.2 to 0.3 mL of mannitol during transient cerebral hypoperfusion will be sufficient to disrupt the BBB, thereby dramatically (by 20-folds) decrease the dose requirements compared with injections during normal blood flow. After preliminary studies, 4 doses of intracarotid mannitol were first tested: (1) 2 mL with cerebral hypoperfusion, (2) 4 mL with cerebral hypoperfusion, (3) 4 mL without cerebral hypoperfusion, and (4) 8 mL without cerebral hypoperfusion. Next, we compared the extent to which methods of drug delivery (infusion vs. bolus injection) affected BBB disruption in 12 rabbits. Finally, we assessed the duration of BBB disruption with intracarotid mannitol in another 12 rabbits. We observed that BBB disruption during injection of 4 mL of mannitol with cerebral hypoperfusion was comparable to 8 mL mannitol without cerebral hypoperfusion. Bolus injections of 4 mL mannitol were more effective than steady-state infusions. The BBB disruption with intracarotid mannitol lasted for 60 minutes postinjection. We conclude that cerebral hypoperfusion decreases the dose of intracarotid mannitol by a modest 2-fold. Our results suggest that mechanical factors may play a significant role in the osmotic disruption of the BBB by intracarotid mannitol.     

Treatment of cerebral oedema

Progress in brain imaging, monitoring and physiopathology allows the identification of brain oedema from brain swelling, determination of its interstitial or intracellular nature, as well as blood-brain barrier permeability and the evaluation of the impact on cerebral haemodynamic. Common treatment of all types of cerebral oedema is based on prevention of self-sustained disorders due to increased intracranial pressure resulting in ischemic cerebral oedema. The specific treatment of each type of cerebral oedema is reviewed. Optimization of conventional anti-oedematous strategies is based on the precise determination of the nature of the cerebral oedema and of the blood-brain barrier status.     

Brain oedema following blood-brain barrier disruption: mechanisms and diagnosis

Brain oedema following blood-brain barrier (BBB) disruption, or vasogenic oedema, is present in most cases of brain oedema. According to the Starling's law, water, ions and plasma proteins cross the BBB toward the interstitium if the driving forces for transmural bulk flow are excessive (mechanical origin) and/or if the BBB permeability is enhanced (chemical origin). Both mechanisms coexist in most cases. Excessive elevation of the gradient of hydrostatic pressure with lost of cerebral autoregulation has been proved in ischaemia/reperfusion and trauma, and suggested in acute mountain sickness and eclampsia. The BBB permeability can be enhanced by immediate (chemical mediators) or delayed (cellular infiltration) inflammatory response, or by alteration of the membrane integrity. This later can be transient (hyperosmolar BBB disruption), or permanent by activation of matrix metalloproteinase or by neovascularization with BBB breakdown. The reference method for the diagnosis of vasogenic oedema is the MRI diffusion-weighted imaging.     

Osmotic blood-brain barrier modification: monoclonal antibody, albumin, and methotrexate delivery to cerebrospinal fluid and brain

In the dog, osmotic opening of the blood-brain barrier (BBB) in the posterior circulation via the vertebral artery and in the anterior circulation via the internal carotid artery was utilized to increase the delivery of three substances of varying molecular weight to the central nervous system. The cerebrospinal fluid (CSF) concentration of all three agents dramatically increased after BBB opening. In contrast to methotrexate, Evans blue-albumin and monoclonal antibody (MAb) concentrations in CSF were 6-fold greater when given after posterior rather than anterior circulation BBB opening. Conversely, MAb delivery to brain parenchyma was optimized after osmotic BBB modification via the carotid artery. This suggests that, with higher molecular weight substances, osmotic barrier opening has a differential effect on the blood-brain vs. blood-CSF barriers.     

Steady-state propofol brain:plasma and brain:blood partition coefficients and the effect-site equilibration paradox

Based on volume-flow relationships, CNS agents that are highly lipid soluble (log octanol-water partition coefficient > 2) are expected to have equilibration half-times (T1/2 kE0) that are proportional to brain solubility. Propofol, the most lipophilic anaesthetic in clinical use, has T1/2 kE0 values of 1.7 and 2.9 min in rats and humans, respectively, compared with an expected value of at least 8 min. As a first step in exploring this discrepancy between observed and predicted values, we determined the steady state brain:plasma and brain:blood partition coefficients in rats after a 4-h infusion of propofol. Brain:plasma and brain:blood partition coefficients were 8.2 (SD 1.6) and 3.0 (0.5), respectively. T1/2 kE0 predictions based on brain: blood partitioning in rats are more in agreement with the observed equilibration half-time, suggesting that drug bound to the formed elements of blood participates in the uptake and transfer of propofol to its effect site.      

Beagle pup model of brain injury: regional cerebral blood flow and cerebral prostaglandins

Asphyxia is the most common cause of severe brain injury in very young children, and frequently results in lesions of the periventricular white matter in addition to other neuropathological changes. This study examines the effects of asphyxia on regional cerebral blood flow (rCBF) and the role of prostaglandins (PG's) in its control in the newborn beagle pup. Pups were anesthetized, tracheotomized, paralyzed, artificially ventilated, and randomly assigned to two groups: asphyxial insult produced by discontinuing ventilatory support, and no insult. Experiments for carbon-14-iodoantipyrine autoradiographic determination of rCBF and regional cerebral PG determination were performed on separate groups of pups. These studies demonstrated a significant increase in cortical gray PGE2 levels at a time when rCBF was significantly impaired in response to severe asphyxial insult. No such increase was noted in the periventricular white matter zones.     

Tocolysis with ritodrine worsens cerebral oedema in a patient with brain injury

In a 33-weeks pregnant patient with a head injury, neurological status severely deteriorated after introduction of tocolytic treatment with ritodrine. On admission to the intensive care unit she scored 10 points on the Glasgow coma scale. She gradually recovered and on day 7 there was no neurological deficit, apart from slight confusion. The same day tocolytic treatment with ritodrine was recommended because of imminent premature labour. Fourteen hours after ritodrine infusion was started, the neurological status deteriorated severely. Urgent CT scan showed signs of transtentorial herniation. Ritodrine infusion was stopped and therapy for brain oedema was introduced. The patient made a good neurological recovery. A caesarean section was performed on day 11, because of placenta praevia, and a healthy girl was delivered. The patient was discharged without neurological sequelae. The clinical course and CT findings imply that tocolytic treatment with ritodrine can worsen brain oedema in a patient with a disrupted blood-brain barrier, as in head injury. The mechanism is probably analogous to the one by which ritodrine causes pulmonary oedema, a well-known complication.