52
STROKE
with hypercapnia-increased CBF. In 6th European Conference
on Microcirculation, Aalborg, 1970. New York, S Karger, pp
303-307, 1971
30. Flohr H-W, Brock M, Christ R et al: Arterial pCO2 and blood
flow in different parts of the central nervous system of the
anesthetized cat. In Brock M, Fieschi C, Ingvar DH, Lassen
NA, Schurmann K (eds), Cerebral Blood Flow. New York,
Springer-Verlag, pp 86-88, 1969
31. Nordstrom C-H, Calderini G, Rhencrona S, Siesjo BK: Effects
of phenobarbital anaesthesia on postischemic cerebral blood
flow and oxygen consumption in the rat. In Ingvar DH, Lassen
NA (eds), Cerebral Function Metabolism and Circulation.
Copenhagen, Munksgaard, pp 146-147, 1977
32. Hossmann K-A, Nemoto EM, Cooper H: Postischemic
hypermetabolism in cat brain. Fed Proc, March, 1978,
VOL 10, No
1, JANUARY-FEBRUARY
1979
Abstract, p 684
33. Cantu RC, Ames A III, Dixon J et al: Reversibility of experimental cerebrovascular obstruction induced by complete
ischemia. J Neurosurg 31: 429-431, 1969
34. Fischer EG, Ames A III, Hedley-Whyte ET et al: Reassessment of cerebral capillary changes in acute global ischemia and
their relationship to the "no-reflow phenomenon." Stroke 8:
36-39, 1977
35. Hossmann K-A: (Personal Communication),
Max-PlankInstitut fur Hirnforschung, Abteilung fiir Allgemeine
Neurologie, 5 Koln 91 (Merheim), Ostmerheimer Strasse 200,
(Stadt Krankenhaus) West Germany
36. Bleyaert AL, Stezoski SW, Nemoto EM et al: Augmentation of
ischemic brain damage by repetitive arterial hypertension in
monkeys. Physiologist, August, 1977
Downloaded from http://stroke.ahajournals.org/ by guest on June 14, 2017
Pathophysiological Mechanisms of Brain Edema
Development: Role of Tissue Factors
GEORGE MCHEDLISHVILI, M.D., LEAH NIKOLAISHVILI,
A N D MICHAEL ITKIS
SUMMARY In experiments carried out on adult rabbit "chest-head" preparations the volume changes of
the exposed brain (BrV) were determined in repeated tests during a controlled increase of the systemic venous
pressure (SVP) of about 13 mm Hg. The changes of both SVP and BrV were usually parallel at the onset of
the experiments, but when the brains became preedematous hysteresis appeared in the plots of their
relationships. The hysteresis increased gradually (sometimes with periods of partial decrease) thus indicating a
delay in the draining of blood from the brain's venous system and in the removal of excess extracellular fluid
from the cerebral tissue. Evidence for water filtration through the capillary walls during increase of the SVP,
and, thus, of brain intravascular pressure, was obtained by detecting the dynamics of [Na + ] and [K + ] in the extracellular fluid of the cerebral cortex by ion-selective electrodes. This process appeared reversible in normal
brains while in the preedematous ones the excessive water filtration resulted in brain edema. The preedematous state of the brain is believed to be caused by changes of the mechanical properties of brain tissue
and/or by changes in osmolarity.
Stroke, Vol. 10, No. 1, 1979
THE PATHOPHYSIOLOGICAL mechanisms of
brain edema development have been reviewed by I.
Klatzo1 who described 2 main causes of cerebral
edema — vasogenic and cytotoxic. According to Klatzo, vasogenic edema is caused by an increase in
capillary permeability, while cytotoxic edema
develops without such changes. An increase in
vascular permeability during brain edema has attracted the attention of a number of investigators
whose experimental results showed that different
tracers, which normally did not penetrate the cerebral
vascular walls when administered into the blood
stream, were detected in the cerebral tissue with
different kinds of brain tissue damage and subsequent
edema development.2"6
These data do not establish that increased vascular
permeability is the crucial mechanism in the development of brain edema. The role of circulatory factors in
From the Laboratory of Physiology and Pathology of the
Cerebral Circulation, I. Beritashvili Institute of Physiology,
Georgian Academy of Sciences, Gothua St. 14, 380060, Tbilisi,
USSR.
