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(Stroke. 1997;28:149-154.)
© 1997 American Heart Association, Inc.

Articles

Hyperglycemia and the Vascular Effects of Cerebral Ischemia

Nobuyuki Kawai, MD; Richard F. Keep, PhD A. Lorris Betz, MD, PhD

the Departments of Surgery (Neurosurgery) (N.K., R.F.K., A.L.B), Pediatrics (A.L.B.), and Neurology (A.L.B.), University of Michigan (Ann Arbor).

	Abstract

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Background and Purpose A well-demarcated infarct was observed after 4 hours of rat middle cerebral artery (MCA) occlusion with xylazine/ketamine but not pentobarbital or isoflurane anesthesia. This study examined whether this reflected vascular changes and, because xylazine induces hyperglycemia, whether glucose could cause similar vascular effects in cerebral ischemia.

Methods To examine the effects of anesthetics, rats were anesthetized for thread occlusion of the MCA with either xylazine/ketamine, pentobarbital, or isoflurane. To evaluate the effects of glycemia, acute hyperglycemia was induced by glucose injection. In both experiments, cerebral plasma volume (CPV) was determined using ³H-inulin after 4 hours of permanent occlusion, and cerebral blood flow was measured using [¹⁴C]iodoantipyrine following 2 hours of reperfusion after 2 or 4 hours of occlusion. The presence of cerebral hemorrhage after reperfusion was checked macroscopically and infarct volume with 2,3,5-triphenyltetrazolium staining.

Results The ischemic CPV was about 50% of the contralateral values with xylazine/ketamine but not with the other anesthetics. On reperfusion, ischemic cerebral blood flow with xylazine/ketamine anesthesia was approximately half that with pentobarbital. Use of xylazine/ketamine also resulted in more frequent hemorrhagic infarcts and a larger infarct volume. Induced hyperglycemia resulted in a CPV decrease in the ischemic compared with nonischemic tissue (4.0±0.5 versus 7.4±0.2 µL/g; P<.001). Hyperglycemia also caused poor reperfusion and increased the occurrence of hemorrhagic infarction (hyperglycemia, 15 of 20; normoglycemia, 1 of 11; P<.01).

Conclusions Hyperglycemia induces marked cerebrovascular changes, both during ischemia and during reperfusion, that may exacerbate tissue damage. Change in CPV during ischemia may be a useful clinical indicator in predicting poor hemodynamic recovery and occurrence of hemorrhagic infarction after reperfusion therapy.

Key Words: cerebral blood flow • cerebral blood volume • cerebral hemorrhage • cerebral ischemia • hyperglycemia

	Introduction

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Xylazine with ketamine is a commonly used anesthetic combination in animal research. A number of groups, including our own, have used it for studies of cerebral ischemia.^{1 2 3} In our studies on rat MCA occlusion, it was noted that animals anesthetized with xylazine/ketamine had a very-well-demarcated infarct after 4 hours of ischemia. This was in contrast to results in rats anesthetized with either pentobarbital or isoflurane.

In this study, we examined whether this apparent effect of xylazine/ketamine anesthesia was due to a change in blood volume and whether this anesthesia might also have other cerebrovascular effects, including changes in CBF before and after reperfusion and the occurrence of hemorrhagic infarction on reperfusion. Because xylazine, an ₂-adrenergic agonist, inhibits insulin release from the pancreas,⁴ we examined whether hyperglycemia might have similar effects during and after MCA occlusion and whether insulin pretreatment could prevent the vascular effects of xylazine/ketamine anesthesia.

Although hyperglycemia generally enhances cerebral ischemic injury,^{5 6 7} most attention on a mechanism has focused on the potentially adverse effects of cerebral acidosis.^{8 9} Little attention has been given to the cerebral vasculature, even though there is evidence that hyperglycemia may effect the vasculature during ischemia,^{10 11} a hypothesis further examined in this study.

	Materials and Methods

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Animals and Experimental Protocols
All procedures were approved by the University Committee on Use and Care of Animals at the University of Michigan. Adult male Sprague-Dawley rats (Charles River) weighing between 250 and 300 g were used for all experiments. Rats were allowed free access to food and water before the experiment. Three sets of experiments were undertaken on the basis of the following rationale.

