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Published online before print March 30, 2007, 10.1148/radiol.2432060137
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(Radiology 2007;243:720-726.)
© RSNA, 2007

Experimental Studies

Ischemic Brain Tissue Water Content: CT Monitoring during Middle Cerebral Artery Occlusion and Reperfusion in Rats1

Imanuel Dzialowski, MD, Ernst Klotz, DPhys, Sophia Goericke, MD, Arnd Doerfler, MD, Michael Forsting, MD, and Rüdiger von Kummer, MD

1 From the Departments of Neuroradiology (I.D., R.v.K.) and Neurology (I.D.), Universitaetsklinikum Carl Gustav Carus, University of Dresden, Fetscherstrasse 74, D-01307 Dresden, Germany; Siemens Medical Engineering Group, Forchheim, Germany (E.K.); Department of Neuroradiology, University of Essen, Essen, Germany (S.G., M.F.); and Department of Neuroradiology, University of Erlangen, Erlangen, Germany (A.D.). Received January 24, 2006; revision requested March 23; revision received June 5; accepted June 21; final version accepted September 5. Address correspondence to I.D. (e-mail: imanuel.dzialowski{at}neuro.med.tu-dresden.de).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Purpose: To prospectively perform computed tomography (CT) in rats to determine whether ischemic edema can be reversed by using early arterial reperfusion.

Materials and Methods: This study was approved by the local animal protection committee. A suture model was used to occlude the right middle cerebral artery (MCA) in rats for 1, 2, 3, or 4 hours. X-ray attenuation of the brain was measured directly before reperfusion and repeatedly during reperfusion for up to 24 hours. Infarct volumes were determined with triphenyltetrazolium chloride staining. Means of attenuation and infarct volume were compared between hemispheres and groups with a paired t test and analysis of variance. Mixed linear models were applied to compare attenuation among groups over time.

Results: During MCA occlusion, attenuation decreased to 69.3 HU ± 1.9 (standard deviation) after 1 hour (n = 12), 66.6 HU ± 2.0 after 2 hours (n = 10), 65.4 HU ± 2.9 after 3 hours (n = 11), and 64.1 HU ± 1.8 after 4 hours (n = 9) (P < .0001). After reperfusion, attenuation remained stable in the 1-hour occlusion group (P = .16) but further and steadily declined in the 2-, 3-, and 4-hour occlusion groups (P < .001). Attenuation during reperfusion in the 1-hour occlusion group differed significantly from that in the 2-, 3-, and 4-hour occlusion groups.

Conclusion: CT is able to help monitor ischemic edema after MCA occlusion and reperfusion. Ischemic brain edema was not consistently reversible with reperfusion, even after 1 hour of occlusion, and further increased with reperfusion induced at 2 hours or later.

Supplemental material: http://radiology.rsnajnls.org/cgi/content/full/2432060137/DC1

© RSNA, 2007


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Thrombolytic therapy enabling recanalization of obstructed arteries and restoration of blood supply to ischemic brain tissue is clinically beneficial in patients with acute stroke (1,2), but it is less effective if systemic thrombolysis is performed beyond 3 hours after stroke onset (3). The decline in effectiveness is best explained by the high degree of vulnerability of brain tissue, which does not survive severe ischemia for more than 30 minutes (4).

Cerebral ischemia below the critical perfusion threshold of 10–15 mL blood per 100 g brain tissue per minute causes the gray matter to take up water, even before the blood-brain barrier is disrupted, and allows macromolecules to enter (5–7). Brain tissue water content is inversely correlated with x-ray attenuation and can thus be measured with computed tomography (CT) (8,9). In regard to ischemic brain edema, with each 1% increase in tissue water content, attenuation will decline by approximately 2 HU (10).