the development of brain edema is certainly very important, since the edema is defined as excess accumulation of water in brain tissue and a main source
of water is the blood circulating in the cerebral
vasculature. Also, the level of the systemic arterial
pressure plays an important role in the rate of edema
development.8-9 However, a considerably more important role in the development of brain edema has
been shown recently to be played by the systemic
venous pressure.10
In spite of the significance of circulatory factors,
these factors appear to play a secondary role in the
development of brain edema since the retention of
water within the cerebral tissue seems to be dependent
primarily upon tissue changes. Unfortunately, there is
still very little knowledge of the nature of the cerebral
tissue changes responsible for development of edema.
Attention has been focused on 2 kinds of changes.
In the early 1960s it was assumed8' "•12 that changes
in the mechanical properties of cerebral tissue were
important for development of brain edema, but no experimental evidence to prove this assumption has been
obtained so far. Second, an increase in osmolarity of
TISSUE FACTORS IN BRAIN EDEMA/Mchedlishvili et al.
the cerebral tissue has been considered a factor causing brain edema,1 and there have been several recent
studies on tissue osmolarity in edema.
The aim of the present study was, first, to gain
further insight into the contribution of tissue factors in
development of brain edema and, second, to add a new
dimension to the possible kinds of tissue changes.
Method
Thirty-three adult rabbits of both sexes weighing
2.5 to 3.5 kg were anesthetized with Hexenalum (30
mg/kg body weight i.v.) and, subsequently, further
immobilized with tubocurarin chloride (3 mg/kg i.p.).
Preliminary Surgical Procedure
Downloaded from http://stroke.ahajournals.org/ by guest on June 14, 2017
For reliable control of the most important systemic
circulatory parameters the experiments were carried
out on the "chest-head" preparation14 in which the
blood circulated in the chest (including heart, lungs
and thoracic walls), and also in the neck and head of
the animal. For this purpose, an incision was made
along the sagittal line of the neck, a tracheotomy tube
was inserted for artificial ventilation of the lungs, and
the right common carotid artery and jugular vein were
exposed and ligated. Polyethylene catheters of maximum possible size were inserted in both vessels
directed toward the heart for recording systemic
arterial and venous pressures. Subclavian arteries and
veins were exposed and ligated bilaterally. The aorta
and vena cava were exposed under the diaphragm and
ligated 25 mm caudally together with their proximal
branches. Two polyethylene catheters of maximum
possible size, connected with pressurized reservoir
systems, were then inserted in these blood vessels
directed toward the heart.
A large craniotomy was made in the parietal region
of the cerebral hemispheres. The dura mater was not
opened until the beginning of the experiment. Through
an incision along the sagittal line below the occiput the
fourth ventricle of the brain was opened for draining
the cerebrospinal fluid. The animals were heparinized
(1,500 units/kg body weight).
Monitored Parameters
The systemic arterial pressure was recorded by
means of a catheter inserted into the common carotid
artery. The systemic venous pressure was recorded
through a catheter in the jugular vein. The cerebral
venous pressure was recorded through a glass canula
in the sagittal sinus. The 3 pressure transducers
(EMT-35) of the electromanometers of the Mingograf
81 (Elema, Sweden) were set at the same level as the
animal's heart atrium. The mean pressures were
recorded by electrical integration. Both the systemic
arterial and venous pressures were stabilized, or
changed, by using 2 independent pressurized reservoir
systems, one connected with the abdominal aorta and
the other with the vena cava. The reservoir systems
were filled with blood-substituting colloids containing
53
either Polyglukin, or Gelatinine (G. Mukhadze
Institute of Hematology and Blood Transfusion,
Tbilisi).