Influence of Anesthetics on Cerebral Vasculature
To examine the effects of different anesthetics on the cerebral vasculature, rats were initially anesthetized for MCA occlusion with either xylazine (10 mg/kg) and ketamine hydrochloride (50 mg/kg), sodium pentobarbital (50 mg/kg), or 1.5% of isoflurane in room air. Anesthetics were administered intraperitoneally except for isoflurane, for which rats were endotracheally intubated and connected to a small-animal ventilator.

These rats were used for four sets of experiments, for each of which the rats were reanesthetized with pentobarbital. In one set, CPV was measured after 4 hours of permanent MCA occlusion. In a second set, CBF was measured at the same time point. In a third set, CBF was measured after reperfusion. In this third set of animals, the presence of hemorrhage in the ischemic brain after reperfusion was checked macroscopically. Initially, these reperfusion experiments involved 4 hours of occlusion and 2 hours of reperfusion, but a group with 2 hours of occlusion with 2 hours of reperfusion was added to examine whether a less severe primary ischemic insult would produce similar vascular changes. Finally, to examine whether the early effects of anesthetics on cerebral vasculature during ischemia might correlate with alterations in infarct volume, the infarct lesion was measured morphologically using TTC staining after 4 hours of occlusion and 2 hours of reperfusion in pentobarbital- and xylazine/ketamine-anesthetized rats.

Effects of Hyperglycemia on Cerebral Vasculature
To evaluate the effects of glycemia on the cerebral vasculature, acute hyperglycemia was induced by intraperitoneal administration of 2 mL of 2.8 mol/L D-glucose 20 minutes before MCA occlusion in sodium pentobarbital–anesthetized rats (50 mg/kg IP). Because of a small increase in plasma osmolality (approximately 20 mOsm/kg) after glucose injection, normoglycemic controls received a similar osmotic load of mannitol. These rats were used to determine CPV after 4 hours of permanent occlusion and CBF following 2 hours of reperfusion after 2 or 4 hours of occlusion. As in the anesthetic experiments, the presence of hemorrhage in the ischemic brain after reperfusion was checked macroscopically in the rats used in the CBF study. Hemorrhage was also determined in an additional group of 13 rats. Again, the area of cerebral infarction was quantified by TTC staining in glucose-injected and mannitol-injected rats following 2 hours of reperfusion after 4 hours of occlusion.

To examine specifically whether the effects of xylazine/ketamine anesthesia on CPV during ischemia might be related to hyperglycemia, rats were pretreated with insulin. In those rats, 3 IU/kg of regular insulin was administered intraperitoneally 60 minutes before the injection of xylazine/ketamine.

Effects of Anesthetics and Hyperglycemia on Ischemic Brain Temperature
Brain temperature affects ischemic brain damage, and since brain temperature might differ under different anesthetics, this parameter was measured in pentobarbital- and xylazine/ketamine-anesthetized rats undergoing MCA occlusion. With 4 rats in each group, ipsilateral and contralateral brain temperatures were monitored for 60 minutes after the occlusion. To examine the effects of hyperglycemia, brain temperatures were also monitored in glucose- and mannitol-injected rats (4 per group).

MCA Occlusion
The MCA was occluded using the suture method of Zea Longa et al.¹² Animals either were studied after permanent occlusion or they were reanesthetized and the suture was withdrawn back into the external carotid artery to restore internal carotid artery–MCA blood flow.

Cerebral Plasma Volume
CPV was measured using ³H-inulin. This compound does not enter red blood cells nor does it measurably cross the blood-brain barrier in 30 minutes in nonischemic brain.¹³ It may enter brain in ischemic tissue once the blood-brain barrier breaks down, but any such entry was limited in these experiments by circulating the isotope for only 2 minutes and by using 4 hours of permanent ischemia. Blood-brain barrier disruption is minimal at that time point.²

