Modification of acute focal ischemia in rabbits by poloxamer 188.
H J Colbassani, D L Barrow, K M Sweeney, R A Bakay, I J Check and R L Hunter
Stroke. 1989;20:1241-1246
doi: 10.1161/01.STR.20.9.1241
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1989 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/20/9/1241
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/
Downloaded from http://stroke.ahajournals.org/ by guest on March 4, 2014
1241
Modification of Acute Focal Ischemia in
Rabbits by Poloxamer 188
Harold J. Colbassani, MD, Daniel L. Barrow, MD, Kevin M. Sweeney, MD,
Roy A.E. Bakay, MD, Irene J. Check, PhD, and Robert L. Hunter, MD, PhD
We studied the effect of a synthetic copolymer surfactant, poloxamer 188, on cerebral blood flow
in a rabbit model of focal cerebral ischemia. Following retro-orbital craniectomy, the parietal
branch of the middle cerebral artery was occluded with bipolar current. Cerebral blood flow
was measured by the hydrogen clearance technique using platinum-iridium electrodes placed
within the parietal cortex. Ten rabbits were infused with 50 nig/kg poloxamer 188 in saline
beginning 30 minutes after occlusion; 12 control rabbits received an equal volume of saline.
Poloxamer 188 increased blood flow significantly in areas of severe or moderate ischemia but
had little effect in areas with mild or no ischemia. The improvement in blood flow could not be
accounted for by hemodilution, and the copolymer did not affect blood viscosity at any shear
rate from 1 to 100 sec"1. We hypothesize that poloxamer 188 increases circulation in ischemic
tissue by inhibiting adhesive interactions among proteins (fibrin and fibrinogen) and cells in the
microcirculation. (Stroke 1989;20:1241-1246)
A rterial stenosis, thrombosis, embolization, and
/ \
vasospasm often reduce regional brain perA. \ ~ fusion, resulting in focal cerebral ischemia.
This ischemia may produce neurologic deficits that
are reversible or irreversible, depending on the
depth and duration of ischemia. Numerous studies
have suggested that the progression to irreversible
damage can be influenced by therapeutic intervention. Therefore, agents that influence cerebral blood
flow in pathologic states have potential as therapeutic agents in cerebral vascular disease.
Hemorheologic studies have identified hematocrit
and whole-blood viscosity as factors that influence
cerebral blood flow.1-4 Several clinical reports including the Framingham Study found a correlation
between hematocrit and the risk of cerebral
infarction.5-7 Harrison et al5 studied patients with
occlusive vascular disease and found that the size of
the infarct is directly proportional to the hematocrit.
Several therapeutic modalities that influence
hematocrit and blood viscosity have been evaluated
for the treatment of focal cerebral ischemia.8-14
Sundt et al12 demonstrated that lowering the hematFrom the Departments of Surgery (Section of Neurologic
Surgery) (H.J.C., D.L.B., K.M.S., R.A.E.B.) and Pathology
(I.J.C., R.L.H.), Emory University, Atlanta, Georgia.
Supported by a grant from CytRx Corporation, Norcross,
Georgia.
Address for correspondence: Daniel L. Barrow, MD, Division
of Neurosurgery, The Emory Clinic, 1365 Clifton Road NE,
Atlanta, GA 30322.
Received January 25, 1989; accepted March 23, 1989.
ocrit by hemodilution before an ischemic event was
protective and reduced infarct size. Wood et al14
found a significant increase in cerebral blood flow in
the presence of focal ischemia after hemodilution
with low-molecular-weight dextran. Hint15 pointed
out that diluting plasma proteins, notably fibrinogen,
by administering low-molecular-weight dextran
decreases plasma viscosity at the level of the microcirculation. The increased blood flow following
hemodilution results in an increased oxygen carrying
capacity of the blood; this effect is maximal at a
hematocrit of approximately 30%.15>16 Fein17 measured oxygen availability and found oxygen extraction to be maximal at a hematocrit of 35%.
Strand et al18 reported a randomized controlled
trial of hemodilution in patients with acute ischemic
stroke, which revealed significant short- and longterm improvement in the neurologic recovery of
patients treated with hemodilution.