Brain volume changes were continuously recorded
through a strain gauge, one end of which was fastened
to the stereotaxic device and the other placed in contact with the brain surface in the parietal region. The
contact end was a plate about 5 mm diameter. The
strain gauge was switched into a Watson bridge whose
signals were amplified by the preamplifiers EMT-12
with the DC-compensator EMT-16 of the Mingograf
81. The device was calibrated before each experiment
so that it was possible to evaluate in the record the
amount of brain surface expansion above the initial
level. The brain, expanding into an almost circular
craniotomy (diameter 2r) hole, may be considered as a
spheric segment, since the pressure causing its expansion should be equal in all directions. The volume
change of such a segment is proportional to change of
its height (h) as determined from the following formula:
Vs=
-L ,rh(3r 2 + h2)=
ixr'h(l+3^
The area of the craniotomy hole irr2 = const. = S.
Under the present experimental conditions h is always
much smaller than the radius of craniotomy hole r and
therefore the size of
should be so insignificantly
small that it can be ignored. Even if, for instance,
h = -L r, then Vs = - i - Sh (1.08), i.e. V8 s -L Sh,
then the error would be 8 percent. But actually the
changes of brain volume (A Vb) are measured by
changes of the height of the expanding brain (A h b ): A
Vb = — S A hb. Under these conditions the error
would be much smaller, since A h « r. Proceeding
from this proportionality the recorded brain level
changes were designated as "the brain volume
changes."
The concentration of sodium and potassium in the
extracellular fluid was monitored by sodium and
potassium ion-selective electrodes on the surface of
the parietal cortex.
All the parameters were recorded on the Mingograf
81 (Elema, Sweden). Since not all the parameters
could be recorded simultaneously in rabbits, different
combinations were used in individual experiments.
The brain water content was determined as a
percentage of wet weight. The brain hemispheres were
removed from the skull and all free fluid carefully
wiped from the ventricles with filter paper. After we
determined the fresh weight of the pieces of the
parietal lobe, including cortex and white matter, the
pieces were placed in a constant temperature oven for
evaporation of water at 100° C until a constant weight
was reached.
The experimental results were treated statistically
and presented as mean values and standard errors.
STROKE
54
VOL
10, No
1, JANUARY-FEBRUARY
1979
'"I
15-
50.8
U
ASVP
6
8
10
£
0.6"
E
0.4'
0.2-
CD
4
[mm Hg]
Downloaded from http://stroke.ahajournals.org/ by guest on June 14, 2017
FIGURE 1. Changes of the brain level in the craniotomy
hole (ABrL) which reflect the brain volume changes under
conditions of increase and subsequent decrease of the
systemic venous pressure (ASVPj in a normal rabbit brain.
139
• — •
—I
UJ
E
Testing Brain Resistance to Edema Development
An increase of the systemic venous pressure and,
thus, overfilling the brain vasculature with blood, was
found to be a factor contributing to the development
of brain edema.10 A controlled artificial elevation of
the systemic venous pressure was used to test the extent to which the brain is predisposed to edema
development. The systemic venous pressure was
gradually elevated by approximately 13 ± 1 mm Hg
and then returned to its initial level by use of the
pressurized reservoir system connected with the vena
cava so that there was a linear progressive rise and
then a drop. This procedure, with a progressive elevation and then fall of the systemic venous pressure,
lasted approximately 4 minutes (see below). The brain
volume changes were simultaneously recorded with
the venous pressure changes and the relationship
between these 2 parameters was further ascertained by
plotting them on Cartesian coordinates. In some experiments an X-Y recorder was used. To determine
the comparative magnitude of hysteresis, irrespective
of the height of elevation of the systemic venous
pressure and the slope of the curve, the area of
hysteresis was determined and divided into the distance between the crossing-point of the X-Y axes and
the bend point of the curve.
The results of experiments were interpreted as
follows: 1) A rise of the curve on the plot meant an increase of blood volume in the brain vasculature
and/or an increase in the brain tissue volume caused
by edema; 2) a fall of the curve meant reversal of the
above process; 3) hysteresis indicated that in spite of a
decrease of the intravascular pressure the blood
volume in the brain and/or the brain tissue volume
remained increased (the latter indicated edema); 4) if
the descending curve lowered under the ascending one
it indicated that an active process caused the
withdrawal of the blood from the brain and/or of
water from cerebral tissue into the blood stream; 5)
the slope of the ascending curve indicated the exten-
UJ
10
|1.L 1080-°
Min
FIGURE 2. Rise in the brain level in the craniotomy hole
(ABrL). This reflects the increase of the brain volume
changes and the decrease in the concentration of the sodium
ions (fNa+J) with no detectable changes of the potassium
([K+]) in the extracellular fluid of the cerebral cortex during
a short increase of the systemic venous pressure (SVP). The
systemic arterial pressure (SAP) remained unchanged.