For the experiment, rats were anesthetized, and body temperature was maintained at 37°C using a rectal probe and a feedback-controlled heating pad. Cannulas were placed in both femoral arteries for blood sampling and for measurement of blood pressure and into the femoral vein for isotope injection. After 4 hours of occlusion, all rats were reanesthetized with sodium pentobarbital. Twenty µCi of ³H-inulin was injected and was allowed to circulate for 2 minutes. At the end of the experiment, terminal plasma samples were taken, and the rats were killed by decapitation. Brains were then rapidly removed and separated into cortices and basal ganglia. Cortices were flattened on a piece of Parafilm, and using a 7-mm-diameter cork borer, punches were made of the ipsilateral and contralateral cortices to obtain tissue samples from the center of the MCA distribution. Samples were immediately weighed and digested in methylbenzethonium hydroxide. Scintillation fluid was added to the brain and plasma samples, which were then counted in a Beckman 3801 liquid scintillation counter. The CPV was calculated as distribution volume, defined as (disintegrations per minute per gram of brain)/(disintegrations per minute per milliliter of plasma).

Cerebral Blood Flow
CBF was measured by the indicator fractionation technique.¹⁴ The method uses an intravenous bolus injection of a CBF indicator followed by a constant rate of blood withdrawal through a femoral artery catheter to obtain the integral of the arterial isotope concentration. Animal preparation for the CBF study was the same as for the CPV measurements, except for the placement of an arterial withdrawal cannula. The withdrawal was started 5 seconds before intravenous injection of a 100-µL ethanol solution containing 10 µCi of 4-[N-methyl-¹⁴C]-iodoantipyrine. Exactly 10 seconds later, the animal was killed by decapitation, and blood withdrawal was stopped. The sample of withdrawn arterial blood and the brain tissue samples were treated as described above for the CPV measurement, except whole blood samples were bleached with 30% H₂O₂ before counting.

Blood flow rates for the individual pieces of brain tissue were calculated as Fb/Mb=Qb(T) Fs/Qs(T) Mb, where Fb is the brain blood flow; Mb is the brain mass (in grams); Qb(T) is the quantity of indicator in the tissue at time T; Fs is the rate of blood withdrawal from t=0 to t=T; and Qs(T) is the quantity of indicator present in the withdrawal at time T. CBF is expressed as milliliters per grams per minute.

Morphometric Measurement of Infarct Size
The area of cerebral infarction was quantified using TTC staining. The brains were sectioned coronally with a brain slicer at 2-mm intervals from the frontal pole. All slices were incubated for 20 minutes in a 2% solution of TTC at 37°C and fixed by immersion in 2% paraformaldehyde solution. Using a computerized image analysis system (NIH image, version 1.55), the area of infarction of each section was first determined by measuring the area of normally staining brain in the hemisphere ipsilateral and contralateral to the MCA occlusion. The area of infarction was then determined as the difference in normal tissue area between the contralateral and ipsilateral hemispheres. The total lesion volume was calculated by summing the infarct area in each section and multiplying by the distance between sections.

Brain Temperature
Brain temperature was measured using chromel/constantan thermocouples (diameter, 0.06 mm; Omega Engineering) linked to a digital thermometer (model 450-AET; Omega Engineering). Thermocouples were placed bilaterally in the core area of the MCA distribution, 1 mm anterior and superior to the zygomatic arch and at a depth of 2 mm.

Statistical Analysis
Comparison of variables among groups was made by ANOVA with a Newman-Keuls multiple-comparisons test. Within a group of animals, results from ipsilateral and contralateral hemispheres were compared by two-tailed paired Student's t test. For results on the presence or absence of hemorrhagic infarction, a ² test was used. Differences were considered to be significant at the P<.05 level.

	Results

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Effects of Anesthetics on Cerebral Vasculature
Rats awoke from anesthesia within 90 minutes in the xylazine/ketamine and the pentobarbital groups. On the other hand, isoflurane-anesthetized rats were conscious within 10 minutes after discontinuation of the inhalation anesthetic. All animals showed some motor and behavioral impairments during ischemia (typically, a spontaneous contralateral circling). Physiological parameters from the rats are given in Table 1. Moderate hyperglycemia was present in the xylazine/ketamine group compared with the pentobarbital and isoflurane groups. There were no significant differences in arterial blood gas tensions, pH, hematocrit level, and plasma osmolality.

