The effects of etomidate in the cat middle cerebral artery occlusion model of brain ischaemia. An experimental study

The effects of etomidate on focal cerebral ischaemia following transorbital occlusion of the cat middle cerebral artery were investigated. Etomidate had no effect on CBF before or after onset of ischaemia by comparison with controls, but caused a greater fall in CBF in cats with high preocclusion or initial ischaemic CBF than in those in which CBF was lower. There were more sustained rises in Kp on SG. The established flow threshold for water accumulation was lost; more gyri with CBF above and fewer gyri with CBF below the flow threshold accumulated water. The relationship between mean occlusion CBF and in vitro GABA uptake was lost; uptakes from MG were lower and from SG and EG higher than expected. In the ischaemic penumbra there was a trend towards reduction in CBF, disruption of ion homeostasis and cerebral oedema formation, whilst in areas of lower flow there was some recovery of GABA uptake and less cerebral oedema following administration of etomidate.     

The effects of hyperglycaemia on changes during reperfusion following focal cerebral ischaemia in the cat.

The effects of isosmolar loads of glucose and saline after onset of focal cerebral ischaemia (middle cerebral artery occlusion) were compared in cats. In cats given saline cerebral blood flow (CBF) fell and then rose slightly on the marginal gyrus (infarct penumbra). There was a sustained fall in CBF on the suprasylvian and ectosylvian gyri (infarct core). Reperfusion restored blood flow to preocclusion levels with no overall postischaemic hypoperfusion. Below ischaemic flows of 14 ml/100 g/min brain specific gravity was reduced in a smaller proportion of gyri by contrast with non reperfused cortex, suggesting that in some gyri resolution of cerebral oedema had taken place. GABA uptake was normal in the infarct core, but was reduced within the ischaemic penumbra. In animals given glucose after occlusion, CBF fell on the marginal gyrus during reperfusion. The degree of resolution of cerebral oedema was less than in saline infused cats. GABA uptake showed a pattern of abnormality similar to that seen in saline infused cats, except that uptake values were lower in the infarct core. Pial surface potassium activity remained elevated in the penumbra following reperfusion in glucose infused cats, but returned to normal in saline infused cats. Implications for the management of cerebral ischaemia in man are discussed.     

Blood volume expansion with hetastarch in acute ischaemic stroke: the effects on local cerebral blood flow and computer mapped EEG

Focal cerebral ischaemia was induced in seven anaesthetized monkeys by unilateral middle cerebral artery (MCA) occlusion. Local cerebral blood flow (CBF) and computer mapped EEG (CME) changes were then studied as blood volume and cardiac output (CO) were varied. CO was increased by colloidal volume expansion and decreased by exsanguination. Local CBF fell to 24 +/- 9% of control values in ischaemic areas following MCA occlusion and increased to 43 +/- 19% of control values (p less than 0.01) when CO was increased by 130 +/- 70% with colloid infusion. Local CBF to nonischaemic regions was not altered significantly by blood volume expansion. Exsanguination led to return of CO to control levels and was associated with reduction of local CBF in ischaemic regions to 24 +/- 12% of control values (p less than 0.05). CME showed bifrontal or ipsilateral slow wave foci (delta) following MCA occlusion. Blood volume expansion brought about a marked reduction of this slow wave activity and exsanguination led to recurrence of the slow wave foci. This data demonstrated that colloidal blood volume expansion induced an increase in local CBF and improved neuroelectric status of ischaemic brain following MCA occlusion. It was also shown that a reduction of blood volume and cardiac output resulted in a reduction in local CBF and a worsening of neuroelectric status in ischaemic areas. This study supports the contention that blood volume and cardiac output maintenance is extremely important in the management of acute ischaemic stroke.     

