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(Stroke. 1996;27:1405-1410.)
© 1996 American Heart Association, Inc.

Articles

Acute Changes in Intracranial Pressure and Pressure-Volume Index After Forebrain Ischemia in Normoglycemic and Hyperglycemic Rats

Yuji Morimoto, MD, PhD; Yoshiko Morimoto, MD; David S. Warner, MD Robert D. Pearlstein, PhD

the Departments of Anesthesiology (Y.M., Y.M., D.S.W.) and Surgery (R.D.P.), Duke University Medical Center, Durham, NC.

Correspondence to David S. Warner, MD, Department of Anesthesiology, Box 3094, Duke University Medical Center, Durham, NC 27710. E-mail warne002@mc.duke.edu.


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 down arrowIntroduction 
 down arrowReferences 
 
Background and Purpose Hyperglycemia enhances the deleterious effect of global cerebral ischemia. One possible explanation is that increased anaerobic glycolysis leads to exaggeration of intracellular acidosis and increased postischemic edema. To examine the importance of this edema on postischemic cerebral perfusion dynamics, we measured acute changes in intracranial pressure (ICP), specific gravity, and the pressure-volume index (PVI) after forebrain ischemia in normoglycemic and hyperglycemic rats.

Methods Rats underwent 15 minutes of forebrain ischemia and 90 minutes of reperfusion. ICP and mean arterial pressure were continuously monitored. Before ischemia, rats received either saline or glucose intravenously. Ninety minutes after ischemia, the specific gravity of the neocortex was measured. In a second experiment, the PVI was measured at 20 and 60 minutes after ischemia.

Results Preischemic ICP (mean±SD) was 7±1 mm Hg in both groups. A peak ICP ({approx}11 mm Hg) occurred within 15 to 20 minutes after ischemia in both groups. Between 25 and 80 minutes after ischemia, ICP was significantly but only slightly greater in hyperglycemic than in normoglycemic rats. Cerebral perfusion pressure was similar between groups and remained greater than 100 mm Hg. Specific gravity was also similar for both groups but was less than normal values. The PVI in hyperglycemic rats was lower than in normoglycemic rats, indicating reduced compliance.

Conclusions These findings indicate that hyperglycemia-augmented intraischemic tissue acidosis does not contribute to worsened outcome by means of compromised cerebral perfusion pressure during the early stages of recovery. Nevertheless, evidence was found for decreased cerebral compliance, indicating an effect of hyperglycemia on intracranial volume compartments other than cortical parenchyma.


Key Words: brain edema • cerebral ischemia, global • hyperglycemia • intracranial pressure • rats


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 down arrowIntroduction 
 down arrowReferences 
 
Numerous investigations have found that hyperglycemia enhances the deleterious effects of ischemic insults.1 2 3 This worsened outcome is often manifested as an increased incidence of postischemic seizures and death.1 4 5 The mechanistic basis for these observations remains unresolved. One possible explanation is that increased anaerobic glycolysis leads to exaggeration of cerebral intracellular acidosis.6 7 However, in vitro studies have shown that the magnitude of acidosis seen in either normoglycemic or hyperglycemic ischemia actually provides protection for hippocampal or cortical neurons exposed to simulated ischemic insults.8 9 These findings suggest that hyperglycemia-enhanced lactic acidosis may not directly cause worsened ischemic neuronal injury.

Hyperglycemia-augmented ischemic brain damage has been associated with enhanced edema formation.1 10 In vitro studies have shown that acidosis causes neuronal and glial cell swelling consistent with an imbibition of water as hydrogen ion is exchanged for sodium.11 12 Accordingly, we speculated that hyperglycemia causes increased edema because of enhanced acidosis, which may lead to intracranial hypertension and a resultant compromise of postischemic CPP. Such a process would constitute a secondary insult perhaps contributing to worsened outcome. To test this hypothesis, we measured acute changes in ICP, specific gravity, and the PVI in both normoglycemic and hyperglycemic rats during the early recovery period after a severe forebrain ischemia insult.


*    Materials and Methods
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 *Materials and Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 down arrowIntroduction 
 down arrowReferences 
 
This study was approved by the Duke University Animal Care and Use Committee.