These results indicated that the increase in the brain volume
is, at least partly, dependent on the enhanced water filtration from the capillaries into the tissue spaces resulting in
dilution of the extracellular fluid in it.
sibility of the brain tissue.
The criteria for the appearance of edema in the
brain at the end of the present experiments were: a) an
increased brain volume when the systemic venous
pressure was no longer increased; b) an increase in
water content in the cerebral tissue as compared with
the control; c) a considerable decrease in the slope of
the ascending curve of brain volume changes during an
increase of the systemic venous pressure; d) significant
simultaneous increase in the potassium ion concentration and a decrease in the sodium ion concentration of
extracellular fluid, indicating a disturbance of cell
membrane function in the cerebral cortex.
TISSUE FACTORS IN BRAIN EDEMA/Mchedlishvili el al.
55
M
[mEq/l]
[mEq/l]
40-
155-
Downloaded from http://stroke.ahajournals.org/ by guest on June 14, 2017
145-
30-
135 -
20-
125-
10-
fl=-Q28!Q44
[mEq/l]
ISO
mEq/l]
100
125-
75-
100-
50-
75-
25
= 48.5:12.3
0J
I1S-1
50-1
FIGURE 3. Significant decrease in concentration of the
sodium ions and insignificant changes in the concentration
of potassium ions in the extracellular fluid of the cerebral
cortex following the controllable increase of the systemic
venous pressure. This indicated an increased transcapillary
water filtration in the brain tissue under these conditions in
rabbits.
Results
In the tests designed to estimate brain resistance to
development of edema, the systemic venous pressure
(SVP) was raised gradually over 111.6 =t 9 sec by
13 ± mm Hg, and then lowered during the subsequent
113.2 ± 9 sec reaching its initial level as a rule. These
changes in the venous pressure were followed by a
temporary rise of the brain level at the recording site
by 0.9 ± 0.01 mm, reflecting a change of the brain
volume. At the onset of most experiments, a parallel
relationship between the SVP and the brain level (i.e.
volume) was observed. A rise of the SVP was followed
by a brain volume increase, and an SVP decrease
along with a brain volume decrease until they reached
their initial values. These 2 parameters in the plots
showed that, usually, there was no hysteresis initially
(fig. 1).
The SVP affected the brain volume through an increase of the cerebral venous pressure. There was a
linear relation between an increase of venous pressures
in the cranial vena cava and in the sagittal sinus of the
brain. The correlation coefficient varied from 9.900 to
9.993, and the regression coefficient varied from 0.66
0J
FIGURE 4. A considerable decrease in the concentration of
the sodium ions with a simultaneous increase in the concentration of the potassium ions in the extracellular fluid of the
cerebral cortex of rabbits. This indicated disturbance of the
cellular plasmatic membrane function under conditions of
brain edema appearance.
to 1.72 in different experiments. The adequate regression equation was: y = (0.776 ± 0.45) x + 4.63.
The results showed that simultaneously with the increase of the SVP, and hence of the cerebral venous
pressure, there was a decrease in [Na + ] with no
marked change in [K + ] in the extracellular fluid of the
brain (fig. 2). The data obtained in all experiments are
summarized in figure 3: the mean decrease of sodium
in the tissue was 13 ± 1.4 mEq/l (P > 0.001) while
decreases of potassium were insignificant: — 0.28
± 0.44 mEq/l (P > 0.5). As the cerebral intravascular pressure regained its starting value the sodium
ion concentration in the extracellular fluid also
showed a trend to return to its initial level. During
later experiments when brain edema developed, the
sodium ion concentration continued to decrease but at
that time the changes were more marked, the decrease
was 47 ± 13.4 mEq/l. This occured simultaneously
with an increase in potassium ion concentration in the
extracellular spaces of the cerebral cortex by
48.5 ± 12.3 mEq/l (fig. 4).