Blood volume expansion with hetastarch in acute ischaemic stroke: the effects on local cerebral blood flow and computer mapped EEG

Focal cerebral ischaemia was induced in seven anaesthetized monkeys by unilateral middle cerebral artery (MCA) occlusion. Local cerebral blood flow (CBF) and computer mapped EEG (CME) changes were then studied as blood volume and cardiac output (CO) were varied. CO was increased by colloidal volume expansion and decreased by exsanguination. Local CBF fell to 24 ± 9% of control values in ischaemic areas following MCA occlusion and increased to 43 ± 19% of control values (p < 0.01) when CO was increased by 130 ± 70% with colloid infusion. Local CBF to nonischaemic regions was not altered significantly by blood volume expansion. Exsanguination led to return of CO to control levels and was associated with reduction of local CBF in ischaemic regions to 24 ± 12% of control values (p < 0.05).

CME showed bifrontal or ipsilateral slow wave foci (delta) following MCA occlusion. Blood volume expansion brought about a marked reduction of this slow wave activity and exsanguination led to recurrence of the slow wave foci.

This data demonstrated that colloidal blood volume expansion induced an increase in local CBF and improved neuroelectric status of ischaemic brain following MCA occlusion. It was also shown that a reduction of blood volume and cardiac output resulted in a reduction in local CBF and a worsening of neuroelectric status in ischaemic areas. This study supports the contention that blood volume and cardiac output maintenance is extremely important in the management of acute ischaemic stroke.     

Observations on cerebral ischaemia in cats at injury threshold levels

Abstract

The potential for recovery of brain tissue subjected to ischaemia at a threshold level of injury was evaluated in cats subjected to 20 min middle cerebral artery occlusion. In addition to assessment of regional cerebral blood flow and water content, the permeability of the bloodbrain barrier and morphological changes detected by light microscopy were studied at various time intervals. Our observations revealed that although a similar reduction of blood flow during arterial occlusion was found both in the caudate nucleus and the cerebral cortex, the reactive hyperaemia was consistently higher in the caudate nucleus than in the cortex. After 24 h the caudate nucleus also revealed a significantly higher water content and increased vascular permeability than the cortex. Morphological observations at 24 h in areas affected by ischaemia showed widespread, marked ischaemic neuronal injury, whereas at 3 d there was, in addition, a vigorous proliferative reaction of vascular elements. Cats sacrificed at 14 d revealed a remarkably good preservation of neurons, both in the caudate nucleus and cortex which otherwise showed a few circumscribedsmall, infarcts surrounded by normal nerve cells. Our study suggests that neurons injured at threshold level have a considerable capacity for recovery. Otherwise, with a similar degree of ischaemiathe caudate nucleus appears more prone to increased vascular permeability and oedema than the cerebral cortex.     

Amelioration of ischaemic cerebral oedema by a free radical scavenger, AVS: 1,2-bis(nicotinamido)-propane. An experimental study using a regional ischaemia model in cats

The effect of a free radical scavenger, AVS: 1,2-bis(nicotinamido)-propane, on the blood flow, oedema, and energy metabolites in the cortical area rendered ischaemic by the occlusion of the middle and the internal cerebral arteries was studied using cats. The development of cortical oedema was assessed by the changes in the specific gravity as well as the water and electrolyte contents of the cortical samples obtained 4 h after the arterial occlusion. Compared to the control group receiving saline, the AVS group exhibited a significant amelioration of cortical oedema, whereas no effect of AVS on the cortical blood flow was observed. The decrease of the energy charge and the increase of lactate in the ischaemic cortical area were less pronounced in the AVS groups. These data indicate that AVS possesses an action to mitigate the development of cortical oedema following regional ischaemia. The possible mechanism of action of AVS is discussed in reference to the free radical hypothesis.     