Surgical Preparation
Male Sprague-Dawley rats (Harlan, Indianapolis, Ind; body weight, 280 to 325 g) were fasted from food for 12 to 16 hours before the experiment. Rats were then anesthetized with 4% halothane in O2, endotracheally intubated, and mechanically ventilated with a delivered gas mixture of 1.0% to 1.5% halothane in 50% O2/balance N2. The tail artery was cannulated to monitor arterial blood pressure. Through a ventral neck incision, the right external jugular vein was cannulated, and the common carotid arteries were isolated and encircled with suture. Rats were then turned prone, and the heads were fixed into a stereotaxic frame. After dissection of the posterior neck muscles, a 23-gauge needle was inserted into the cisterna magna through the atlanto-occipital membrane for continuous measurement of ICP. The membrane around the needle was sealed with cyanoacrylate glue. Backflow of asanguineous cerebrospinal fluid was ensured. The transducer (ETH-400, CB Science, Inc) was zeroed to the level of the external auditory meatus. Pilot studies were performed to ensure that appropriate changes in ICP occurred at this measurement site in the postischemic preparation in response to jugular venous compression, hypercapnia, and balloting of exposed supratentorial dura. Bipolar electroencephalographic activity was obtained from active needle electrodes inserted in the temporal muscle bilaterally and a ground lead in the tail (DP-301, Warner Instrument Corp). A calibrated 22-gauge needle thermistor (model 73ATA, Yellow Springs Instrument Co, Inc) was percutaneously placed adjacent to the skull beneath the temporal muscle, and pericranial temperature was thenceforth servoregulated at 37.0±0.1°C by surface heating or cooling. Finally, heparin (50 IU) was given intravenously. MAP, ICP, electroencephalographic activity, and pericranial temperature were continuously monitored and recorded with a Macintosh computer (7100/66, Apple Computer Co) with the use of a MacLab 4E analog-to-digital convertor (AD Instrument Pty Ltd).

After surgical preparation, the end-tidal concentration of halothane was reduced to 0.5% to 0.7%. A 30-minute interval was allowed for manipulation of plasma glucose. Rats were randomly assigned to one of two groups. In normoglycemic rats, 1.5 mL of 0.9% NaCl was infused over 25 minutes intravenously. In hyperglycemic rats, 1.5 mL of 25% dextrose in 0.9% NaCl was infused over the same interval. Blood samples for plasma glucose, PaO2, PaCO2, arterial pH, and hematocrit determination were obtained 5 minutes before the onset of ischemia.

Ischemia was induced according to established protocol.13 14 Hypotension (MAP=30±5 mm Hg) was induced with trimethaphan camsylate (1.5 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. Fifteen minutes later, the vascular clamps were released, any shed blood was reinfused, and 0.3 mEq NaHCO3 was given to minimize systemic acidosis.

Experiment 1
Eight normoglycemic and eight hyperglycemic rats were studied. MAP and ICP were continuously monitored in all rats until 90 minutes after ischemia. CPP was calculated by subtracting ICP from MAP. Blood samples for PaO2, PaCO2, arterial pH, and hematocrit determination were obtained 10, 20, 30, 60, and 90 minutes after ischemia.

Ninety minutes after ischemia, the rats were decapitated and the brains were rapidly removed. Each whole brain was coronally cut into 2-mm-thick sections. The sections were immersed in kerosene, which allowed dissection of gray matter from the frontoparietal cortex into 30- to 50-mg samples. Specific gravity of the neocortex was measured with a bromobenzene-kerosene linear density gradient.15 The gradient was calibrated before we analyzed samples from each brain using standard droplets with known densities made of K2SO4 in H2O. Only gradients with linearity of >0.998 were used. Samples were introduced into the gradient column, and their position was measured 3 minutes later. Specific gravity for the samples was calculated in relation to the positions of the standards. The mean value of the bilateral samples was regarded as the representative value. As a control, normal cortical specific gravity was measured in 10 nonischemic rats. For this, fasted rats were anesthetized with 4% halothane in O2. The rats were decapitated, and cortical specific gravity was measured.

Experiment 2
The PVI was determined as an estimate of cerebral compliance in normoglycemic (n=5) and hyperglycemic (n=5) rats treated in a manner identical to those studied in experiment 1, with one exception. During surgical preparation, a second needle (25 gauge) was inserted through the atlanto-occiptal membrane into the cisterna magna. At 20 and 60 minutes after 15 minutes of forebrain ischemia, the PVI was determined. The change in ICP that occurred after injection of 0.05 mL of 0.9% NaCl over 1 second into the cisterna magna through the second needle was recorded. The PVI was calculated by the following equation16 :

where Po is basal ICP value before injection of NaCl and Pp is peak value of ICP after injection of NaCl. Blood samples for PaO2, PaCO2, and arterial pH determination were obtained before each PVI measurement.

