(Stroke. 1995;26:2149-2153.)
© 1995 American Heart Association, Inc.
Articles |
Long-term High-Colloid Oncotic Therapy for Ischemic Brain Edema in Gerbils
From the Laboratory of Experimental Medicine (Y.H.) and the Department of Neurology (S.H., M.Y.), Jichi Medical School, Tochigi-ken; and the Department of Neurosurgery, Musashino Red-Cross Hospital (U.I.), Tokyo, Japan.
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Abstract |
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Background and Purpose We evaluated the effects of long-term administration of high-colloid oncotic pressure on ischemic brain edema in Mongolian gerbils.
Methods Animals that exhibited stroke after 35 minutes of unilateral forebrain ischemia were used. The gerbils were divided into albumin- (1 g/kg body wt, 25% albumin; n=30) and saline-injected (4 mL/kg; n=30) groups. Both agents were administered intravenously every 12 hours starting immediately after the recirculation. Plasma colloid oncotic pressure, serum sodium and potassium concentrations, and brain water, sodium, and potassium content were measured 24, 48, and 72 hours after recirculation.
Results Plasma colloid oncotic pressure at 24, 48, and 72 hours after recirculation was significantly higher in the albumin- (26.1±2.3 mm Hg) than in the saline-treated group (18.5±1.9 mm Hg; P<.01), and brain water content of the ischemic hemisphere was significantly lower in the albumin group (79.5%, 80.2%, and 80.5%, respectively) than in the saline group (80.9%, 81.6%, and 82.1%, respectively; P<.05) at all three time points. Brain sodium content at 24 hours was significantly lower in the albumin than in the saline group (P<.05), while brain potassium content at 24 and 48 hours was significantly higher in the albumin than in the saline group (P<.05). The changes in brain water and sodium plus potassium content, which were calculated from differences between the ischemic and nonischemic hemispheres, showed a significant correlation in both groups (P<.01), but there was no significant difference between the linear regression lines for both groups.
Conclusions Long-term high-colloid oncotic pressure was effective in treating ischemic brain edema, probably acting by diminishing the bulk flow through the disrupted blood-brain barrier and ameliorating the vasogenic edema.
Key Words: albumin • brain edema • cerebral ischemia • colloid oncotic pressure • gerbils
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Introduction |
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The efficacy of colloid oncotic pressure (COP) in treating brain edema is still controversial. Colloid oncotic therapy with albumin and furosemide reduces cerebral vasogenic edema due to cold injury in dogs,1 and increased serum COP causes a reduction in the size of cerebral infarction in a canine ischemic model.2 Also, in patients with increased intracranial pressure (ICP), COP therapy reduces the ICP.3 Some reports, however, indicate that COP therapy has no effect on brain edema.4 5 Regardless of the effect of COP therapy, the duration of treatment did not exceed 24 hours in all experiments previously reported. In human patients, however, long-term (2 weeks) high-COP therapy suppresses or reduces the brain edema associated with cerebral putaminal hemorrhage6 and contusion.7 High-COP therapy has not been studied in ischemic brain edema. We therefore administered albumin or saline to Mongolian gerbils every 12 hours for 72 hours after performing temporary unilateral carotid occlusion; we then measured plasma COP, serum sodium, serum potassium, brain water, and brain sodium and potassium content 24, 48, and 72 hours after recirculation.
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Materials and Methods |
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Adult Mongolian gerbils of either sex weighing 60 to 80 g were used. Surgical procedures and general care were conducted in accordance with standards of the Jichi Medical School Guide for Care of Laboratory Animals.
Each animal was anesthetized by inhalation of 2% halothane in 70% N2O and 30% O2. A midline cervical incision was made, and the left common carotid artery was gently exposed and occluded with a Heifetz aneurysm clip after discontinuation of halothane anesthesia. The skin incision was then sutured, and each animal was placed in an uncovered polypropylene box (600 mm wide by 500 mm long by 150 mm deep). The animal's behavior was observed for 10 minutes after occlusion and scored with a stroke index.8 Sixty animals that had scored more than 10 points of a full score of 25 (of 143 animals, 42% were positive) were selected as the stroke-positive animals.
After 35 minutes of occlusion, the clip was removed to restore the circulation. Animals were killed by decapitation 24, 48, or 72 hours after the restoration of circulation. Another five animals were used as a normal control group. Experiments were conducted at 22°C to 23°C and 50% to 55% humidity.
The animals were divided randomly into two groups: those given albumin and those given saline. Albumin (1 g/kg body wt, 25% albumin [Green Cross Co]; n=30) or saline (4 mL/kg; n=30) was administered intravenously through the jugular vein immediately after recirculation, and this was repeated every 12 hours until the animals were killed. All animals were fed ad libitum during the observation period. Saline (8 mL/kg body wt) was injected intraperitoneally every 12 hours to maintain normal serum water and electrolyte levels.