In the course of testing the SVP increase and the
brain surface level, and hence of the brain volume, the
56
STROKE
response gradually changed. Initially the brain and the
SVP changes were usually parallel in the plots*, as in
figure 1 (these periods lasted up to one hour or even
more in some experiments). Later, a delay in the
decrease in brain volume during the drop of the SVP
took place, i.e. the hysteresis remained increased
despite the decrease of the SVP (and, thus, of the
cerebral venous pressure). The brain volume increased
only slightly during the rise of the SVP. The water
content increased in the cerebral tissue. There was a
considerable decrease of [Na+] simultaneously with
increase of [K+] in the extracellular fluid of the
cerebral cortex.
Downloaded from http://stroke.ahajournals.org/ by guest on June 14, 2017
Discussion
The methods in the present study made it possible
to monitor important physiological parameters
necessary for a better understanding of the experimental results relating to the development of brain edema.
The parameters were: a) the systemic arterial and
venous pressures, and cerebral venous pressure, all of
which could be changed arbitrarily or stabilized at any
level; b) the intracranial and the intraventricular
pressures remained stabilized during the experiments
because of a large trephin opening of the skull and
draining of the fourth ventricle of the brain; c) the
brain volume changes, which were continuously
recorded, were thought, first, to represent changes of
the blood volume in the cerebral vessels and, second,
to result from the amount of water in the cerebral
tissue. The latter was monitored also by continuous
recording of the concentrations of pNa and pK in the
extracellular fluid of the cerebral cortex.
The brain was widely exposed and had prolonged
contact with the atmosphere during the experiments
which produced changes in cerebral tissue, promoting
edema development.15'16 In addition, there was a
repeated increase in the systemic venous pressure
(during the tests) causing blood stagnation in the
cerebral vessels and, hence, some cerebral hypoxia.
The increase in the blood volume and in blood
pressure in the cerebral vasculature are probably the
major determinant factors in the development of brain
edema.10
Draining the fourth ventricle made it unlikely that
the volume changes of the brain were dependent upon
volume changes of the cerebrospinal fluid. Nor was
brain volume influenced by changes of intrathoracic
pressure (the lungs were artificially ventilated at a constant rate and volume throughout the experiments).
Thus, it was reasonable to believe that the increase of
the brain volume during every rise of the systemic
venous pressure was caused, first, by an increase in
blood volume in the cerebral vasculature (especially in
the venous and in the capillary systems) and, secondly,
by excessive water filtration into the cerebral tissue.
The present studies provided evidence for both of
* However, sometimes hysteresis was in evidence from the very
beginning of the experiments, indicating that the brain was
predisposed to edema development in these cases.
VOL 10, No
1, JANUARY-FEBRUARY
1979
0.2
1.6
0
1.4
0.4
1.2-
0.2
1.0
0
I o.e
/
7
J, o.e
m
<] 0.6
0.4
0.4
0.2
0.2
4
e
12
A SVP [mm Hg]
4
6
12
16
6 SVP [mm Hg]
FIGURE 5. Changes of the brain level (ABrL), which
reflect changes of the brain volume, following the increase
and the subsequent decrease of the systemic venous pressure
(ASVPj in the tests repeatedly carried out in an experiment
on a rabbit. The results showed the appearance and the
steady increase of hysteresis in the plots of these two
parameters.
these phenomena: a) the linear increase of the cerebral
venous pressure when the systemic venous pressure
rose and b) the concentration of the sodium ions fell
with almost no detectable change in the concentration
of the potassium ions.
Abundant water filtration from blood into the
cerebral tissue might be explained by the fact that
water easily penetrates the capillary membranes.7'"
The data obtained in the present experiments made it
possible to calculate the amount of water that can pass
from blood into cerebral tissue during periods of" increased intravascular pressure.
The existing data18-19 suggest that the extracellular
spaces in the brain constitute about 13 percent of its
volume, i.e., 1 cm3 tissue contains about 130 microliters of extracellular fluid. A decrease of sodium concentration in the fluid, detected in the present experiments when the potassium ion concentration did
not increase or else decreased, indicated that this was
a result of extracellular fluid dilution by water passing
from the blood vessels. If this were a result of sodium
ion escape into neuronal cell cytoplasm, the potassium
ion concentration should be considerably increased
simultaneously.