View this table: [in this window] [in a new window]   Table 1. Physiological Parameters

There was a clearly demarcated white infarct in rats after 4 hours of permanent MCA occlusion when the initial occlusion had been performed with xylazine/ketamine anesthesia. This was not the case when the occlusion had been performed with either pentobarbital or isoflurane anesthesia. This anesthetic effect appears to be due to differences in blood volume. In xylazine/ketamine anesthesia, the CPV of the ischemic core was significantly decreased (3.4±0.5 µL/g) compared with that of the contralateral side (6.7±0.3 µL/g; P<.001). This was not found with the other two anesthetics (Figure).

View larger version (46K): [in this window] [in a new window]   Figure 1. CPV in the ischemic and nonischemic (contralateral) core samples from xylazine/ketamine- (X/K), pentobarbital- (Pento), and isoflurane-anesthetized rats. Measurements were made with 3H-inulin after 4 hours of MCA occlusion. Values are mean±SE; n=5 to 6. ***Significant difference (P<.001) between the ischemic and nonischemic hemispheres.

The difference in CPV between xylazine/ketamine- and pentobarbital-anesthetized rats after 4 hours of permanent ischemia was not accompanied by a significant decrease in CBF, although the former tended to be lower (3±1 and 6±2 mL·100 g^-1·min^-1). CBFs in the contralateral core were also not significantly different between the two anesthesias (59±5 and 57±8 mL·100 g^-1·min^-1 in xylazine/ketamine- and pentobarbital-anesthetized rats, respectively).

CBFs on reperfusion were, however, significantly affected by the type of anesthesia used for the initial occlusion. After 2 hours of ischemia and 2 hours of reperfusion, blood flow was hyperemic (123±16% of contralateral hemisphere) in the pentobarbital group, whereas the core CBF recovered to only 55±11% of the contralateral hemisphere value in the xylazine/ketamine group (P<.01; n=5). After 4 hours of ischemia and 2 hours of reperfusion, there was also a difference in CBF between the two groups, with the pentobarbital and xylazine/ketamine groups returning to 52±18% and 12±7% of contralateral values (P<.05; n=6). At neither time point was there a significant difference in contralateral CBF between the pentobarbital and xylazine/ketamine groups, which were 71±6 and 72±5 mL·100 g^-1·min^-1 in the 2-hour temporary occlusion experiment and 62±6 and 57±7 mL·100 g^-1·min^-1 with 4 hours of occlusion, respectively.

In the reperfusion experiments, 5 of 11 animals (45%) in the xylazine/ketamine group showed macroscopic transformation into hemorrhagic infarction, whereas none of 11 animals in the pentobarbital group showed hemorrhagic change (P<.05). It was of interest that restoration of CBF after 4 hours of occlusion led to a higher incidence of hemorrhagic infarction (4 of 6) than 2 hours of temporary occlusion (1 of 5) (Table 2). In coronal sections, hemorrhagic infarction was observed in the subcortex, and it usually extended to the cerebral cortex. The hemorrhage was restricted to the infarcted brain and was surrounded by a pale infarct area.

View this table: [in this window] [in a new window]   Table 2. Occurrence of Hemorrhagic Infarction

Effects of Induced Hyperglycemia on Cerebral Vasculature
Physiological parameters for the glucose- and mannitol-injected groups of pentobarbital-anesthetized rats are given in Table 1. Glucose injection induced moderate to severe hyperglycemia at the onset of occlusion. The increases in plasma osmolality in both groups were not significantly different.

A clearly demarcated infarct similar to that with xylazine/ketamine anesthesia was observed in glucose-injected hyperglycemic rats but not in mannitol-injected rats. This difference again appeared to result from decreased blood volume in the ischemic tissue. CPVs in the ischemic and nonischemic cores were 4.0±0.5 and 7.4±0.2 µL/g (P<.001; n=5), respectively, in the glucose-infused rats. There was no significant difference in ischemic and nonischemic tissues in the mannitol-injected control rats (5.6±0.6 and 7.0±0.2 µL/g, respectively).