Normal PVI was also measured in nonischemic normoglycemic rats (n=5). After surgical preparation, these rats were stabilized under 0.5% halothane for 60 minutes. After physiological values were obtained, PVI was measured in the same manner.

Statistical Analysis
All parametric data are presented as mean±SD. Most physiological values were compared qualitatively to preserve statistical power. ICP, CPP, and specific gravity in experiment 1 and PVI and MAP in experiment 2 were compared between hyperglycemic and normoglycemic rats with Student's (or Welch's when variance was unequal) t test. Statistical significance was assumed at P<.05.


*    Results
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 *Results
down arrowDiscussion
 down arrowReferences
 down arrowIntroduction 
 down arrowReferences 
 
In experiment 1, physiological values were similar between groups with the exception of preischemic plasma glucose values (Table 1Down). PaCO2 was maintained within normal range throughout the protocol in both groups. Mean preischemic ICP was 7±1 mm Hg in both groups (Fig 1ADown). ICP decreased similarly between groups during ischemia. A peak ICP ({approx}11 mm Hg) occurred within 15 to 20 minutes after ischemia in both groups. ICP then gradually decreased and returned to preischemic values within 90 minutes after ischemia in both groups. ICP in hyperglycemic rats was only slightly but significantly greater than that in normoglycemic rats between 25 and 80 minutes after ischemia. However, CPP was similar between groups and remained >100 mm Hg during recirculation in all animals (Fig 1BDown). The specific gravity of the neocortex was similar for both groups and was less than values measured in nonischemic controls (Fig 2Down).


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  		Table 1. Physiological Values in Experiment 1



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  		Figure 1. Changes in ICP (A) and CPP (B) during preischemic, intraischemic, and postischemic intervals in normoglycemic ({square}) and hyperglycemic ({bullet}) rats (experiment 1). Ischemia onset and offset are depicted by arrows. Values are mean±SD. *P<.05 between group differences for ICP at respective postischemic intervals. There were no significant differences for CPP.



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  		Figure 2. Specific gravity of neocortex 90 minutes after forebrain ischemia in normoglycemic and hyperglycemic rats (experiment 1). Values are mean+SD. Control specific gravity values were obtained from 10 fasted rats subjected to no ischemia.

In experiment 2, physiological values were similar between groups, with the exception of preischemic plasma glucose values (Table 2Down). Normal PVI obtained from nonischemic normoglycemic rats was 0.115±0.035 mL (Fig 3Down). Postischemic PVI values in normoglycemic rats were similar to the values measured in nonischemic rats. Postischemic PVI values in hyperglycemic rats were lower than those in normoglycemic rats, and a significant difference was seen 60 minutes after ischemia. In the second PVI measurement, ICP values in hyperglycemic and normoglycemic rats were 7±1 and 9±3 mm Hg, respectively. These values were similar to those measured 60 minutes after ischemia in experiment 1. Accordingly, the effect of NaCl injection at the first PVI measurement can be neglected in the second measurement.


View this table:
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  		Table 2. Physiological Values in Experiment 2



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  		Figure 3. PVI (experiment 2) measured at 20 and 60 minutes after forebrain ischemia in normoglycemic and hyperglycemic rats. Values are mean+SD. Control PVI values were obtained from five sham-operated normoglycemic rats (subjected to no ischemia) 60 minutes after completion of surgical preparation.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 *Discussion
down arrowReferences
 down arrowIntroduction 
 down arrowReferences 
 
A reliable effect of hyperglycemia on ischemic pathophysiology is enhanced lactic acidosis. Cerebral lactate has been reported to accumulate to {approx}20 µmol/g after 15 minutes of forebrain ischemia in hyperglycemic rats, nearly double that observed in moderately hypoglycemic counterparts.6 In addition, extracellular and intracellular pH undergo a greater decrease during and/or after ischemia in hyperglycemic animals.6 17 18 19 The significance of these findings is still unknown.