There is some controversy, however, as to whether subtle brain tissue hypoattenuation, which results in the obscuration of brain structures because of diminishment of contrast between gray matter and white matter (eg, "obscuration of lentiform nucleus" [11] or "loss of insular ribbon" [12]), in its very early stage truly reflects early ischemic edema or instead reflects a potentially reversible decrease in cerebral blood volume (CBV) (13,14). In 786 patients with stroke imaged within 6 hours of symptom onset, the positive predictive value for early hypoattenuation was 96% (15), which suggests that once the degree of hypoattenuation becomes clearly visible to the human eye it is unlikely to reverse. It is uncertain, however, if hypoattenuation at CT is reversible at its subtle, very early stages. Thus, the purpose of our study was to prospectively perform CT in rats to determine whether ischemic edema can be reversed by using early arterial reperfusion.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Animal Model and Experimental Protocol
The study was approved by the local animal protection committee. We induced focal cerebral ischemia in 60 male Wistar rats (in-house breed, Experimental Animal Research Laboratory, University of Essen, Essen, Germany) weighing 280–340 g by using the intraluminal suture occlusion method (16,17). Normal hemispheres and animals that underwent sham operations served as controls. Rats were allowed free access to food and water before and after the procedure. They were anesthetized with a preparation of ketamine (4 mg per 100 grams of body weight; Ketavet, Parke-Davis, Berlin, Germany) and xylazine (1.5 mg/100 g; Rompun, Bayer, Leverkusen, Germany) administered intramuscularly. Rectal temperature was maintained at 37°C by using a feedback-regulated heating pad throughout the surgery.

In all animals, the middle cerebral artery (MCA) was occluded with a transvascular approach (I.D., S.G.) as previously described (16). To standardize and facilitate the surgical procedure, we chose to exclusively occlude the right MCA. In brief, the right common carotid artery and external carotid artery were exposed through a midline neck incision and ligated with a 4.0 monofilament nylon suture (Ethicon; Johnson & Johnson International, Brussels, Belgium). For MCA occlusion, we inserted a 4.0 monofilament nylon suture (Ethicon) whose tip had been coated with silicone into the common carotid artery and gently advanced it into the internal carotid artery to a point approximately 17 mm distal to the carotid bifurcation. Mild resistance to this advancement indicated that the suture had entered the anterior cerebral artery, thus occluding the origins of the MCA and the posterior communicating artery.

Animals were randomly assigned to one of four groups: reperfusion after 1 hour (n = 15), 2 hours (n = 15), 3 hours (n = 15), or 4 hours (n = 15) of MCA occlusion. In each of these groups, two animals underwent sham surgery to enable us to control for procedure-related fluctuation in attenuation measurements. In sham-operated rats, we advanced the occlusive suture just distal to the carotid bifurcation, allowing free perfusion of the complete circle of Willis, and measured attenuation at the end of the respective sham-occlusion period.

Brain Scanning
At the end of the respective occlusion or sham-occlusion period, animals were reanesthetized as described above and positioned in the CT scanner (Somatom 4.0 plus; Siemens, Erlangen, Germany). CT images were obtained in 2-mm coronal sections parallel to the skull base at 140 kV and 77 mA. Image matrix was 512 x 512 pixels, and field of view was 50 mm, which resulted in a 0.01-mm2 pixel size. We induced reperfusion within 5 minutes after this baseline CT examination was performed. The neck wound was reopened, the occlusive suture was withdrawn until the suture's silicone-coated tip appeared in the carotid bifurcation, and the neck wound was closed again. CT measurements were performed serially at 20, 40, and 60 minutes and at 2, 3, 4, 5, 6, and 24 hours after reperfusion (Fig 1). During CT scanning, anesthesia was maintained up to 6 hours after reperfusion by using intramuscular ketamine (1.3 mg/100 g) and xylazine (0.5 mg/100 g) injections and was repeated at the initial higher dose before the 24-hour measurement.