For measurement of plasma COP and serum sodium and potassium, the animals were anesthetized with ether 24, 48, or 72 hours after recirculation. A blood sample was collected before decapitation from the vena cava and used for measurements. COP was measured with a colloid osmometer (Wescor Inc, 4420), and sodium and potassium were measured with a flame photometer (Corning Medical, 480) with lithium as an internal standard. To measure brain water, sodium, and potassium content, each brain was removed quickly after decapitation. After removal of the cerebellum and brain stem, cerebral hemispheres anterior to the optic chiasm were removed. After the bilateral cerebral hemispheres along the corpus callosum were cut, 1 mm of the mesial surfaces of the cerebral hemisphere was further discarded to avoid any inconsistency of ischemia grade. The remaining hemispheres were used for the experiment. Samples were placed in preweighed aluminum foil and weighed (wet weight), then dried to constant weight at 100°C for 2 days and weighed again (dry weight). The water content was calculated as water content (%)=([wet weight-dry weight]/wet weight)x100. The dehydrated samples were digested with 0.4 mL concentrated nitric acid and incinerated on a hot plate at 80°C. The samples were dissolved again with 0.2 mL 0.1 N nitric acid. Sodium and potassium were measured with a flame photometer.
Statistical Analysis
Data are presented as mean±SD. Statistical evaluation
was performed with Student's t test for unpaired samples.
The linear regression line between 
H2O and Na+K in
the ischemic hemisphere (left side) was calculated by linear
regression analysis, and the lines for both groups were
compared by ANCOVA. A level of P<.05 was accepted as
statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The plasma COP was significantly higher in the animals treated with albumin than in the control and saline-treated groups (P<.01) (Fig 1
). COP did not
differ between the saline and control groups.
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The serum concentration of sodium and potassium in both groups was normal and did not differ significantly from that of the control group.
The water content of the ischemic hemisphere (left side) was
significantly higher in the saline versus the control group
(P<.05) and increased continuously during the observation
period (Fig 2). The water content of the
ischemic hemisphere in the albumin group also increased
significantly compared with the control group (P<.05),
although the degree of increase was significantly smaller in the
albumin versus the saline group at all three time points
(P<.05).
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The water content of the nonischemic hemisphere (right
side) in both groups was normal and did not differ significantly from
that in the control group. The sodium content of the ischemic
hemisphere in both groups was significantly increased versus that in
the control group (P<.05) (Fig 3). The degree of increase in the sodium
content was smaller in the albumin than in the saline group,
being significantly smaller 24 hours after recirculation
(P<.05). The sodium content of the nonischemic
hemisphere in both groups was normal and not significantly different
from that in the control group. The brain potassium content of the
ischemic hemisphere in both groups decreased significantly
compared with the control group (P<.05) (Fig 4). The degree of decrease in the
potassium content was smaller in the albumin than in the saline
group and significant 24 and 48 hours after recirculation
(P<.05). The potassium content of the
nonischemic hemisphere in both groups was normal and not
significantly different from that in the control group. The
H2O and Na+K in the ischemic hemisphere
were calculated on the basis of differences in brain water, sodium, and
potassium levels between the ischemic and
nonischemic hemisphere in each animal. There was a
significant correlation in both saline and albumin groups
between the increase in the water content (H2O) and the
sum of the increase or decrease of sodium and potassium (Na+K) in
the ischemic hemisphere (P<.01) (Fig 5). Furthermore, the difference of the
linear regression lines between the groups was not significant. The
means of H2O and Na+K were significantly smaller
in the albumin than in the saline group
(P<.01).
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Discussion |
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Hyperosmotic therapy is a treatment for brain edema that extracts water from the brain parenchyma into the blood by increasing the plasma crystalloid osmotic pressure.
Osmotic diuretics of small molecular weight such as mannitol,
urea, and glycerol have been used clinically for this
therapy.4 9 These osmotic diuretics maintain a
high crystalloid osmotic pressure gradient between the blood and
intercellular fluid of the brain tissue at the normal blood-brain
barrier (BBB), through which neither small nor large molecules can pass
freely. However, they are not effective when the BBB is disrupted by
injury, cerebrovascular disease, or inflammation,4 5 with
the endothelium becoming porous and allowing all
crystalloids and small molecules except for serum proteins to pass
freely. These diuretics also induce a rebound phenomenon after
they are withdrawn4 5 and cause systemic serum electrolyte
derangement.4 10 Therefore, long-term use of these
osmotic agents is problematic. In contrast, COP therapy
decreases bulk flow from the blood to the brain parenchyma via
capillaries only where the BBB is disrupted, thus reducing vasogenic
edema. The movement of water (Jv; bulk flow) from the blood to the
brain parenchyma through the normal BBB can be described by a modified
Starling's equation: Jv=Lp(P-[
p
p
+
ss]), where Lp is hydraulic conductivity,
p is the colloid oncotic reflection coefficient, and
s is the crystalloid osmotic reflection
coefficient.11 12 Neither small molecules, including
electrolytes such as sodium and potassium, nor large molecules such as
albumin can pass freely through the normal BBB. The hydrostatic
pressure gradient (P) and COP (p) plus crystalloid osmotic
pressure gradient (s) between the inside and outside of the
capillary wall are equally balanced. Moreover, the Lp is extremely
small. Therefore, the bulk flow of water is normally almost
zero.11 12 When the crystalloid osmotic pressure of the
blood is increased by osmotic diuretics of small molecules such
as mannitol, the crystalloid osmotic pressure gradient (s) drives
water from the brain parenchyma into the blood.