Measurement of somatosensory evoked potential in the Mongolian gerbil: the effects of cerebral ischaemia

Normal somatosensory evoked potential (SEP) as well as changes after incomplete cerebral ischaemia following bilateral carotid artery occlusion (BCO) were characterized in the Mongolian gerbil. BCO significantly decreased cerebral blood flow (CBF). Reperfusion CBF at 10 min and 2, 3 and 4 h was significantly below preischaemic control values. BCO decreased SEP amplitude but had no effect on EP-P3 central conduction time. BCO did significantly increase EP-P11 central conduction time. Reperfusion amplitudes at 10 min and 2, 3 and 4 h revealed a significant increase only at 4 h when compared to the ischaemic amplitude. EP-P11 central conduction time at 10 min reperfusion showed dramatic improvement compared to ischaemic values, although values at 2, 3 and 4 h reperfusion were not statistically different from ischaemic values. A separate group of animals prepared identically but without BCO showed no significant changes in either SEP or CBF over time. These studies establish the protocol necessary to measure SEP in the Mongolian gerbil. In the future SEP may be used as an integral tool in the study of the primary determinants of neurophysiological recovery following cerebral ischaemia.     

Amelioration of ischaemic cerebral oedema by a free radical scavenger,AVS: 1,2-bis(nicotinamido)-propane. An experimental study using a regional ischaemia model in cats

The effect of a free radical scavenger, AVS: 1,2-bis(nicotinamido)-propane, on the blood f1ow, oedema, and energy metabolites in the cortical area rendered ischaemic by the occlusion of the middle and the internal cerebral arteries was studied using cats. The development of cortical oedema was assessed by the changes in the specific gravity as well as the water and electrolyte contents of the cortical samples obtained 4 h after the arterial occlusion. Compared to the control group receiving saline, the AVS group exhibited a significant amelioration of cortical oedema, whereas no effect of AVS on the cortical blood flow was observed. The decrease of the energy charge and the increase of lactate in the ischaemic cortical area were less pronounced in the AVS groups. These data indicate that AVS possesses an action to mitigate the development of cortical oedema following regional ischaemia. The possible mechanism of action of AVS is discussed in reference to the free radical hypothesis.     

Patterns of EEG frequency content during experimental transient ischaemia in subhuman primates

EEGs were recorded with depth electrodes in 8 monkeys undergoing transient middle cerebral artery ligation. Electrodes measured EEG, cerebral blood flow (CBF), and tissue oxygen simultaneously during and after occlusion. An EEG frequency analysis was performed. Electrode sites were examined microscopically, and infarction size, tissue vacuolization index, and neuronal morphology were described quantitatively. Serial neurological examinations were performed. Two patterns of EEG frequency change were delineated, dependent upon degree of ischaemia. Mild ischaemia, as indicated by less severe clinical deficits, higher CBF during occlusion, and minor pathological changes was associated with large increases in slow EEG activity and decreases in fast EEG activity during occlusion, with recovery of slow activities to baseline, but continued suppression of fast activities 24 h later. Severe ischaemia was associated with suppression of both fast and slow frequencies during occlusion, with slow activities returning to baseline and fast activities remaining suppressed 24 h later. The best quantitative EEG indicator of severity of ischaemia was suppression of slow wave activity during occlusion. The best EEG indicator that an ischaemic event had occurred 24 h previously was continued suppression of fast EEG activities. These data may be helpful in the design of EEG frequency analysis studies for monitoring the time course of human cerebral ischaemia and for retrospective diagnosis of transient ischaemic attacks (TIAs).     

Cerebral protective effect of flunarizine in a canine model of cerebral ischaemia

To test the effect of flunarizine on cerebral ischaemia, 15 dogs were subjected to ischaemia, using the 'canine model of the completely ischaemic brain regulated with a perfusion method' in which the cerebral blood flow (CBF) can be fully regulated. Five animals served as untreated controls, 10 received flunarizine, a calcium antagonist (1 mg/kg in 5 dogs and 3 mg/kg in 5 dogs), before the ischaemic period. After 1 h CBF was restored and recovery of the electrical activity of the brain and the degree of brain swelling were observed for 3 h. At the end of the experiments, the degree of extravasation of Evans blue was examined. Remarkable recovery of EEG was found in the groups given flunarizine when compared with untreated controls. However, no significant difference was found between untreated controls and flunarizine treated groups for the degree of brain swelling and the degree of extravasation of Evans blue. These results suggest that the treatment of flunarizine is of benefit for functional recovery against cerebral ischaemia, but does not suppress ischaemic brain oedema.     