After 2 hours of temporary occlusion, 2 hours of reperfusion resulted in poor restoration of blood flow in glucose- compared with mannitol-injected control rats (53±14% and 109±18% of contralateral CBF, respectively, n=4; P<.05). After 4 hours of temporary occlusion, hyperglycemia again led to poor reperfusion compared with findings in normoglycemic rats (43±13% and 106±7% of contralateral CBF, respectively, n=5; P<.01). At both time points there was no significant difference in contralateral CBF between the mannitol- and glucose-injected rats, which was 68±6 and 54±3 mL·100 g^-1·min^-1 in the 2-hour temporary occlusion experiment and 61±6 and 58±7 mL·100 g^-1·min^-1 with 4 hours of occlusion, respectively.

Glucose infusion not only mimicked the effects of xylazine/ketamine anesthesia on CPV and CBF, but it also led to an increased occurrence of cerebral hemorrhage on reperfusion. Fifteen of 20 (75%) glucose-injected rats displayed hemorrhage, whereas only one hemorrhage was found in the 11 mannitol-injected normoglycemic rats (P<.01; Table 2).

Pretreatment of xylazine/ketamine-anesthetized rats with insulin prevented the hyperglycemia normally found with this anesthesia (Table 1). Insulin also prevented the decrease in CPV in the ischemic core found in nontreated rats, with ischemic and nonischemic CPVs being 5.8±0.4 and 6.0±0.3 µL/g, respectively.

Effect of Anesthetics and Hyperglycemia on Infarct Volume
After 4 hours of ischemia and 2 hours of reperfusion, the total TTC-stained lesion volume in the xylazine/ketamine group was 169.5±47.3 mm³, significantly larger than that in the pentobarbital group (21.8±11.0 mm³; P<.001). Similarly, a significant difference in TTC lesion was observed between the mannitol- and glucose-injected groups (39.1±22.9 mm³ and 157.6±37.5 mm³, respectively; P<.001). The infarct areas in the pentobarbital- and mannitol-injected groups were usually restricted to the subcortex, whereas the cerebral cortex was also involved in the xylazine/ketamine and glucose-injected groups.

Effect of Anesthetics and Hyperglycemia on Brain Temperature
Before MCA occlusion, the ipsilateral brain temperature was not significantly different in the xylazine/ketamine- and pentobarbital-anesthetized rats (36.8±0.2°C and 36.9±0.2°C). In both groups, brain temperature in the ipsilateral tissue fell in response to MCA occlusion. This decline did not vary with time over the first hour of occlusion; therefore, an average temperature was calculated for that period. There were no significant differences in brain temperature between xylazine/ketamine-anesthetized (ipsilateral brain, 35.5±0.2°C; contralateral, 36.9±0.1°C) and pentobarbital-anesthetized (35.5±0.1°C and 37.1±0.1°C, respectively) rats during that period. Similarly, there were no significant differences in brain temperature between glucose-injected (ipsilateral brain, 35.3±0.2°C; contralateral, 36.6±0.1°C) and mannitol-injected (35.5±0.2°C and 36.7±0.2°C, respectively) rats during MCA occlusion.

	Discussion

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Xylazine-Ketamine Anesthesia
This study shows that MCA occlusion under xylazine/ketamine anesthesia is associated with cerebrovascular changes during cerebral ischemia compared with pentobarbital and isoflurane anesthesia. This was first noted because of the clear demarcation of the infarct after MCA occlusion in xylazine/ketamine-anesthetized rats. This appears to be due to a decrease in cerebral blood volume in the ischemic tissue, since CPV was decreased by about 50% compared with the contralateral hemisphere value. Xylazine/ketamine anesthesia was also associated with other cerebrovascular changes, poor reperfusion, and a greatly increased occurrence of cerebral hemorrhage on reperfusion. It is possible that, rather than xylazine/ketamine inducing such cerebrovascular effects during ischemia/reperfusion, it is pentobarbital or isoflurane anesthesia that prevents such changes. This, however, seems unlikely because pentobarbital-anesthetized rats undergo similar vascular changes if glucose is injected.