Figure 1
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  		Figure 1: CT images of attenuation of developing ischemic brain edema in rat with reperfusion after 3 hours of right MCA occlusion and include one of three 2-mm coronal CT sections through the rat brain at each time point before and during reperfusion. {circ} = regions of interest (ROIs) positioned in lateral caudoputamen and adjacent frontoparietal cortex. Numbers in ROIs = attenuation measurement in Hounsfield units. Bottom: Triphenyltetrazolium chloride (TTC)–stained 2-mm coronal slice in the same rat. Areas of infarcted brain tissue stain white; normal tissue stains red. (Original magnification, x6.)

 
Infarct Staining
Immediately after the 24-hour examination, rats were sacrificed and their brains were rapidly removed. Brains and skull bases were carefully examined for subarachnoid hemorrhage, as well as for lost silicone coatings that possibly disturbed intracranial reperfusion. For infarct staining, we (I.D., S.G.) incubated 2-mm brain slices for 30 minutes in a 4% solution of 2,3,5-TTC at 37°C. Brain slices were fixed with immersion in a 10% buffered formalin solution. TTC stains normal brain tissue (intact cellular membranes) red, while necrotic tissue remains grayish (Fig 1) (18).

Image Analysis
TTC-stained brain slices were photographed, digitized, and processed on a computer (Macintosh; Apple Computer, Cupertino, Calif) by using public-domain software (Image 1.41; Wayne Rasband, U.S. National Institutes of Health, Bethesda, Md) (I.D.). We quantified infarct volumes by summing the unstained areas on each slice and multiplying the resulting value by slice thickness.

For the assessment of attenuation, we selected three consecutive sections, beginning 6 mm ventral to the anterior margin of the auditory canal representing the MCA territory. In these coronal sections, we determined attenuation in an ROI in both hemispheres (Fig 1). We reproducibly positioned a 7-mm2 ROI in the lateral lower quadrant of the affected hemisphere by using a coordinate system (I.D.). This localization was chosen to (a) measure attenuation in the lateral segment of the caudoputamen and the lower part of frontoparietal cortex, both of which are usually affected in our occlusion model (17,19), and (b) avoid partial volume effects with cerebrospinal fluid in the ventricles and subarachnoid space. We positioned the corresponding ROI in the unaffected hemisphere with a mirror function. The 7-mm2 ROI size was chosen to optimize signal-to-noise ratio.

Data Evaluation
Rats suspected of having subarachnoid hemorrhage or lost silicone coatings were excluded from further analysis. We determined mean attenuation for each hemisphere within the ROIs in three consecutive sections through the brain. To identify rats without successful MCA occlusion, we determined the difference in attenuation between the ROIs of both hemispheres at the end of the respective occlusion period for each rat and compared that difference with the difference in sham-operated animals. Assuming that no MCA occlusion occurred, we excluded animals from further analysis if (a) the difference in attenuation between both hemispheres at the end of the MCA-occlusion period did not exceed the mean ± standard deviation of that in the sham-operated animals and (b) no infarct was demonstrated at TTC staining.

Statistical Analysis
We analyzed the data both before and after exclusion of rats without successful MCA occlusion. Attenuation values are expressed as means ± standard deviations. A statistically significant difference was accepted at a P value of less than .05. Analysis was performed with statistical software (SPSS, version 13.0, SPSS, Chicago, Ill; SAS, version 9.1, SAS Institute, Cary, NC).

