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(Stroke. 1995;26:655-660.)
© 1995 American Heart Association, Inc.

Articles

Temporal Thresholds for Hyperglycemia-Augmented Ischemic Brain Damage in Rats

David S. Warner, MD; Michael M. Todd, MD; Franklin Dexter, MD, PhD; Paula Ludwig Alice M. McAllister

From the Department of Anesthesiology, Duke University Medical Center, Durham, NC (D.S.W., P.L.), and the Department of Anesthesia, University of Iowa, Iowa City (M.M.T., F.D., A.M.M.).

Correspondence to David S. Warner, MD, Department of Anesthesiology, Box 3094, Duke University Medical Center, Durham, NC 27710.


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Background and Purpose Although acute hyperglycemia is known to increase global ischemic brain damage, the duration of ischemia necessary to elicit such an effect is unknown. Accordingly, an experiment was performed to determine the duration of forebrain ischemia at which hyperglycemia becomes a factor in histological and behavioral outcome in rats.

Methods Fasted rats were anesthetized and prepared for forebrain ischemia. Before ischemia, rats received either intravenous saline (plasma glucose, 112±18 mg/dL) or glucose (plasma glucose, 343±50 mg/dL). After 4, 8, 12, or 15 minutes of ischemia (n=12), recovery was allowed. Rats surviving 7 days underwent evaluation of motor function and then histological analysis of damage in the caudate putamen, hippocampal CA1, and substantia nigra pars reticulata.

Results After 4 minutes of ischemia, damage was present in all structures. Only in the caudate putamen was hyperglycemia associated with worsened damage, but this did not result in seizures or death. After 8 minutes of ischemia, seizures occurred in 33% of hyperglycemic rats, and a hyperglycemic effect on damage in the CA1 and substantia nigra pars reticulata was observed. No seizures or mortality occurred in normoglycemic rats regardless of duration of ischemia. Longer durations of ischemia resulted in an increased incidence of seizures and mortality in hyperglycemic rats only. Among surviving rats, motor function was worsened in hyperglycemic rats after 12 minutes of ischemia.

Conclusions Hyperglycemia-augmented brain damage is evident after global ischemic insults as brief as 4 minutes and becomes critical to survival after 8 minutes of ischemia.


Key Words: cerebral ischemia • hyperglycemia • neuronal damage • rats


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Hyperglycemia has been associated with worsened outcome in a variety of animal models of global ischemia.1 2 3 This worsened outcome is typically manifested as an increased incidence of postischemic seizures and death.4 5 Numerous elements of the pathophysiology of global ischemic injury are also altered by hyperglycemia, including accumulation of lactate,6 enhanced tissue acidosis,7 8 greater edema,1 9 10 11 12 increased blood-brain barrier permeability,13 accentuation of postischemic hypoperfusion,14 impairment of restitution of high-energy metabolites,6 15 and accelerated delayed neuronal necrosis.4

Several studies examining mechanisms by which hyperglycemia worsens ischemic brain damage have systematically varied the postischemic recirculation intervals at which histological or biochemical events were analyzed.4 6 11 Other studies have continuously monitored cerebral physiological events throughout ischemia and recirculation in an effort to associate preischemic blood glucose with development of energy failure, intracellular acidosis, and lactic acid accumulation as a function of duration of ischemia.7 16 17 18 19 Despite this, the duration of near-complete ischemia at which preischemic hyperglycemia becomes relevant to histological and/or behavioral outcome remains unknown. In other words, does hyperglycemia influence injury in the face of very brief insults or only after longer, more severe injuries such as those used by most investigators? Such information would be of value when discussing both the clinical relevance of and the mechanistic basis for hyperglycemia-augmented ischemic brain damage. Accordingly, this study was designed to compare outcome in normoglycemic and hyperglycemic rats subjected to variable intervals of forebrain ischemia followed by a 7-day recovery interval.