Xylazine is an ₂-adrenergic agonist, and it is reported to block the pancreatic insulin secretion, resulting in a moderate hyperglycemia.⁴ The hypothesis that the cerebrovascular effects found with xylazine/ketamine anesthesia are due to hyperglycemia was supported by the finding that these effects could be mimicked by glucose injection in pentobarbital-anesthetized rats. Furthermore, insulin pretreatment in xylazine/ketamine-anesthetized rats prevented the changes in CPV in the ischemic tissue. Because of these effects, which may have contributed to the increased infarct volume found in this study, the use of xylazine/ketamine anesthesia without control of the blood glucose concentration should be carefully considered for ischemic studies.

Hyperglycemia and the Cerebrovasculature in Ischemia
There is considerable evidence that hyperglycemia can exacerbate brain injury after cerebral ischemia, particularly in models of global^{11 15} and focal ischemia with reperfusion.^{3 7 16} The latter was confirmed by the measurements of infarct volume in this study. As a mechanism for the adverse effect of hyperglycemia, most attention has focused on the neuronal effects of increased tissue lactate production and lowered tissue pH.^{8 9} Recently, however, the role of lactate in ischemic damage has been questioned, since brain lactate does not correlate with ischemic damage in hypothermic and hyperthermic rats subjected to global cerebral ischemia with reperfusion.¹⁷ An alternate, or supplementary, hypothesis to a direct neuronal effect is that hyperglycemia could enhance ischemic injury via an effect on the vasculature.

Despite the generally accepted importance of glucose in ischemic brain injury, relatively few experimental studies have addressed the effect of hyperglycemia on the cerebral vasculature and blood flow during ischemia either with or without reperfusion. There is some evidence that hyperglycemia can impede reperfusion after a global ischemia event,^{10 18} and the work of Venables et al¹⁹ suggests that this may also occur with focal ischemia. The results from the present study indicate that hyperglycemia (induced by either glucose injection or xylazine/ketamine anesthesia) can indeed have a profound effect on reperfusion after focal cerebral ischemia, with blood flows returning to only 50% to 75% of those found in control rats.

Another potential indicator of vascular injury is hemorrhage. Examining MCA occlusion in cats, de Courten-Myers et al²⁰ found that the incidence and extent of hemorrhagic infarction on reperfusion were much greater in hyperglycemic compared with normoglycemic animals. In the present study, we also found that hyperglycemia (induced by either glucose injection or xylazine/ketamine anesthesia) greatly increased the incidence of hemorrhagic infarction on reperfusion. In this model, it is possible that the nylon monofilament used to occlude the MCA might damage the endothelium, thus causing the extensive hemorrhage on reperfusion. However, we have found that hyperglycemia increases the occurrence of hemorrhagic infarction in another ischemic model, reperfusion after bilateral common carotid occlusion in Fischer 344 rats (unpublished data), that does not involve a foreign body being inserted into a cerebral vessel.

The occurrence of hemorrhage on reperfusion is of particular clinical importance because it is the major complication in the use of thrombolytic drugs to restore CBF after an ischemic event. Recently, two major trials, one European and one American, for ischemic stroke with recombinant tissue plasminogen activator have been published.^{21 22} Although an improvement in neurological outcome was found in patients treated with intravenous tissue plasminogen activator in both studies, the incidence of large parenchymal hemorrhage was 20% and 6%, respectively, in each trial. At present, it is not possible to predict whether hemorrhagic infarction will occur. In the past, the duration of symptoms was regarded as a most important prognostic factor in hemorrhagic infarction, and it was commonly accepted that the occluded vessels could be reopened safely if the thrombolytic therapy was conducted within 6 hours.^{23 24} However, hemorrhagic infarction was reported to occur even within 2 hours of occlusion. In our studies, the increased risk of hemorrhagic infarction on reperfusion in hyperglycemic rats was associated with a very marked decrease in CPV during the ischemic event. It is possible, therefore, that cerebral blood volume could be used as a measure of vascular dysfunction and perhaps a predictor of enhanced risk of hemorrhage in thrombolytic therapy. In humans, cerebral blood volume measurement is possible using enhanced CT scan, MRI, single-photon emission tomography, and near-infrared spectroscopy.