Patterns of EEG frequency content during experimental transient ischaemia in subhuman primates

EEGs were recorded with depth electrodes in 8 monkeys undergoing transient middle cerebral artery ligation. Electrodes measured EEG, cerebral blood flow (CBF), and tissue oxygen simultaneously during and after occlusion. An EEG frequency analysis was performed, Electrode sites were examined microscopically, and infarction size, tissue vacuolization index, and neuronal morphology were described quantitatively. Serial neurological examinations were performed. Two patterns of EEG frequency change were delineated, dependent upon degree of ischaemia. Mild ischaemia, as indicated by less severe clinical deficits, higher CBF during occlusion, and minor pathological changes was associated with large increases in slow EEG activity and decreases in fast EEG activity during occlusion, with recovery of slow activities to baseline, but continued suppression of fast activities 24 h later. Severe ischaemia was associated with suppression of both fast and slow frequencies during occlusion, with slow activities returning to baseline and fast activities remaining suppressed 24 h later. The best quantitative EEG indicator of severity of ischaemia was suppression of slow wave activity during occlusion. The best EEG indicator that an ischaemic event had occurred24 h previously was continued suppression of fast EEG activities. These data may be helpful in the design of EEG frequency analysis studies for monitoring the time course of human cerebral ischaemia and for retrospective diagnosis of transient ischaemic attacks (TIAs).     

Effects of cervical spinal cord stimulation in experimental ischaemic oedema

Abstract

Cervical spinal cord stimulation (SCS) has been used in an animal model of acute ischaemic brain oedema. In anaesthetized rats a temporary carotid bilateral occlusion of 60 minutes was carried out, followed by a reperfusion period of 30 minutes before sacrifice. Two electrodes were placed in each side of the duramater at C2 level. SCS was started either 60 minutes before ischaemia or at the beginning of the reperfusion period. The parameters of stimulation were: pulse width 0.1 ms; frequency of 25 cps; intensity at one third of the threshold which produced motor responses. The specific gravity of the brain was measured at different areas using a microgravimetric technique in a bromobenzene-petroleum column. Our results indicate that: 1) cervical SCS reduces ischaemic cerebral oedemai, 2) the effect is more prominent using stimulation during the reperfusion period, and 3) there were no differences in mortality rates or in the pathological study.     

Measurement of somatosensory evoked potential in the Mongolian gerbil: the effects of cerebral ischaemia

Normal somatosensory evoked potential (SEP) as well as changes after incomplete cerebral ischaemia following bilateral carotid artery occlusion (BCO) were characterized in the Mongolian gerbil. BCO significantly decreased cerebral blood flow (CBF). Reperfusion CBF at 10 min and 2, 3 and 4 h was significantly below preischaemic control values. BCO decreased SEP amplitude but had no effect on EP-P₃ central conduction time. BCO did significantly increase EP-P₁₁ central conduction time. Reperfusion amplitudes at 10 min and 2, 3 and 4 h revealed a significant increase only at 4 h when compared to the ischaemic amplitude. EP-P₁₁ central conduction time at 10 min reperfusion showed dramatic improvement compared to ischaemic values, although values at 2, 3 and 4 h reperfusion were not statistically different from ischaemic values. A separate group of animals prepared identically but without BCO showed no significant changes in either SEP or CBF over time. These studies establish the protocol necessary to measure SEP in the Mongolian gerbil. In the future SEP may be used as an integral tool in the study of the primary determinants of neurophysiological recovery following cerebral ischaemia.     