Unlike cerebral capillaries, capillaries in peripheral
parts of the body have porous endothelia, through which small molecules
such as electrolytes can pass freely through water-filled pores of
60 to 240 Å in diameter in the capillary wall. Therefore, the
crystalloid osmotic pressure gradient (s) between the inside and
outside of the capillary is zero.
Brain capillaries with BBB disruption in our model come to resemble
these porous endothelia. As not all serum albumin leaks through
the disrupted BBB in ischemic edema,13 14 15 16 the COP
gradient (p) may not become zero. The movement of water (Jv) in
this situation depends on the difference in the hydrostatic pressure
(P) and COP gradient (p) between the blood and intercellular
fluid of the brain parenchyma.
Therefore, Starling's equation can be described as
Jv=Lp(P-pp), and Lp may become more than
100-fold larger than that of normal BBB.11 12 We thus
performed the present study to reveal the effect of long-term
high-colloid oncotic therapy on vasogenic edema through the
disrupted BBB after temporary cerebral ischemia.
Plasma COP depends on the concentration of the various plasma proteins. The three major groups of plasma proteins are albumin, fibrinogen, and globulin, and COP is due mainly to albumin (75%).17 In the present study, we measured only the total plasma COP and not the COP for each plasma protein. Albumin is safe as a long-term treatment because it is a physiological material and does not change the serum electrolyte balance. Furthermore, it has a longer half-life than small molecules.18 For these reasons, we maintained a high plasma COP level for a long period with repeated albumin administration. The protocol that we used for albumin administration maintained plasma COP at 5 mm Hg higher than the normal level, as reported previously.1 2 3 6 7 In our preliminary study, plasma COP after albumin administration was maintained at a constant level for 12 hours. The high COP did not affect the blood electrolyte balance.
In gerbils, albumin extravasates from brain capillaries 6 hours
after recirculation following 30 minutes of unilateral forebrain
ischemia and continues to extravasate for more than 72
hours.19 As the severity and delay of BBB disruption in
ischemia depend on the duration of
ischemia,13 14 the BBB disruption in our study
probably occurred within 6 hours and continued for more than 72 hours
after recirculation. However, not all serum albumin may
extravasate from brain capillaries during this
period.13 14 15 16 The decrease of brain water content and
inhibition of the increase in sodium and decrease in potassium in the
brain with COP therapy are likely due to the COP-induced decrease in
bulk flow. From differences in the average values of H2O
and Na+K between the saline- and albumin-treated
groups, we calculated that the Na+K concentration was 149.9 mEq/L in
the decreased edema fluid resulting from high COP therapy. This
concentration is almost equal to that in gerbil serum. The linear
regression lines for two groups were significantly correlated. As both
H2O and Na+K decrease along the same linear
regression line as a result of high COP therapy, and the Na+K
concentration in the decreased edema fluid is almost equal to that in
gerbil serum, the decrease in the water content due to COP therapy is
ascribed to reduction of bulk flow (Jv) induced by the enhanced COP
gradient (p). The increased COP gradient (p) per se does
not influence the water content of the brain in nonischemic
areas because extraction of water from the brain parenchyma in areas
with a normal BBB was small. This is in contrast to hyperosmotic
therapy with small molecules.4 5 This colloid oncotic
therapy may work only in the area where the BBB is disrupted and not in
the area where the BBB is normal. In vasogenic edema across the
disrupted BBB shown in this study, Starling's law was applicable to
explain the movement of water (bulk flow). However, the plasma COP
concentration was measured by an osmometer, which uses a
protein-impermeable membrane (p=1). Therefore, it is
likely that the actual COP gradient across the disrupted BBB
(p<1) in vivo after ischemia is less than that
measured by the osmometer. Long-term high-colloid oncotic
therapy may actually work to reduce edema formation via some mechanisms
other than elevated albumin oncotic pressure. Albumin
may act as a scavenger of oxygen free radicals and improve the
microcirculation20 and may act on other membrane systems
(eg, glial and/or neuronal membranes) via the interstitial
fluid, thus reducing the degree of cytotoxic edema. Further study is
necessary to clarify these points.
In conclusion, we have studied the effect of albumin on brain edema after recirculation following the temporary ischemia by unilateral occlusion of the common carotid artery in gerbils and demonstrated that the resulting increase of plasma COP ameliorated brain edema.
The increase in plasma COP gradient produced by albumin administration inhibits the bulk flow of water through the disrupted BBB. Albumin has a longer half-life than osmotic diuretics. It is safer for use in long-term therapy because it is a physiological material and does not alter serum electrolytes.
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Acknowledgments |
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This work was supported in part by a grant-in-aid for scientific research on priority areas from the Ministry of Education, Science, and Culture, Japan.
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Footnotes |
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Reprint requests to Yoji Hakamata, 3311-1, Minamikawachi-machi, Kawachi-gun, Tochigi-ken 329-04, Japan.
Received November 21, 1994; revision received June 15, 1995; accepted June 28, 1995.
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