The mechanism by which hyperglycemia alters the cerebrovascular response to ischemia and reperfusion has still to be elucidated; however, there is evidence that it may involve endothelial cell injury. Paljarvi et al²⁵ found that reperfusion after global ischemia caused excessive endothelial cell swelling and decreased luminal diameter in hyperglycemic rats while having little effect in normoglycemic rats. They postulated that such endothelial swelling hampered postischemic perfusion and could lead to complete plugging of vessels. The effect of hyperglycemia on endothelial cell swelling and plugging during focal cerebral ischemia has not been examined. However, Garcia et al²⁶ observed endothelial cell swelling accompanied by a decrease in the luminal surface within the initial 30 minutes of MCA occlusion. In those experiments, they did not deliberately induce hyperglycemia, but the anesthetic used at the onset of the occlusion, halothane, is known to cause a hyperglycemia.²⁷

Experiments designed to determine the mechanisms involved in the cerebrovascular response to hyperglycemia are a necessary next step to devising therapies to prevent these changes. They should also help to elucidate whether changes in ischemic blood volume may occur in response to stroke risk factors other than hyperglycemia. If that is the case, CPV may be of great clinical use in predicting the occurrence of cerebral hemorrhage after reperfusion therapy.

	Selected Abbreviations and Acronyms

 

CBF = cerebral blood flow CPV = cerebral plasma volume MCA = middle cerebral artery TTC = 2,3,5-triphenyltetrazolium

	Acknowledgments

 
This work was supported by National Institutes of Health grant NS-23870. Dr Kawai is a research fellow from the Department of Neurological Surgery, Kagawa Medical School (Japan).

	Footnotes

 
Reprint requests to Richard F. Keep, PhD, Department of Surgery (Neurosurgery), University of Michigan, R5605 Kresge I, Ann Arbor, MI 48109-0532. E-mail rkeep@umich.edu.

Received March 25, 1996; revision received August 19, 1996; accepted September 18, 1996.

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Editorial Comment

W. Dalton Dietrich, PhD, Guest Editor

Department of NeurologyUniversity of Miami School of MedicineMiami, Fla

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References Introduction

 
The study by Kawai and colleagues examined the effects of different anesthetics and glucose-induced hyperglycemia on the cerebral vascular and neuronal consequences of MCA occlusion in rats. The authors report that ischemic CPV and postischemic CBF values differ with xylazine/ketamine, pentobarbital, and isoflurane anesthesia. Compared with the other anesthetics, more frequent hemorrhagic infarcts and larger infarct volumes were also documented with xylazine/ketamine anesthesia. Interestingly, induced hyperglycemia in pentobarbital-anesthetized rats led to vascular and infarct changes that were similar to those observed under xylazine/ketamine anesthesia.

The finding that anesthetic type is an important factor in determining the relative severity of the vascular and neuronal consequences of focal ischemia has significant implications in the field of ischemic brain injury. Because no apparent differences in ischemic severity or brain temperature were documented among various ischemic groups, it appears that other factors, including hyperglycemia, are important to this outcome. The detrimental consequences of preischemic hyperglycemia in experimental models of cerebral ischemia have long been appreciated. However, as the authors correctly point out, limited data are available concerning the effects of ischemic hyperglycemia on the cerebral vasculature. The present findings clearly indicate that this is an area that requires additional study.

The results also indicate an interesting relationship between ischemic plasma volume and the occurrence of hemorrhagic infarction and infarct volume after transient focal ischemia. Because of the clinical importance of hemorrhagic transformation during reperfusion therapy, this potential indicator of stroke outcome merits future investigation. Finally, because infarct volume was assessed at 4 hours after ischemia, more chronic survival periods should be investigated to determine the long-term consequences of these important but early outcome measures.

	Selected Abbreviations and Acronyms

 

CBF = cerebral blood flow CPV = cerebral plasma volume MCA = middle cerebral artery TTC = 2,3,5-triphenyltetrazolium

Observations were made after 2 hours of reperfusion following either 2 or 4 hours of MCA occlusion. The difference between two anesthetics is significant by ² test (P<.05). The difference between the mannitol and glucose groups is also significant (P<.01).

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