In vitro investigations have shown that acidosis causes neuronal and glial cell swelling.11 12 It is thought that this swelling is due to activation of the Na+-H+ exchanger rather than inhibition of the Na+-K+ transporter.11 12 20 If allowed to persist, this swelling may be lethal to neurons, and the effect would be expected to be accentuated with increased glucose availability. Effects of hyperglycemia on ischemic edema would also be expected to have relevance to whole-organ physiology within the noncompliant cranial vault. In fact, ICP rose to {approx}40 mm Hg during early recirculation in hyperglycemic dogs exposed to incomplete ischemia produced by ventricular infusion of cerebrospinal fluid.21 Normoglycemic dogs, in contrast, were found to achieve a maximal postischemic ICP of {approx}20 mm Hg. There have been no studies designed to directly compare the effect of hyperglycemia on ICP changes after forebrain ischemia in the rat, in which neurological and histologic outcome events have been best defined.2 4 5 22 23 Contrary to our expectations, preischemic hyperglycemia caused only a small increase in ICP. CPP was similar between hyperglycemic and normoglycemic rats and remained >100 mm Hg during the acute postischemic recovery interval. These data indicate that hyperglycemia-augmented intraischemic tissue acidosis does not contribute to worsened outcome by means of compromised CPP during early stages of recovery.

It has been reported that brain edema is biphasic after forebrain ischemia in the hyperglycemic rat.10 The first phase most likely reflects cytotoxic edema, with a peak effect occurring at {approx}30 minutes after reperfusion.24 Thereafter, brain edema rapidly resolves but reoccurs {approx}24 hours later, coincident with onset of seizures and tissue necrosis consistent with vasogenic edema. The purpose of this study was to examine effects of the first phase of edema on ICP and CPP. This is the interval when a direct effect of intracellular lactic acidosis would be most likely to occur. Because the observation interval was carried out for 90 minutes after recirculation, it is likely that the peak acute ICP effects of ischemia and hyperglycemia were captured. Additional work is required to determine whether the ICP effects of hyperglycemia occurring in the late reperfusion phase are important to outcome.

Although ICP values were found to be similar between groups, an effect of hyperglycemia on PVI was observed. The PVI is an established technique for measurement of intracranial compliance, providing an estimate of volume buffering capacity within the intracranial vault.16 25 The PVI is obtained from the change in ICP after the bolus infusion of a known volume of fluid. The pressure-volume curve becomes linear when the logarithm of pressure is plotted against volume change. Accordingly, low PVI values indicate decreased compliance. The PVI is thought to represent the algebraic sum of separate PVI values of the various compartments of the intracranial vault.16 Reported PVI values in normal rats have ranged between 0.0518±0.018 mL26 and 0.0911±0.010 mL.27 These values are smaller than those observed for normal rats in our study. The reason why the results are different among reports is unclear. However, the time interval over which the bolus injection occurred was not described in the other studies. Because PVI values would be expected to be a function of the duration of bolus injection,28 direct comparison between these studies is difficult.

In this experiment, postischemic PVI values in normoglycemic rats were similar to control values. On the other hand, PVI values (ie, compliance) in hyperglycemic rats were decreased, and this persisted after ICP had nearly recovered to baseline. The cause of this is unknown, although several possibilities can be considered. Because postischemic cortical specific gravity was similar between glycemic groups, it is likely that factors other than edema in cortical parenchyma account for the difference in compliance. This is consistent with evidence that PVI is predominantly influenced by the intravascular compartment.29 30 Direct volume effects of acute hyperglycemia on intravascular volume are undefined, although postischemic cerebral blood flow is known to sustain greater impairment in hyperglycemic animals.31 32 It has also been established that in brain with intact autoregulation, PVI becomes reduced with reduced MAP.33 This presumably is attributable to vasodilation and increased capacitance. The rapidity with which autoregulation recovers in the forebrain ischemia model is unknown. However, when linear regression analysis was applied to data derived from ischemic animals in our study, a significant relationship between MAP and PVI was observed (R2=.44, P=.002). Lower MAP was associated with a lower PVI (ie, decreased compliance). Although MAP values were not significantly different between the glycemic groups, a trend for lower values was present in the hyperglycemic animals. Differences in MAP therefore may have contributed to differences in PVI.

Several methodological issues deserve discussion. We elected to measure ICP from the cisterna magna as opposed to a supratentorial measurement site where the ischemic tissue is located. This was for two reasons. First, although a more direct measurement could be obtained from the lateral ventricles, prior work has demonstrated that penetration of the cortex with probes >50 µm in diameter is likely to elicit spreading depression,34 an event that poses an undesirable potential interaction with ischemic brain.35 Second, we were unsuccessful in obtaining reliable ICP recordings from the application of an ICP monitor (Camino) to the surface of the exposed cortex. Accordingly, measurements were taken from the cisterna magna after reliable responses to maneuvers including hypercapnia, jugular venous occlusion, and balloting of the exposed dura had been documented in pilot animals.