*    Materials and Methods
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 up arrowAbstract
 up arrowIntroduction
 *Materials and Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
This study was approved by the University of Iowa Animal Care and Use Committee. Male Sprague-Dawley rats (body weight, 300 to 325 g; Harlan) were fasted from food for 12 to 16 hours before the experiment. All rats were then anesthetized with 4% halothane in O2, endotracheally intubated, and mechanically ventilated with a delivered gas mixture of 1.0% to 1.6% halothane in 30% O2/balance N2. The tail artery was cannulated, and mean arterial pressure (MAP) was continuously recorded. Through a ventral neck incision, the common carotid arteries were isolated and encircled with suture. The right internal jugular vein was cannulated, and heparin (35 IU) was given intravenously. Muscle paralysis was obtained with a 0.2-mg bolus of succinylcholine, repeated as necessary. Bipolar electroencephalographic activity was monitored from active needle electrodes inserted in the temporalis muscle bilaterally, a reference lead in the prefrontal region, and a ground lead in the tail. Finally, a 22-gauge needle thermistor was percutaneously placed adjacent to the skull, and the pericranial temperature was servo-regulated at 37.0±0.1°C by surface heating or cooling. The halothane concentration was reduced to 0.5% for the remainder of the experiment.

After surgical preparation, a 30-minute interval was allowed for manipulation of plasma glucose. Rats were randomly assigned to one of two groups. In the first (normoglycemia), 1.5 mL of 0.9% NaCl was infused intravenously over 25 minutes. In the second (hyperglycemia), 1.5 mL of 25% dextrose in 0.9% NaCl was infused over the same interval. Blood samples for determination of plasma glucose, PaO2, PaCO2, arterial pH, and hematocrit levels were obtained 5 minutes before onset of ischemia.

Before onset of ischemia, rats from each group were randomly subdivided into four groups on the basis of the duration of ischemia incurred. Otherwise, the protocol for producing forebrain ischemia was the same for all animals.20 21 Hypotension (MAP, 30±5 mm Hg) was induced with trimethaphan (1.75 mg IV) and maintained by withdrawal and reinfusion of blood through the jugular catheter as necessary. Immediately after onset of hypotension, the carotid arteries were occluded bilaterally with temporary aneurysm clips. After 4, 8, 12, or 15 minutes, the vascular clamps were released, any shed blood was reinfused, and 0.27 mEq NaHCO3 was given to minimize systemic acidosis. The catheters were removed, and incision sites were closed with suture. Approximately 20 minutes after the ischemic insult, halothane anesthesia was discontinued, and the animals were awakened. On recovery of spontaneous ventilation, the trachea was extubated. Rats were then placed in a chamber containing 50% O2/50% N2 for at least 30 minutes before being returned to their cages. Over the 7-day recovery period, the animals were continuously observed for the presence/absence of generalized seizure activity and mortality/survival. No attempt was made to manipulate plasma glucose levels or treat convulsions in the postischemic recovery period.

Motor function tests were performed 7 days after ischemia.22 Briefly, the rats were placed on a 29x30-cm screen (grid size, 0.6x0.7 cm) that could be rotated from 0° (horizontal) to 90° (vertical). The animal was placed on the horizontal screen, and the screen was then rotated into the vertical plane. The duration of time that the animal was able to hold on to the vertical screen was recorded to a maximum of 15 seconds (allowing a total of 3 points). Next, the animal was placed at the center of a horizontal wooden rod (2.5-cm diameter), and the time that the animal was able to remain balanced on the rod was recorded to a maximum of 30 seconds (allowing a total of 3 points). Finally, a prehensile traction test was administered. The time that the animal was able to cling to a horizontal rope was recorded to a maximum of 5 seconds. From these three tests, a total motor score (9 possible points) was computed.

After neurological testing, rats were anesthetized with 4% halothane in O2. After endotracheal intubation, ventilation was mechanically controlled by a respirator delivering 3% halothane in 30% O2/balance N2. The brains were perfused through the ascending aorta with a 30-second flush of 0.9% saline followed by 250 mL of buffered 4% formalin (pH 7.35). The brains were allowed to stabilize at 4°C in situ overnight before removal and storage in 4% formalin.

The brains were cut coronally into 3.0-mm-thick slices and dehydrated in graded strengths of ethanol. After being rinsed in xylene and embedded in paraffin, 5-µm-thick sections were serially cut and stained with celestine blue and acid fuchsin.23 Sectioning intervals were adapted to obtain specific standardized levels of the hippocampus (bregma -3.8 mm), substantia nigra pars reticulata (SNPR) (bregma -5.3 mm), and caudate putamen (bregma -0.03 mm).24

Brain injury was quantified by applying a rating scale of damage to CA1 neurons of the hippocampal formation in both hemispheres. Damage was graded on a scale of 0 to 4 (0, no observed histological changes; 1, 1% to 5% of neurons damaged; 2, 6% to 50% of neurons damaged; and 3, >50% of neurons damaged; 4, infarct)25 by one experimenter who was blinded to group allocation. For the SNPR and caudate putamen a 0-to-4 damage scale identical to that used for hippocampal CA1 was used. Damage scores for each region, taken from the most severely affected hemisphere of each animal, were used for statistical analysis.