Differences in means of attenuation between hemispheres at the end of the respective occlusion period were tested by using a paired t test. Differences in means of attenuation between groups were tested with an analysis of variance model by using specified contrasts and with Bonferroni adjustment of P values. To compare development of attenuation over time in control and ischemic hemispheres and among groups, we applied mixed linear models that included an adjustment of the P value for post hoc multiple Tukey-Kramer tests. The models included the factor MCA occlusion group and the two repeated measures factors—hemisphere and reperfusion time. Compound symmetry for the measures in different regions and at different time points in the same animal was assumed. We compared mean infarct volumes in normal and ischemic hemispheres by using a paired t test and performed analysis of variance to assess for differences among groups.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Of 60 rats with attempted MCA occlusion, three (5%) died before reaching the desired infarct interval, four (7%) were suspected of having subarachnoid hemorrhage, and none showed mechanical impairment of reperfusion. These seven animals were excluded from further analysis, leaving a total of 53 animals for the four groups: 1-hour (n = 14), 2-hour (n = 14), 3-hour (n = 14), and 4-hour (n = 11). Results from this primary analysis are given in Table 1. We then identified 11 (18%) of 60 animals without successful MCA occlusion that were evenly distributed among the four groups. For further analysis, we excluded these rats in addition to those mentioned above, leaving a total of 42 rats for the four groups: 1-hour (n = 12), 2-hour (n = 10), 3-hour (n = 11), and 4-hour (n = 9).


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  		Table 1. Attenuation after MCA Occlusion and during Reperfusion in Rats

 
Another seven rats died during the reperfusion period, mainly between the 6- and 24-hour measurement. These deaths were distributed among the groups as follows: 1-hour (n = 1), 2-hour (n = 2), 3-hour (n = 3), and 4-hour (n = 1). All values obtained until death were considered for evaluation.

Sham-operated Animals
Mean attenuation was 71.3 HU ± 1.6 in normal and 70.1 HU ± 2.4 in sham-operated hemispheres (Table 2). Attenuation fluctuated between occlusion groups but did not differ significantly.


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  		Table 2. Attenuation in ROI after Sham Surgery in Rats

 
Attenuation
Mean attenuation in the nonischemic hemispheres remained constant at 71.4 HU ± 2.2 in all groups during contralateral occlusion and reperfusion (Fig 2). In the ischemic hemispheres, attenuation decreased to 69.3 HU ± 1.9 after 1 hour, 66.6 HU ± 2.0 after 2 hours, 65.4 HU ± 2.9 after 3 hours, and 64.1 HU ± 1.8 after 4 hours of MCA occlusion (P < .0001 for all groups) (Fig 2). Attenuation at the end of the respective occlusion period in the 1-hour group significantly differed from that in the 2-, 3-, and 4-hour groups (P < .01).


Figure 2
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  		Figure 2: Graph of attenuation measured in Hounsfield units in ROIs in control and ischemic hemispheres after 1, 2, 3, and 4 hours of MCA occlusion (MCAO) and during reperfusion. At end of MCA occlusion (time point 0), attenuation in ischemic hemispheres had significantly decreased in all groups compared with that in control hemispheres (P < .0001). Degree of hypoattenuation after 1 hour (1h) differed significantly from that after 2 (2h), 3 (3h), and 4 (4h) hours of MCA occlusion. During reperfusion, attenuation remained constant in 1-hour occlusion group (P = .16). After 2, 3, and 4 hours of MCA occlusion, attenuation decreased further and steadily (P < .0001 for all groups). Bars show mean values; error bars show standard deviations.

 
During reperfusion, mean attenuation remained stable after 1 hour of MCA occlusion (P = .16) (Fig 2). In eight of 12 rats in this group, however, attenuation further decreased, whereas in four of 12 rats, attenuation returned to preocclusive values during reperfusion (Fig 3).


Figure 3
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  		Figure 3: Dichotomized graph of attenuation given in Hounsfield units in ROIs after 1 hour of MCA occlusion and during reperfusion. In four rats, we observed reversal of attenuation to baseline values with reperfusion. In eight rats, however, attenuation further declined after reperfusion. Bars show mean values; error bars show standard deviations.

 
Brain tissue attenuation decreased further and steadily during reperfusion after 2, 3, or 4 hours of MCA occlusion (P < .0001) (Fig 2). Courses of attenuation during reperfusion after 2, 3, or 4 hours of MCA occlusion significantly differed from that after 1 hour of occlusion (P < .01). Decrease in attenuation among 2-, 3-, and 4-hour occlusion groups, however, did not significantly differ during reperfusion.

