Experimental intracerebral hemorrhage: relationship between brain edema, blood flow, and blood-brain barrier permeability in rats

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✓ There have been few investigations of brain edema formation after intracerebral hemorrhage (ICH), despite the fact that mass effect and edema are important clinical complications. The present study was designed to investigate the time course for the formation and resolution of brain edema and to determine how changes in cerebral blood flow (CBF) and blood-brain barrier (BBB) permeability are temporally related to edema formation following ICH.

Anesthetized adult rats received a sterile injection of 100 µl of autologous blood into the caudate nucleus. Water and ion contents were measured immediately, at 4 and 12 hours, and daily to Day 7 (10 time points, six rats at each time) after experimental ICH. The water content of the ipsilateral basal ganglia increased progressively (p < 0.002) over the first 24 hours, then remained constant until after Day 5, when the edema began to resolve. Edema was most severe in the tissue immediately surrounding the hemorrhage; however, it was also present in the ipsilateral cortex, the contralateral cortex, and the basal ganglia. Measurements of local CBF (using [14C]-iodoantipyrine) and BBB permeability (using [3H]-α-aminoisobutyric acid) were obtained in separate groups of six to eight rats at various time intervals between 1 and 48 hours after ICH. Cerebral blood flow was reduced to 50% of control at 1 hour, returned to control values by 4 hours, but then decreased to less than 50% of control between 24 and 48 hours after ICH. The BBB permeability increased significantly prior to the occurrence of significant edema in the tissue surrounding the clot. However, BBB permeability in the more distant structures remained normal despite the development of edema.

These results demonstrate a time course for the formation and resolution of brain edema following ICH similar to that observed during focal ischemia. Brain edema forms in the immediate vicinity of the clot as a result of both BBB disruption and the local generation of osmotically active substances and then spreads to adjacent structures. While local ischemia, due to the mass effect of the hemorrhage, may play a role in producing cytotoxic and vasogenic edema, the release of toxic substances from the clot should also be considered. Since edema is nearly maximal by 24 hours after ICH, therapy directed at reducing edema formation must be instituted within the 1st day.

Article Information

Address reprint requests to: Guo-Yuan Yang, M.D., Ph.D., R5605 Kresge I, University of Michigan, Ann Arbor, Michigan 48109–0532.

© AANS, except where prohibited by US copyright law.

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Figures

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    Drawing demonstrating the procedure for sampling brain tissue for water and ion content measurement. Two coronal sections, each 2 mm thick, were cut through and immediately posterior to the hemorrhage. Each section was divided into four areas: ipsilateral cortex, ipsilateral basal ganglia, contralateral cortex, and contralateral basal ganglia. The tissue samples were then processed for measurement of water, sodium, potassium, and chloride contents as described in the Materials and Methods section.

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    Magnetic resonance images, coronal view, following placement of 100 µl of autologous blood in the right caudate nucleus. A and B: One hour following instillation, the hematoma is low in signal intensity with a thin rim of surrounding edema (A). There is no abnormality in the adjacent posterior slice (B). C and D: Two days later, the hematoma is higher in signal intensity, and there is prominent edema in the corpus callosum that extends posteriorly and into the opposite hemisphere. Edema also involves the overlying cortex.

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    Graphs showing changes in water (A), sodium (B), potassium (C), and chloride (D) levels in the hemorrhagic section following injection of 100 µl of autologous blood. Water and ion contents were measured in groups of six rats immediately (Time 0) and at various intervals between Day 1 and Day 7 following intracerebral hemorrhage. The values shown are the means ± standard error of the means of the differences between values at Time 0 and those at subsequent times. Measurements were made in four brain regions: ipsilateral basal ganglia (solid squares), ipsilateral cortex (solid circles), contralateral basal ganglia (open squares), and contralateral cortex (open circles).

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    Scatterplots demonstrating the relationship between cation and water levels following intracerebral hemorrhage. The sum of the brain contents of sodium and potassium (brain [NA] + [K], in µl/gm dry weight) was divided by the sum of the sodium and potassium concentrations in plasma (plasma [Na] + [K], estimated to be 150 µl/ml) to obtain a measure of the osmolar force generated by brain cations. This result was plotted against the measured brain water content for individual samples obtained in both the hemorrhagic and the adjacent sections. Data were examined via linear regression analysis (Table 2) over the initial phase of edema formation (immediately and at 4 and 12 hours) in the ipsilateral (A) and contralateral (C) basal ganglia and during the maintenance phase (≥ 24 hours to 4 days) in the ipsilateral (B) and contralateral (D) basal ganglia.

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    Graphs showing changes following intracerebral hemorrhage (ICH) in samples of tissue from the basal ganglia (left) or cortex (right) that were ipsilateral (squares) or contralateral (circles) to either injection of 100 µl of autologous blood (solid symbols) or a sham procedure (open symbols). Values shown are means ± standard error of the means for six animals. Significance of difference: * = p < 0.05, † = p < 0.01, and ‡ = p < 0.001, comparing the ICH group with the sham-operated group at the same time point based upon a two-tailed Student t-test. Upper: Cerebral blood flow measured using [14C]-iodoantipyrine. Lower: Measurement of blood-brain barrier (BBB) permeability to [3H]-α-aminoisobutyric acid (AIB).

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