In an effort to increase the oxygen carrying
capacity of blood by means other than hemodilution, perfluorocarbon emulsions prepared as blood
substitutes have been used for the treatment of
focal cerebral ischemia.19-22 Better neurologic function and reduced evidence of infarction were attributed to a reduction in blood viscosity secondary to
hemodilution and to better tissue perfusion because
of the small particle size of the fluorocarbon
emulsion.
Poloxamer 188 is currently undergoing Phase I
clinical studies as a hemorheologic agent. Poloxamer 188 is a nonionic block polymer surfactant
Downloaded from http://stroke.ahajournals.org/ by guest on March 4, 2014
1242
Stroke Vol 20, No 9, September 1989
composed of a single chain of hydrophobic polyoxypropylene flanked by two chains of hydrophilic
polyoxyethylene. In earlier studies, poloxamer 188
by itself was found to produce beneficial effects in
several situations in which blood flow was impaired.
The surfactant reduced tissue damage in a rabbit
model of frostbite,23-24 increased survival in dogs
with hemorrhagic shock,25'26 and maintained electroencephalographic activity in an isolated perfused
ischemic brain preparation.27 Poloxamer 188 was
reported to reduce viscosity without hemodilution.28
In rabbits, we evaluated the effects of poloxamer 188 on cerebral blood flow in the distribution
of the middle cerebral artery, which had been
surgically occluded. Our results demonstrate an
increase in cerebral blood flow without changes in
either hematocrit or viscosity, suggesting a new
mechanism of action.
Materials and Methods
We chose rabbits because the internal carotid
artery is the predominant supplier of blood to the
cerebral hemispheres and because there are few
external-to-internal anastomoses. In addition, Meyer
et al29 have used a rabbit model of cerebral ischemia
with excellent reproducibility of ischemic zones
following middle cerebral artery occlusion.
Twenty-two New Zealand White rabbits weighing 3.5-4.5 kg were sedated with a mixture of
ketamine and xylazine. A peripheral intravenous
cannula was placed in the marginal ear vein. A
tracheostomy was performed, and the rabbits were
anesthetized with 0.5% halothane in 70% N2O/30%
O2. Paralysis was achieved using 1-2 mg/hr pancuronium bromide. The rabbits were placed on a
warming blanket to maintain normothermia (38.539.0° C). A cutdown was performed in the right
groin, and catheters were placed in the femoral
artery and vein. Ventilation was adjusted to maintain Po2 at >100 torr and Pco2 at 35-45 torr. Serum
glucose concentration was measured hourly and
was corrected with insulin if >200 mg/dl.
Each rabbit's head was fixed in a stereotactic
head frame, and the left hemisphere was exposed
via a retro-orbital craniectomy involving the parietal bone just lateral to the superior sagittal sinus,
the temporal bone to just below the zygomatic arch,
and the frontal bone down to the optic canal. The
craniectomy was done using a high-speed drill to
prevent compression of the underlying brain.
A dural incision was made, and the middle cerebral artery was identified at the anterior inferior
margin of the craniectomy between the frontal and
temporal lobes. The main parietal branch of the
middle cerebral artery was identified, and two to
four platinum-iridium electrodes 25 pm thick were
inserted into the parietal cortex in the distribution
of this parietal branch as well as into the vascular
distribution between the frontal and parietal
branches. A silver-silver chloride reference electrode was placed into the temporalis muscle. The
exposed cortex was covered with a plastic film to
prevent dehydration and surface oxygenation. The
electrodes were allowed to stabilize for 1 hour
before cerebral blood flow was measured.
Cerebral bloodflowwas determined by the hydrogen clearance technique following administration of
5% H2 administered intratracheally. Before starting
and after concluding these experiments, aliquots of
blood from 10 rabbits were obtained in which to
measure hematocrit and whole-blood viscosity; the
latter was determined using the Litt-Kron capillary
step-response whole-blood viscometer (Philadelphia, Pennsylvania).30-31 Cerebral blood flow was
determined until values were stable for two consecutive measurements (baseline). At this point the
main parietal branch of the middle cerebral artery
was occluded using a bipolar current, and cerebral
blood flow (initial extent of ischemia) was determined 20 minutes after occlusion. Initial extent of
ischemia demonstrated at each electrode was classified as minimal (>40 ml/100 g/min), mild (26-40
ml/100 g/min), moderate (16-25 ml/100 g/min), or
severe (0-15 ml/100 g/min).