Infarct Volume
In two rats, quality of TTC staining was not sufficient to measure infarct volume. We did not observe any infarcts in the nonischemic hemispheres. Mean infarct volumes in the ischemic hemispheres were 51 mm3 ± 72 (median, 18 mm3; range, 0–225 mm3) in the 1-hour occlusion group, 106 mm3 ± 71 (median, 116 mm3; range, 12–179 mm3) in the 2-hour occlusion group, 91 mm3 ± 74 (median, 59 mm3; range, 17–212 mm3) in the 3-hour occlusion group, and 152 mm3 ± 53 (median, 172 mm3; range, 69–222 mm3) in the 4-hour occlusion group (P < .01 for all groups). Between groups, infarct volumes differed significantly only after 1 hour and 4 hours of MCA occlusion (P = .006). In the 1-hour occlusion group, all four of 12 rats with normalizing attenuation during reperfusion did not develop infarctions, whereas all eight of 12 rats with decreasing attenuation showed infarctions at TTC staining.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 References
 
We used a well-established experimental model to induce transient focal ischemia in rats that reliably reduces and reestablishes cerebral blood flow (CBF) in the lateral caudoputamen and adjacent frontoparietal cortex during MCA occlusion and reperfusion (17,20). Therefore, we did not determine CBF in our study. Critical reduction in CBF causes gray matter to immediately take up water (5–7,21). Measuring experimental early ischemic edema by means of attenuation has been introduced only recently, but results suggest a close inverse correlation between attenuation and tissue water content (10).

Nonetheless, this method has limitations. Accuracy of attenuation measurement is affected by limited spatial resolution and possible volume averaging, depending on the choice of ROI; in our study, measurement of attenuation in control hemispheres yielded random noise of 2–3 HU. We positioned the ROI in the lateral caudoputamen and adjacent frontoparietal cortex—areas likely to suffer early and severe reduction in CBF. Because we did not control for CBF, we cannot determine the incidence of ROIs without critical reduction in CBF. However, in 18% of rats, decrease in attenuation did not exceed the level of random noise, which suggests that either no MCA infarction was achieved or the location of the ROI was insufficient for detection of true change. We excluded these data from final analysis to reduce this methodologic limitation of our study.

In our study, we found that early ischemic edema did not consistently recover, even if reperfusion was induced as early as 1 hour after arterial occlusion, and further increased if reperfusion was induced 2 hours or later after occlusion. This observation is consistent with previous work. Yang et al (22) used an identical experimental model of focal ischemia in rats and measured tissue water content and Na+,K-adenosine triphosphatase (ATPase) activity 30, 60, and 120 minutes after MCA occlusion and after 24 hours of reperfusion. In their study results, reduction of ATPase activity preceded ischemic edema that had developed after only 1 hour of ischemia or later. Once ischemic edema had developed, it could not be resolved with reperfusion (22). In a model of transient global ischemia, specific gravity of brain tissue recovered after only 15 minutes and remained stable after 30 and 60 minutes of transient dense ischemia (21). Ischemic edema in gerbils remained stable after 30 minutes and slightly increased after 60 minutes of transient ischemia during the following 20 hours (23).

In four of 12 rats in our study, attenuation decreased by only approximately 2 HU during 1 hour of ischemia and returned to normal or elevated values immediately after reperfusion. We believe that this observation most probably reflects true resolution of ischemic brain edema in brain regions with severe reduction of CBF in a relatively small volume of brain tissue only.