These experiments show that the amount of water in
the brain from the blood stream was increased by
about 10 percent, that is, by approximately 0.1 microliter for each microliter of tissue fluid. Therefore, the
extracellular fluid was also increased by approximately 10 percent, and the whole brain volume
by about 1.3 percent. The fact that the increase of the
brain volume was considerably greater during an increase of systemic venous pressure led us to believe
TISSUE FACTORS IN BRAIN EDEMA/Mchedlishvili et al.
Downloaded from http://stroke.ahajournals.org/ by guest on June 14, 2017
that volume changes are largely caused by the increase
of the blood volume in the cerebral vasculature.
At the beginning of our experiments the brain
volume increased and decreased in parallel with the
systemic venous pressure and the initial concentration of the sodium ions was found in the extracellular
fluid of the cerebral tissue. This proved the reversibility of the processes, i.e. when the blood volume in
the cerebral vessels is decreased it is followed by a
return of the extracellular fluid into the capillaries.
In the course of the individual experiments the
brains became preedematous, i.e. predisposed to
edema development, the hysteresis was observed in the
plots of brain volume changes against systemic venous
pressure changes. This phenomenon was assumed to
depend on the delay of the return of excess blood from
the cerebral vessels and on the delay in removal of excess fluid from the extracellular tissue spaces. Water
also may be transferred into the cell cytoplasm
because a disturbance in the active transport of
sodium and potassium ions was evident in this period
with a considerable increase in potassium ion concentration in the extracellular fluid. The main source of
potassium is cell cytoplasm.20
Because of the large channels connecting intra- and
extracranial venous systems, and the linear relationship of the pressures in them, shown in the present experiments, the detention of blood in the cerebral
venous system under these conditions may be explained by changes in the mechanical properties of
cerebral tissue, and an increase in its compliance and a
decrease in its elasticity.8- "• 12 Further, the retention
of water inside the tissue spaces might be explained by
the changes in the mechanical properties of cerebral
tissue since this would cause a comparative decrease
of the pressure inside the tissue spaces under these
conditions. On the other hand, the retention of water
in the tissue spaces could be dependent on an increase
in osmolarity of cerebral tissue.13
In the light of these considerations it is reasonable
to conclude that the changes in the mechanical properties of the cerebral tissue play an important role in the
control of blood volume in the cerebral vasculature
and in the water exchange between blood and tissue
spaces. Furthermore, the present experiments have
shown that the properties of cerebral tissue may
change in both directions and, thus, may cause not
only disturbances, but may also contribute to the active draining of blood from the cerebral vasculature
and/or of water from the cerebral tissue spaces, hence
compensating for the edema development.
Together with the circulatory factors investigated
previously10 the present study demonstrates an important role for tissue factors responsible for the development of edema. These factors seem to be largely the
changes in the mechanical properties of cerebral
tissue, and changes of the osmolarity of the tissue.
Acknowledgment
The authors are indebted to Prof. Dr. med. Manfred Kessler,
Max-Planck-Institut
fur
Systemphysiologie,
Dortmund,
57
Bundesrepublik Deutschland, for kindly supplying the potassium
ion-selective electrodes.
References
1. Klatzo I: Pathophysiological aspects of brain edema. In Reulen
HJ, Schurmann K (eds) Steroids and Brain Edema, pp 1-8.
Berlin, Springer-Verlag 1972
2. Bakay L: Changes in barrier effect in pathological states. In
Lajtha J, Ford DH (eds) Brain-Barrier Systems. Prog Brain
Res 29: 315-345, 1968
3. Barlow CF: Physiology and pathophysiology of protein
permeability in the central nervous system. In Reulen HJ,
Schurmann K (eds) Steroids and Brain Edema, pp 139-146.
Berlin, Springer-Verlag 1972
4. Hossmann K-A, Olsson Y: Functional aspects of abnormal
protein passage across the blood-brain barrier. In Reulen HJ
and Schurmann K (eds) Steroid and Brain Edema pp 9-17.