The first five rabbits were allocated to the control
group. Thirty minutes after occlusion, 10 minutes
after blood flow determination, the second five
rabbits were given a bolus injection of a formulation
of poloxamer 188 for intravenous administration
(RheothRx, CytRx Corp., Norcross, Georgia) at 0.6
mg/ml blood volume followed by an infusion of 0.6
mg/ml blood volume/hr until the end of the experiment. Poloxamer 188 has also been referred to as
Pluronic F68, a trademark of BASF Corp. (Wyandotte, Michigan). Thereafter, rabbits were alternately allocated to control and treatment groups.
The 12 control rabbits were given a volume of saline
equal to that of poloxamer 188 given to the 10
treated rabbits. Cerebral blood flow was determined
1, 2, 3, and 4 hours after occlusion. The effect of
treatment was assessed by calculating the percentage change in blood flow detected by each electrode
at various times relative to the initial extent of
ischemia. At approximately 6 hours, the rabbits
were killed by intravenous injection of euthanasia
agent.
Data from each electrode were analyzed separately. Data for groups of rabbits are expressed as
mean±SEM. Differences between groups were analyzed using Student's paired (for hematocrit and viscosity) and unpaired t tests and Fisher's exact test.
Results
The surgical occlusion of the parietal branch of
the middle cerebral artery was complete in all
rabbits. Consequently, the extent of ischemia
recorded by each electrode depended on its anatomic placement in the brain relative to the vascular
supply and the collateral circulation. Three electrodes were placed in the cortex of 17 rabbits, four
in three rabbits, and two in two rabbits, for a total of
67 electrodes in 22 rabbits.
Downloaded from http://stroke.ahajournals.org/ by guest on March 4, 2014
Colbassani et al Poloxamer 188 in Acute Focal Ischemia
zuu-
80
Saline Controls
a
on" a
100-
D
B
On
0D
m
D
*
-
"Si
a
15
I
-100-
O
300-3
1243
a
_ a
a a
.
-
•
:
•
•
•
_ n
Poloxamer 188-Treated
as o
200 ••
100-i
Time after occlusion (hours)
DD
a
o
a
a
a
B a
° Rn
a
a
-100
FIGURE 1. Graph of effect ofpoloxamer 188 on cerebral
blood flow determined by hydrogen washout technique in
10 rabbits (30 electrodes) with poloxamer 188 (•) and in
12 controls (37 electrodes) treated with saline (o). Baseline blood flow was determined, and parietal branch of
middle cerebral artery was occluded with bipolar current
at time 0. Initial extent of ischemia was measured at 20
minutes. Treatment was started at 30 minutes, and blood
flow was determined over 4 hours. Results are shown as
mean±SEMfor all electrodes in each group. Differences
between control and treated groups are significant at 1, 3,
and 4 hours (p=0.03, 0.001, and 0.001, respectively, by
Student's t test).
2. Scatterplot of change in cerebral blood flow
vs. initial extent of ischemia for each electrode in (top) 12
rabbits treated with saline (controls) and in (bottom) 10
rabbits treated with poloxamer 188. Shaded areas represent range of no change in blood flow (-20% to 20%).
Blood flow was improved in significantly higher and was
decreased in significantly lower proportion of electrodes
from treated than from control rabbits (p=0.001 and
0.005, respectively, by Fisher's exact test).
Baseline blood flow was 75 ±6 ml/100 g brain
tissue/min in the control group and 76 ±3 ml/100 g
brain tissue/min in the treated group. Twenty minutes after occlusion, both groups showed similar
initial extents of ischemia (28±2% vs. 27±3% of
baseline, control vs. treatment). However, by 30
minutes after the start of treatment (1 hour after
occlusion), the groups differed significantly (Figure
1). After 3.5 hours of treatment (4 hours after
occlusion), bloodflowin the control group remained
essentially unchanged (27±2%). In treated rabbits,
brain perfusion improved after treatment; by 3.5
hours, blood flow had increased to 39±3 ml/100
g/min, a 69±13% improvement over the initial
extent of ischemia. The difference in cerebral blood
flow between groups at 4 hours after occlusion was
significant (/?=0.001, t test).