The alternate explanation that this phenomenon might have been caused by a transient reduction in CBV appears less likely. Although Zimmerman (14) has suggested that because of the higher CT attenuation of blood, early ischemic changes at CT could instead be explained by a reduction in CBV, a straightforward calculation shows that this does not explain visible changes in attenuation. See Appendix E1 (http://radiology.rsnajnls.org/cgi/content/full/2432060137/DC1) for details. A CBV change of 1 mL/100 mL changes CT attenuation by only about 0.2 HU. Even a decrease in cortical CBV to 0 mL/100 mL (ie, a complete collapse of all capillary vessels) would not lower the CT attenuation by more than about 1 HU. Because capillaries still seem to be perfused in the early phases of ischemia (24,25), it is unlikely that CBV effects would exceed 0.5 HU. This presumption coincides with results of a recent study (26) that show CT attenuation increasing by 0.2–0.5 HU in hyperemic brain tissue whose regional CBV was increased by 25%–40%. On the other hand, a similar calculation (see Appendix E1) shows that even small changes in water content have a much more pronounced effect on attenuation. Gray matter, with its higher initial water content, is affected more strongly than white matter. Subtle obscurations of brain structures due to a diminished contrast between gray matter and white matter are therefore more readily explained by a change in net water content.

To our knowledge, CT has not been previously reported for monitoring the degree of ischemic edema during transient focal ischemia. There have been numerous studies (27), however, on experimental magnetic resonance (MR) imaging during transient focal ischemia that have considerably improved our understanding of evolving ischemic changes in the brain. Nonetheless, we consider our results important for two reasons. First, a majority of patients with acute stroke worldwide are still being examined with CT because of its availability. Yet the number of published experimental studies elucidating its understanding are few (8–10).

Second, decline of the apparent diffusion coefficient at diffusion-weighted MR imaging seems to reflect a different pathophysiology than does a decline in attenuation at CT (28). Both apparent diffusion coefficient decrease and CT attenuation decrease seem to be determined by CBF (13). The apparent diffusion coefficient declines at CBF values of 20–30 mL/100 g/min, exactly the CBF threshold at which the extracellular fluid space shrinks because of ischemic cell swelling (6,29,30) but net tissue water content remains stable. Only in ischemic brain areas with a CBF of less than 10 mL/100 g/min does net tissue water content increase, driven by an osmotic gradient between ischemic tissue and an intravascular compartment (6,22,31). Net tissue water uptake is associated with a decrease in CT attenuation that is linearly proportional to the specific gravity of brain tissue. This implies that brain tissue volumes with increased signal intensity on diffusion-weighted MR images and an associated decreased apparent diffusion coefficient may include both brain tissue that is irreversibly injured and tissue that can recover if CBF is restored. CT hypoattenuation, however, seems to reflect early ischemic edema that resolves only with reperfusion within a narrow time window and therefore might be a marker for irreversibly injured brain tissue.

Practical applications: We regard the early assessment of irreversibly injured brain tissue to be of utmost importance when decisions about reperfusion strategies are to be made. Our study results provide evidence that hypoattenuated ischemic brain tissue will go on to infarction if not reperfused within 1 hour from the onset of ischemia. In humans, this critical interval might be longer than it is in rodents. However, patients with acute stroke rarely undergo CT examination before 2 hours from symptom onset. Furthermore, CT hypoattenuation in its potentially reversible stage is hard to detect. In our study, brain tissue in ROIs with a decrease of more than 4 HU compared with that of control ROIs consistently went on to infarction. An image contrast of less than 4 HU, however, is beyond the resolution of the human eye. In patients with acute ischemic stroke at presentation, visible hypoattenuating regions at CT represent the core of infarction that cannot be salvaged by using reperfusion strategies. If this core exceeds one-third of the MCA territory or has an Alberta Stroke Program Early CT score of less than 8, the chances for thrombolysis-induced intracranial hemorrhage increase considerably (32,33).


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
References
 


   FOOTNOTES
 

Abbreviations: CBF = cerebral blood flow • CBV = cerebral blood volume • MCA = middle cerebral artery • ROI = region of interest • TTC = triphenyltetrazolium chloride

Author contributions: Guarantors of integrity of entire study, I.D., R.v.K.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, I.D., E.K., R.v.K.; experimental studies, I.D., S.G., A.D.; and manuscript editing, I.D., E.K., M.F., R.v.K.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 

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