Colloidal volume expansion during acute cerebral ischaemia: assessed by local cerebral blood flow and computerized power ratio index

Colloidal volume expansion during acute cerebral ischaemia was assessed by local cerebral blood flow (CBF) and the power ratio index (PRI) in 8 anaesthetized Macaque monkeys. Focal cerebral ischaemia was produced by right middle cerebral artery occlusion. The animals were then volume expanded (to maximum cardiac output) with 6% hetastarch and then exsanguinated to baseline cardiac output. During volume expansion, local CBF in the ischaemic hemisphere increased from 25 ± 12 to 39 ± 23 cc/100 g/min (p > 0.01) and during exsanguination decreased to 32 ± 18 cc/100 g/min. Local CBF did not change significantly in the nonischaemic hemisphere. EEG power data, as assessed by PRI [(delta + theta power/alpha + beta power) × 100] changed significantly during blood volume manipulation. The mean PRI value in the right hemisphere deteriorated by increasing from 65 ± 22 to 94 ± 25 (p > 0.01) following vessel occlusion but improved by decreasing to 81 ± 23 (p > 0.05) following volume expansion. Following exsanguination, the PRI value increased to 87 ± 21. These data demonstrate the benefits of volume expansion during acute cerebral ischaemia. Changes in local CBF were consistently associated with changes in the PRI maps and values.     

Colloidal volume expansion during acute cerebral ischaemia: assessed by local cerebral blood flow and computerized power ratio index

Colloidal volume expansion during acute cerebral ischaemia was assessed by local cerebral blood flow (CBF) and the power ratio index (PRI) in 8 anaesthetized Macaque monkeys. Focal cerebral ischaemia was produced by right middle cerebral artery occlusion. The animals were then volume expanded (to maximum cardiac output) with 6% hetastarch and then exsanguinated to baseline cardiac output. During volume expansion, local CBF in the ischaemic hemisphere increased from 25 +/- 12 to 39 +/- 23 cc/100 g/min (p less than 0.01) and during exsanguination decreased to 32 +/- 18 cc/100 g/min. Local CBF did not change significantly in the nonischaemic hemisphere. EEG power data, as assessed by PRI [(delta + theta power/alpha + beta power) x 100] changed significantly during blood volume manipulation. The mean PRI value in the right hemisphere deteriorated by increasing from 65 +/- 22 to 94 +/- 25 (p less than 0.01) following vessel occlusion but improved by decreasing to 81 +/- 23 (p less than 0.05) following volume expansion. Following exsanguination, the PRI value increased to 87 +/- 21. These data demonstrate the benefits of volume expansion during acute cerebral ischaemia. Changes in local CBF were consistently associated with changes in the PRI maps and values.     

Effect of Fluosol-DA and hetastarch on local cerebral blood flow, cortical O2 availability and computerized EEG data during cerebral ischaemia.

This study was designed to assess the effects of volume expansion with Fluosol-DA and hetastarch on local cerebral blood flow (CBF), cortical O2 availability (O2a) and computerized EEG power data during cerebral ischaemia in a primate stroke model. Focal cerebral ischaemia was produced in 20 anaesthetized Macaca monkeys by right unilateral middle cerebral artery (MCA) occlusion by the transorbital technique. Following occlusion of the right MCA, monkeys were randomized into one of the following treatment groups: Group A--Fluosol-DA 15 ml kg-1 i.v. + 40% O2; Group B--Fluosol-DA 15 ml kg-1 i.v. + 100% O2; Group C--hetastarch 30 ml kg-1 i.v. + 40% O2; Group D--hetastarch 30 ml kg-1 i.v. + 100% O2. In Group A, local CBF increased and EEG power data improved while O2a showed no change in the right MCA territory. In Group B, local CBF increased from 84% (P less than 0.001), O2a improved significantly, and EEG power data showed significant improvement in the right hemisphere. Cardiac output did not change during the Fluosol-DA infusions. In Groups C and D, local CBF increased significantly, O2a did not change, and EEG power data improved significantly in the right hemisphere. Cardiac output also increased significantly during the hetastarch infusions. These results show that Fluosol-DA and hetastarch improve local CBF and EEG power data in ischaemic brain. Only the Fluosol-DA + 100% O2 increased the O2a in the ischaemic brain. We conclude that the benefits with Fluosol-DA are due to its ability to increase O2 delivery to ischaemic brain.     