Another concern is the use of cerebral cortex as a prototype site for measurement of edema by determining tissue specific gravity. Prior work with this model has demonstrated consistent histological damage in the cortex, which is accentuated by hyperglycemia.4 Fifteen minutes of ischemia results in >50% neuronal necrosis and occasional small infarcts in surviving animals.23 Other structures undergo similar injury, most notably the hippocampus and caudoputamen. Prior work has demonstrated that a similar temporal profile of postischemic edema is present in those structures.10 An alternative method would have been use of the wet-dry weight method for determining water content in the intact hemisphere. Although less able to provide regionally specific information, such a technique could provide a sound correlate to macroscopic events such as ICP and PVI.

In summary, we evaluated acute changes in ICP, CPP, and PVI after 15 minutes of forebrain ischemia in normoglycemic and hyperglycemic rats. ICP in hyperglycemic rats was slightly greater than that in normoglycemic rats after ischemia. However, a peak ICP value of only {approx}11 mm Hg was reached, and ICP returned to preischemic values within 90 minutes after ischemia in both groups. Moreover, CPP was similar between groups and remained >100 mm Hg during recirculation. The PVI in hyperglycemic rats was significantly lower (indicating decreased compliance) than that in normoglycemic rats after ischemia, although the specific gravity of neocortex was similar between groups. These findings indicate that hyperglycemia-augmented intraischemic tissue acidosis does not contribute to worsened outcome by means of compromised CPP during the early stages of recovery. The significance of the observed reduction in intracranial compliance for outcome from hyperglycemic ischemia remains to be determined.


*    Selected Abbreviations and Acronyms
 
CPP = cerebral perfusion pressure
ICP = intracranial pressure
MAP = mean arterial blood pressure
PVI = pressure-volume index


*    Acknowledgments
 
This study was supported by US Public Health Service grant GM39771.

Received December 14, 1995; revision received March 26, 1996; accepted April 24, 1996.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 up arrowDiscussion
 *References
down arrowIntroduction 
 down arrowReferences 
 

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Editorial Comment

J. Paul Muizelaar, MD, PhD, Guest Editor

Department of Neurosurgery, Wayne State University, Detroit, Mich


*    Introduction 
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 up arrowDiscussion
 up arrowReferences
 *Introduction 
down arrowReferences 
 
There might be many mechanisms by which hyperglycemia exacerbates ischemic injury, and exploring the possibility of increased ICP from increased edema is an interesting idea. I suspect that the main reason that ICP was not a factor is the short time period over which it was measured. This is not to say that at a later time hyperglycemia would certainly be associated with higher ICP than normoglycemia. However, 24 to 48 hours after stroke in rats, ICP at least probably becomes high enough to have a significant effect on CPP, and any further increase in ICP would tip the scale.1R

The decrease in PVI with hyperglycemia compared with normoglycemia is not well explained. As the authors have noted, we have described that PVI decreases with lower blood pressure if autoregulation is intact, but actually this was in the minority of cases and not statistically significant.2R On the other hand, when autoregulation was defective, as may very well be the case in the experiments described in the accompanying article, lower blood pressure was statistically significantly associated with a higher PVI. In my opinion, the significant relationship between PVI and MAP that the authors found indicates a certain degree of vasodilation in the microcirculation, but obviously only cerebral blood volume measurements could settle this issue.

Further experiments will be necessary, the first ones to explore whether ICP plays a role much later after temporary middle cerebral artery occlusion and hyperglycemia.


*    Selected Abbreviations and Acronyms
 
CPP = cerebral perfusion pressure
ICP = intracranial pressure
MAP = mean arterial blood pressure
PVI = pressure-volume index

Values are mean±SD. The first PVI measurement was performed 20 minutes after ischemia; the second PVI measurement was performed 60 minutes after ischemia.


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

  1. Forsting M, Reith W, Schabitz W-R, Heiland S, von Kummer R, Hacke W, Sartor K. Decompressive craniectomy for cerebral infarction: an experimental study in rats. Stroke.. 1995;26:259-264.[Abstract/Free Full Text]
  2. Bouma G, Muizelaar J, Bandoh K, Marmarou A. Blood pressure and intracranial pressure-volume dynamics in severe head injury: relationship with cerebral blood flow. J Neurosurg.. 1992;77:15-19.



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Nitric Oxide Redox Species Exert Differential Permeability Effects on the Blood-Brain Barrier
J. Pharmacol. Exp. Ther., May 1, 2000; 293(2): 545 - 550.
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