Berlin, Springer-Verlag 1972
5. Gobiet W, Piaszek L, Schumacher W: Development and time
course of blood-brain barrier disturbances caused by hypoxia.
In Panzholz H et al (eds) pp 46-51. Berlin, Springer-Verlag
1975
6. Ito U, Go KG, Walker JT, Spatz M, Klatzo I: Experimental
cerebral ischemia in Mongolian gerbils. Ill Behaviour of the
blood-brain barrier. Acta Neuropath 34: 1-6, 1976
7. Renkin EM, Pappenheimer JR: Wasserdurchlassigkeit und
Permeabilitat der Capillarwande. Ergeb Physiol 49: 59-126,
1957
8. Mchedlishvili GI, Akhobadze VA: Dynamics of changes in
cerebral circulation in traumatic edema of the brain. Wopr
Neirokhir No 2, 13-19, 1960
9. Schutta HS, Kassel NE, Langfitt TW: Brain swelling produced
by injury and aggravated by arterial hypertension. Brain 91:
281-294, 1968
10. Mchedlishvili GI, Kapuscinski A, Nikolaishvili L: Mechanisms
of postischemic brain edema: contribution of circulatory factors. Stroke 7: 410-416, 1976
11. Mchedlishvili GI, Akhobadze VA: The functional state of
capillary and venous systems of the brain in cerebral traumatic
edema. Physiol Bohemoslov 10: 15-20, 1961
12. Kvitniksky-Ryzhov Y: Morphological reflecting of the relationship of the intracranial pressure and the processes of edemaswelling of the brain. Klinitch Khir 10: 57-65, 1963
13. Hossmann K-A, Takagi S: Osmolarity of brain in cerebral
ischemia. Exp Neurol 51: 124-131, 1976
14. Mchedlishvili GI: "Chest-head" preparation for investigation
of cerebral circulation. Bull Exper Biol Med, 2: 123-125, 1962
15. Prados M, Strowger B, Feindel WH: Studies on cerebral
edema. 1. Reaction of the brain to air exposure; pathologic
changes. Arch Neurol Psychiatry 54: 163-174, 1945
16. Beranek R, Fantis A, Gutmann E, Vrbova G: Pokusne Studie o
mozkovem edemu. Nakladatelstvi Ceskoslovenske Akademie
Ved Praha 1955
17. Bering EA: Water exchange of central nervous system and
cerebrospinal fluid. J Neurosurg 9: 275-287, 1952
18. Brendel W, Reulen HJ: Die experimentalle Erforschung des
Hirnodems. In Kienle G (ed) "Hydrodynamik, Elektrolyt- und
Saure-Basen-Haushalt im Liquor und Nervensystem" pp
207-214 Stuttgart, G Thieme Verlag, 1967
19. Shaywitz BA: Brain inulin space in hydrocephalic and hypernatremic kittens using ventriculocisternal perfusion. Exp
Neurol 34: 16-24, 1972
20. Katzman R, Graziani L, Ginsburg S: Cation exchange in blood,
brain and CSF. In Lajtha A, Ford D (eds) Brain-Barrier
System. Progr Brain Res 29: 283-296, Amsterdam, Elsevier,
1968
21. Mchedlishvili GI, Akhobadze VA: The cerebral arterial system
in brain injury during traumatic edema. Physiol Bohemoslov
10: 8-14, 1961
22. Mchedlishvili GI: Functional Behavior of the Vascular
Mechanisms of the Brain. Leningrad, Nauka Publishing House,
1968
23. Tikk AA: Dynamics of the peripheral venous pressure in acute
state of brain trauma. Vopr Neirokhir 5: 19-22, 1969
Pathophysiological mechanisms of brain edema development: role of tissue factors.
G Mchedlishvili, L Nikolaishvili and M Itkis
Stroke. 1979;10:52-57
doi: 10.1161/01.STR.10.1.52
Downloaded from http://stroke.ahajournals.org/ by guest on June 14, 2017
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1979 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://stroke.ahajournals.org/content/10/1/52
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in
Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.
Once the online version of the published article for which permission is being requested is located, click Request
Permissions in the middle column of the Web page under Services. Further information about this process is
available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Stroke is online at:
http://stroke.ahajournals.org//subscriptions/