The extent of ischemia detected by each electrode ranged widely, from a blood flow as low as 4
to one as high as 78 ml/100 g/min, as expected from
the differences in electrode placement. To examine
the relation between the initial extent of ischemia
and the degree of improvement with treatment, the
percentage change in blood flow at 4 hours was
plotted as a function of the initial extent of ischemia
(Figure 2). Only 11 of 37 (30%) electrodes in control
rabbits (Figure 2, top) compared with 21 of 30 (70%)
in treated rabbits (Figure 2, bottom) showed >20%
improvement in blood flow (p=0.001, Fisher's exact
test). All instances of improved perfusion occurred
in areas of the brain where the initial extent of
ischemia was <45 ml/100 g/min. In 10 electrodes in
control rabbits, perfusion actually decreased by
>20%; such a decrease was seen in only two
electrodes from treated rabbits (p=0.005), and these
two were in areas showing the least initial extent of
ischemia.
Subgroups of electrodes were denned based on
the initial extent of ischemia. Blood flow as a
function of time after occlusion is shown for the two
subgroups of electrodes with the greatest initial
extents of ischemia (Figure 3). The most compromised areas showed the greatest improvement in
blood flow with treatment. Percentage improvement in blood flow 4 hours after occlusion as a
function of the initial extent of ischemia is summarized in Figure 4. Whereas overall, poloxamer 188
increased blood flow by 69%, it improved blood
flow by >120% in tissue with severe initial ischemia
but not at all in areas with minimal initial ischemia.
Areas with intermediate initial extents of ischemia
showed intermediate percentage improvement. The
control rabbits showed no significant improvement
of blood flow in any subgroup of electrodes.
20
40
60
80
Cerebral Blood Row 20 Minutes
Post-occlusion
(cc/100 g/min)
FIGURE
Downloaded from http://stroke.ahajournals.org/ by guest on March 4, 2014
1244
Stroke Vol 20, No 9, September 1989
FIGURE 3. Graph of effect of
1
2
3
Tims after occlusion (hours)
4
1
2
3
Time after occlusion (hours)
Improved perfusion in the treated rabbits was not
explained by hemodilution or by changes in viscosity. Over the course of the experiment, hematocrits
of five treated and five control rabbits increased by
0.6±0.4% and 0.4±0.6%, respectively. Viscosity
measured at shear rates of 1 to 100 sec"1 (Table 1)
increased with decreasing shear rate in both groups,
but there were no differences between groups.
Minimal
>40
Degree of Ischemia
Discussion
Poloxamer 188 increased blood flow by an average of 121% in areas of rabbit brain with severe
ischemia produced by surgical occlusion of the
middle cerebral artery; the surfactant had lesser
effects in areas with moderate or mild ischemia and
no significant effect in adjacent areas with minimal
or no ischemia. This apparently selective effect of
poloxamer 188 to enhance blood flow in ischemic
tissue was not accompanied by changes in hematocrit or bulk viscosity of blood measured at either
high or low shear rates. Ours were acute studies,
and we did not evaluate preservation of brain function. However, studies in several other systems in
which comparable doses of poloxamer 188 were
used demonstrate preservation of function in addition to increasing blood flow in ischemic or damaged tissues. These other systems include isolated
cat brain,27 rabbit frostbite,23-24 dog hemorrhagic
shock,2526 and isolated perfused rat heart32 models.
TABLE 1. Effect of Poloxamer-188 on Viscosity of Blood From
Rabbits
(cerebral blood flow, cc/100 g/min)
4. Bar graph of cerebral blood flow according
to initial extent of ischemia at each electrode in 10 rabbits
treated with poloxamer 188 (filled bars) and in 12 controls
treated with saline (open bars); number of electrodes in
each subgroup are shown. Differences between control
and treated groups were significant for subgroups with
severe (p<0.001), moderate (p<0.02), and mild (p<0.05)
but not with minimal (p=0.5 by Student's t test) initial
extents of ischemia.
FIGURE
poloxamer 188 on cerebral
blood flow in subgroups of
electrodes
demonstrating
regions of moderate (left) or
severe (right) initial extents of
ischemia in rabbits treated
with poloxamer 188 (•; nine
electrodes for moderate, nine
electrodes for severe) and in
controls treated with saline (o;
nine electrodes for moderate,
10 electrodes for severe). Data
from Figure 1 were subgrouped according to initial
extent of ischemia (moderate
ischemia, 16-25 ml/100 gl
min; severe ischemia, 0-15 mil
lOOglmin). Results are shown
as mean±SEM for all electrodes in each subgroup. Differences between control and
treated groups are significant
at all times (p<0.01 by Student's t test).