Physiological values were analyzed qualitatively to preserve statistical power. Because of mortality in some hyperglycemic animals, data sets were not obtained with respect to either neurological or histological outcome in those animals. Furthermore, because no seizures or mortality occurred in any normoglycemic animal, a direct contingency table comparison between these animals and hyperglycemic counterparts was not possible. Thus, outcome values are graphically depicted and described. To obtain an index of the effect of duration of ischemia on probability of worsened outcome in hyperglycemic and normoglycemic animals, odds ratios (ORs) were computed for motor score and damage in the CA1, caudate putamen, and SNPR, as well as for occurrence of seizures where applicable. OR was calculated using maximum likelihood estimation of the standard linear logistic function. OR specifies the odds (similar to the relative risk) that increasing the duration of ischemia by 1 minute will cause an increase in damage. Presence or absence of severe histopathologic damage corresponded to histological grades of death through 3 or 2 through 0, respectively. Equivalently, for motor score, presence or absence of abnormality corresponded to scores of death through 6 or 7 through 9, respectively. All continuous data were summarized as mean±SD. Nonparametric data are presented as median values with interquartile range.


*    Results
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 up arrowIntroduction
 up arrowMaterials and Methods
 *Results
down arrowDiscussion
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Before dextrose infusion, physiological values were similar between the experimental groups (TableDown). Dextrose infusion resulted in plasma glucose values within the range of 275 to 425 mg/dL compared with those of saline-infused rats in the range of 80 to 140 mg/dL. Measured postischemic physiological values were similar between groups with the exception that prolonged intervals of ischemia resulted in a more severe metabolic acidosis at 10 minutes after reperfusion.


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  		Table 1. Preischemia (2 to 5 Min) and Postischemia (10 Min) Physiological Values

All normoglycemic rats survived 7 days, and there was no evidence of generalized seizures regardless of duration of ischemia; thus, an OR for seizure occurrence was not computed for these rats. In the hyperglycemic groups, seizures and mortality did not occur after 4 minutes of ischemia but became progressively more frequent as the duration of ischemia was prolonged (Figs 1Down and 2Down). Of the 19 rats with observed seizures, 17 died (89%). Two additional hyperglycemic rats (one with 8-minute and one with 12-minute ischemia) died without evidence of seizures. For hyperglycemic animals, the OR that increasing the duration of ischemia by 1 minute caused seizures equaled 1.65 (95% confidence interval [CI], >1.33).



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  		Figure 1. Bar graph shows percentages of animals in either hyperglycemic or normoglycemic groups (as a function of duration of forebrain ischemia) without evidence of generalized seizure activity over a 7-day postischemic recovery interval. Shaded bars indicate normoglycemia; solid bars, hyperglycemia.



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  		Figure 2. Bar graph shows percentages of animals in either hyperglycemic or normoglycemic groups (as a function of duration of forebrain ischemia) that survived the full 7-day postischemic recovery interval. Shaded bars indicate normoglycemia; solid bars, hyperglycemia.

Median group values for total motor score are given for 7-day survivors in Fig 3Down. The OR did not reach significance in normoglycemic rats (1.07; 95% lower CI, >0.95). In contrast, an effect for duration of ischemia was present in hyperglycemic rats (1.51; 95% lower CI, >1.25). Differences between groups were graphically apparent after 8 minutes of ischemia.



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  		Figure 3. Graph shows median total motor scores (7 days of recovery) for rats in either normoglycemic or hyperglycemic groups as a function duration of ischemia. A score of 9 indicates optimal performance. Error bars depict the interquartile range.