Evolution and resolution of oedema following severe temporary cerebral ischaemia in the gerbil.

Regional cerebral blood flow (rCBF) and oedema following profound temporary ischaemia were studied in the gerbil. Ninety-four per cent of animals died within 24 hours of reperfusion; 50% by 4 hours. Regional differences in oedema (specific gravity method), Evans blue (EB) staining and rCBF (hydrogen clearance technique) occurred. Oedema developed during arterial occlusion, being inversely proportional to residual flow and was markedly exacerbated during reperfusion. Reperfusion hyperaemia was maximal in the parietal and hippocampal regions (ischaemic rCBF 4 ml 100 g-1 min-1). Oedema was disappearing in all areas by 3 hours of reperfusion and autoregulation returned in the occipital region (mean ischaemia rCBF 8 ml 100 g-1 min-1). EB staining and haemorrhage appeared in the thalamus (rCBF 10 ml 100 g-1 min-1) as oedema was decreasing. It is suggested that the amount of oedema and hyperaemia during reperfusion are dependent on the severity of the ischaemia. Areas of moderate ischaemia (8-10 ml 100 g-1 min-1) show little hyperaemia and greater oedema resolution during reperfusion as compared to areas of severe ischaemia (circa 4 ml 100 g-1 min-1) where there is marked hyperaemia with less oedema resolution. Early in the reperfusion period, oedema is not associated with EB staining and indicates a cytotoxic mechanism. The vasogenic component, with macroscopic haemorrhages and leakage of EB occurs later. In this model it is concluded that the early cytotoxic oedema formation and hyperaemia are phenomena with little bearing on mortality, which correlates better with later vasogenic changes.     

Brain ornithine decarboxylase activity following transient cerebral ischaemia: relationship to cerebral oedema development

Ornithine decarboxylase (ODC) activity, the first and generally rate-limiting enzyme for polyamine synthesis, is stimulated in permanent focal cerebral ischaemia in areas of incomplete ischaemia which are developing ischaemic brain oedema. As polyamines are ubiquitous ornithine-derived molecules which are obligatory in cold-induced vasogenic oedema, we studied the effect of transient dense cerebral ischaemia with reperfusion on ischaemic oedema development and ODC activity. Fifty-nine Mongolian gerbils were anaesthetized with ketamine hydrochloride (160 mg/kg i.p. plus supplementation as needed). Both common carotid arteries were isolated and a tracheotomy placed in position. EEG was monitored with needle electrodes and temperature maintained at 37-38°C. Twenty-nine gerbils underwent 40 min of bilateral carotid artery occlusion followed by reperfusion times of 10 min, 1, 2, 4, 6 or 8 h. Non-ischaemic control groups were monitored for equal intervals. At sacrifice, the brain was rapidly removed and forebrain samples analysed for ODC activity (enzymatic assay) and cerebral oedema (gravimetric determination). Marked loss of EEG amplitude was noted in all gerbils subjected to bilateral carotid artery occlusion. Ischaemia produced significant levels of cortical oedema throughout the reperfusion period (maximal decrease in specific gravity at 4 h postischaemia; control: 1.0456 ± 0.0013; ischaemia: 1.0355 ± 0.0021, mean ± SD; p > 0.0001). Significant subcortical oedema was produced at 10 min, 2 and 4 h postischaemia. A biphasic response was observed in brain ODC activity. Throughout the first 2 h of reperfusion, ODC activity was significantly depressed in ischaemic versus control animals (10 min: 1423 ± 824 versus 3049 ± 1019; 1 h: 704 ± 635 versus 2621 ± 902; 2 h: 348 ± 184 versus 3654 ± 2072 pmoles/g tissue/60 min; p > 0.05). This difference was no longer detectable by 4 h postischaemia and by 6 h, ODC levels were significantly higher in ischaemic animals (ischaemia: 9314 ± 2652; control: 3065 ± 2000 pmoles/g tissue/60 min; p > 0.01). Although not significant, ODC was also greater in ischaemic animals at 8 h postischaemia. ODC levels at 6 and 8 h postischaemia were significantly higher (p > 0.05) than ODC levels at 10 min, 1 and 2 h postischaemia among ischaemic animals. These data indicate that transient ischaemia initially suppresses then stimulates ODC activity over the initial 8 h following transient global ischaemia in the gerbil. Since stimulation of ODC activity does not occur until early cerebral oedema is established, it is unlikely that polyamines are involved in the early cytotoxic oedema. Later stages of ischaemic oedema, however, with mixed cytotoxic and vasogenic components may be affected by the delayed rise in ODC activity after transient ischaemia.     