Histological damage in the hippocampal CA1 sector was present after 4 minutes of ischemia (Fig 4Down). The severity of damage was not influenced by hyperglycemia. Increasing the duration of ischemia from 4 to 8 minutes did not substantively alter the severity of CA1 damage in normoglycemic rats. In contrast, CA1 damage was worsened in the 8-minute hyperglycemic group with 71% of surviving rats assigned a grade of 3, whereas 75% of normoglycemic rats were assigned a grade of 1. For hyperglycemic animals, the OR that increasing the duration of ischemia by 1 minute caused worsened damage equaled 2.01 (95% CI, >1.44). For normoglycemic rats, the OR that increasing the duration of ischemia by 1 minute caused worsened damage equaled 1.50 (95% lower CI, >1.16).



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  		Figure 4. Graph shows median histological damage grades in the hippocampal CA1 sector evaluated 7 days after transient forebrain ischemia in normoglycemic or hyperglycemic rats. 0 indicates no observable damage; 4, infarct. Error bars depict the interquartile range.

In the caudate putamen, the graphically apparent threshold for distinction between normoglycemic and hyperglycemic states occurred by 4 minutes of ischemia (Fig 5Down). All normoglycemic rats (except one) had a damage score of 1 after either 4 or 8 minutes of ischemia. In contrast, after 4 or 8 minutes of ischemia in hyperglycemic rats, grades were typically 2 or 3. For hyperglycemic animals, the OR that increasing the duration of ischemia by 1 minute caused worsened damage equaled 2.28 (95% CI, >1.49). For normoglycemic rats the OR equaled 1.76 (95% lower CI, >1.17).



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  		Figure 5. Graph shows median histological damage grades in the caudate putamen evaluated 7 days after transient forebrain ischemia in normoglycemic or hyperglycemic rats. 0 indicates no observable damage; 4, infarct. Error bars depict the interquartile range.

In the SNPR, the graphically apparent threshold for distinction between normoglycemic and hyperglycemic states occurred by 8 minutes of ischemia (Fig 6Down). After 15 minutes of ischemia, 58% of normoglycemic rats were graded as 3, whereas the remainder were graded as 2. Of the 5 hyperglycemic survivors at the same interval, 4 of 5 had evidence of infarct (grade 4), whereas the remaining rat was scored as a 3. For hyperglycemic animals, the OR that increasing the duration of ischemia by 1 minute caused worsened damage equaled 1.80 (95% CI, >179). For normoglycemic rats the OR equaled 2.07 (95% lower CI, >1.31).



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  		Figure 6. Graph shows median histological damage grades in the substantia nigra pars reticulata (SNPR) evaluated 7 days after transient forebrain ischemia in normoglycemic or hyperglycemic rats. 0 indicates no observable damage; 4, infarct. Error bars depict the interquartile range.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 *Discussion
down arrowReferences
 
It has been clearly established in laboratory models that preischemic hyperglycemia worsens outcome after a global cerebral ischemic insult. Extrapolation of this data to clinical management of humans experiencing a variety of cerebral hypoperfusion states has proved more difficult. Studies have been largely retrospective in design and have attempted to correlate plasma glucose concentrations with eventual neurological outcome.26 27 28 29 30 31 For largely ethical reasons, none have systematically controlled glucose at specific plasma concentrations and then assessed outcome. Despite these limitations, a rather consistent pattern has emerged wherein patients tend to do worse if elevated plasma glucose has been experienced early in the course of their neurological insult. As a result it has been advocated that intravenous administration of glucose be minimized,32 33 despite the findings of Longstreth et al.31

One factor complicating this conclusion is that animal studies examining the issue typically have relied on models of severe ischemia designed to produce a substantial neurological and/or histological deficit. It is thus possible that outcomes from short intervals of ischemia or from insults of relatively mild severity are less likely to be influenced by plasma glucose. Corresponding to this are several examples of clinical events in which an ischemic insult might also be brief or mild (eg, implantation of cardiac defibrillators, temporary occlusion of intracranial arteries, induced hypotension combined with brain retractor pressure). The extent to which plasma glucose influences outcome from brief insults as well as the extent to which animal models of severe ischemia reflect such events warrants investigation.

The results of this experiment indicate that after as little as 4 minutes of ischemia, hyperglycemia-augmented ischemic brain damage is evident in the caudate putamen. In contrast, injury in either the hippocampal CA1 or SNPR is not perceptibly worse in hyperglycemic animals until ischemia has lasted more than 4 minutes. By 8 minutes of ischemia, a hyperglycemic effect becomes evident in both of these structures. This same interval corresponds to a substantial increase in the incidence of convulsions and death. It seems likely therefore that events occurring early in the course of the ischemic insult are directly contributory to hyperglycemia-augmented ischemic brain damage and that outcome from brief ischemic insults may be influenced by the glycemic state, although the effect becomes progressively more important as the duration of ischemia increases.

Multiple factors are known to contribute to hyperglycemia-augmented global ischemic brain damage. The extent of damage has been associated with the severity of preischemic hyperglycemia and of the ischemic insult (ie, near-complete versus complete ischemia).6 34 Our study identifies an additional variable, which is the duration of the ischemic insult. The mechanistic basis by which prolonged intervals of ischemia cause proclivity to hyperglycemic effects is not clear. One consistent hypothesis is that anaerobic glycolysis results in lactic acidosis, which among other things results in substantially worsened edema due to transport of hydrogen ion out of the cell in exchange for sodium.35 Indeed, in a rodent model of near-complete ischemia, both extracellular and intracellular acidosis were enhanced in hyperglycemic rats.36 Although the acidosis was continuously worsened over a 15-minute interval of ischemia, the most severe change in pH occurred within the first several minutes of ischemia. Given the fact that only minor differences were observed between outcomes as a function of glycemic state after 4 minutes of ischemia in our experiment, it can be postulated that more severe states of lactic acidosis can be tolerated if reperfusion is rapidly restored, whereas prolonged exposure to acidosis results in aggravated injury.

It was of some interest that the total motor score assay identified deficits in those hyperglycemic rats undergoing >8 minutes of ischemia. Previous work has shown motor deficits to be transient after forebrain ischemia.22 Other work has shown motor deficits to be a rare sequel to 10 minutes of normoglycemic ischemia; in fact, the total motor score assay has failed to even distinguish between ischemic rats and operated shams.37 This was thought to be due to relatively mild injury to the cortex characteristic of a two-vessel occlusion forebrain ischemia model. Because hyperglycemic rats undergoing 12 or 15 minutes of ischemia were likely to die in the present study, the severity of insult was decidedly worse than that previously investigated with this test. Such results implicate more widespread damage with hyperglycemia, including the less vulnerable structures contributing to motor function in rats.

As previously reported, postischemic seizures were frequently observed in rats undergoing extended periods of ischemia.4 5 In humans, seizure activity is a common sequel to severe ischemic episodes.38 39 A postulated mechanism is based on laboratory evidence that the SNPR plays a central role in preventing generalization of seizure discharges.40 Such discharges may arise from the limbic system, which has been demonstrated to exhibit hyperactivity after an ischemic insult.41 At the same time, inhibitory afferentation to the SNPR is largely derived from the caudate putamen.42 43 Excessive damage to the caudate putamen would be expected to reduce dampening of repetitive hyperexcitation of the postischemic SNPR, resulting in necrosis within the SNPR,44 failure of suppression of epileptogenic stimuli, and generalization of seizure activity. Because hyperglycemia leads to worsening of ischemic damage in the caudate putamen, the probability of seizures would be expected to increase when hyperglycemia is a preexisting condition.

Data from the present experiment are consistent with this hypothesis. With as little as 4 minutes of ischemia, damage in the caudate putamen was appreciably worsened in hyperglycemic animals. Because of the apparently unique vulnerability of the caudate putamen to hyperglycemic ischemia, we propose that more prolonged intervals of ischemia (eg, 8 minutes) increase the propensity of this structure to fail in balancing hyperexcitation of the SNPR, resulting in generalized convulsions.

In conclusion, this study was designed to examine the relationship between duration of global ischemic insults and neurological and/or histological outcome as a function of preischemic glycemic state. With 4-minute ischemia, evidence was found for hyperglycemia-augmented ischemic damage in the caudate putamen. By 8 minutes of ischemia, accentuated damage was found in both the hippocampal CA1 as well as the SNPR that was accompanied by frequent convulsive activity. Although it has long been known that hyperglycemia plays a deleterious role in long episodes of global ischemia, the results from this experiment indicate that hyperglycemia is an important factor in outcome from even short intervals of global ischemia.


*    Acknowledgments
 
This study was supported by American Heart Association Iowa Affiliate, Inc, Grant IA-92-GS-59 and US Public Health Service grant GM39771.

Received July 20, 1994; revision received October 31, 1994; accepted December 29, 1994.


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 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 up arrowDiscussion
 *References
 

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