Influence of blood–brain barrier opening to proteins on development of post-ischaemic brain injury

The effect of the BBB opening to proteins on development of post-ischaemic brain injury was assessed in 32 cats subjected to one hour MCA occlusion. The CBF was measured by hydrogen clearance from electrodes inserted in the caudate and the cerebral cortex within the MCA territory. In 16 animals, a prevention of subsequent reactive hyperaemia was attempted by hypovolaemia, produced by withdrawal of blood just before the release of MCA occlusion. The hypovolaemia was successful in prevention of post-ischaemic hyperaemia in five out of eight cats sacrificedat 3 h and in six out of eight animals killed after 3 and 14 days. In cats sacrificed 3 h after release of MCA occlusion, ischaemic sites, associated with reactive hyperaemia, showed evidence of BBB breakdown to proteins and significantly more severe oedema than at the ischaemic sites without reactive hyperaemia, which otherwise failed to reveal leakage of EB tracer. In the cats sacrificed at 3 and 14 days, the ischaemic sites which showed reactive hyperaemia after release of MCA occlusion, revealed much more severe ischaemic brain tissue injury than was observed at the sites without reactive hyperaemia, which also did not show any EB leakage.

The present study indicates that reactive hyperaemia, which follows release of major cerebral artery occlusion, may play a significant role in the breakdown of the BBB to proteins, and in increasing the severity of post-ischaemic oedema and of ischaemic brain tissue injury.     

Experimental and human ischaemia: is the penumbra present in human ischaemic stroke?

Experimental occlusion of the middle cerebral artery and the reduction of cerebral blood flow (CBF) below 15 ml/100 gm/per minute cause failure of the somatosensory evoked response and lethargy of cortical neurones. Increase of CBF to normal value normalises the bioelectrical activity within the "penumbra"--the zone surrounding the necrotic area. In this "risk zone" neurones can survive only a few hours. So the penumbra is a "therapeutic window" in which therapy can save some neurones from death. However, if decrease of CBF is continued, numerous cells within the penumbra gradually die. The phenomenon of the penumbra, based on experiments, was applied to human ischaemic stroke; however great differences between experimental and human brain ischaemia do exist. The human course of disease and the size of necrotic lesion depend on numerous additional factors. The three very important critical values of CBF which decrease in human brain ischaemia are difficult to examine. New imaging methods play a great diagnostic role in searching for the penumbra, but their diagnostic possibilities and results are limited. In the short-time duration of the therapeutic window both CT and MRI often do not indicate ischaemic lesion. So, it is not known whether the penumbra is present or not. Conclusive estimation of MRI diffusion-weighted imaging and perfusion-imaging and of their coefficient is impossible to obtain in the time exceeding the "therapeutic window'" Numerous additional various diseases and compensatory vascular mechanisms influence the necrotic zone in human focal ischaemia. Probably for this reason a difficulty in the estimation of the penumbra in human is observed. So, it seems that the penumbra--the therapeutic window or risk zone--in human probably occurs only in some cases. It may be one of numerous reasons for the limited effectiveness of ischaemic stroke therapy. It is not known when the penumbra is overspread with oedema, which always appears to a greater or a lesser degree. Maybe the efforts of experimental investigators, physicians and pharmacologists should also be taken into consideration to find drugs decreasing oedema and BBB permeability.