_,
(sec-1)
100
10
1
Time
Before
After
Before
After
Before
After
Viscosity (mean±SEM
centipoise)
Control (n=5)
Treated (n=5)
2.4+0.2
2.6±0.6
2.0±0.4
2.5±0.3
3.2±0.5
3.9±1.2
3.4±0.5
4.1±0.9
6.5±2.6
6.0±3.0
4.4±1.3
4.1±1.1
Downloaded from http://stroke.ahajournals.org/ by guest on March 4, 2014
Colbassani et al
Poloxamer 188 is a nonionic block polymer
surfactant that is not metabolized and is rapidly
excreted by the kidneys.33 The material has been
infused into humans on many occasions as a pump
prime for cardiac bypass surgery34-38 and as an
inactive component of an intravenous hyperalimentation preparation39-40 and of perfluorocarbon blood
substitutes.41 The report of adverse pulmonary reactions due to activation of complement by perfluorocarbon artificial blood is troublesome.42 It is unclear,
however, whether this reaction is due to poloxamer
188, especially considering that the reaction has not
been seen in patients receiving the agent with other
substances. At the time of this writing, a new formulation of poloxamer 188 (RheothRx) is undergoing
Phase I clinical trials. Consequently, questions regarding its safety for use in humans will be resolved in
due course.
Recent studies indicate that poloxamer 188 has a
number of unusual biologic effects. In an in vitro
model, poloxamer 188 increased the flow of blood
through tortuous capillary-sized fibrin-lined channels by as much as 20-fold without affecting bulk
viscosity.43 This agent also reduced pathologic elevations in whole-blood viscosity that were associated with high-molecular-weight polymers of soluble fibrin44 (R.L. Hunter, C. Papadea, C.J.
Gallagher, D.C. Finlayson, and I.J. Check, unpublished data). Progressive microcirculatory obstruction, which occurs primarily at the capillary level
and is compounded by compression from swollen
parenchyma, has been demonstrated in areas of
focal cerebral ischemia. The loss of fluids from the
capillaries produces hemoconcentration, with
increasing viscosity, sludging, and obstruction.45
Under normal conditions, the capillary diameter is
approximately equal to that of erythrocytes. In
ischemic tissue with swelling and damaged endothelial cells, the capillaries are narrowed and intravascular fibrin forms. In this situation, the friction of
erythrocytes passing through the narrowed capillaries probably becomes important. We have proposed
that poloxamer 188 enhances blood flow in the
damaged microvasculature by reducing friction due
to adhesive reactions between the blood cells and
the vessel walls (I.J. Check, R.L. Hunter, unpublished data). There are fundamental relations
between hydrophobicity, adhesion, and friction.46
Damaged cells and certain macromolecules, especially fibrin, frequently have hydrophobic domains
exposed on their surfaces; contact of such domains
produces adhesion and friction. There is no direct
evidence that this mechanism operates in ischemic
cerebral tissue. However, the observation that poloxamer 188 increases cerebral blood flow through
damaged tissue without hemodilution makes it an
interesting reagent for further studies of the pathophysiology of microvascular obstruction in ischemic tissue.
Poloxamer 188 in Acute Focal Ischemia
1245
References
1. Begg TB, Heams JB: Components of blood viscosity. The
relative contribution of hematocrit, plasma fibrinogen and
other proteins, Clin Sci 1966;31:87-93
2. Chien S, Usami S, Taylor HM, Lundberg JL, Gregersen MI:
Effects of hematocrit and plasma proteins on human blood
rheology at low shear rates. JAppl Physiol 1966;21:81-87
3. Thomas DJ, Marshall J, Ross Russell RS, Wetherly-Mein G,
DuBoulay GH, Pearson TC, Symon L, Zilkha E: Effect of
hematocrit on cerebral blood flow in man. Lancet 1977;
2:941-943
4. Wells RE, Merrill EW: Influence of flow properties of blood
upon viscosity-hematocrit relationships. / Clin Invest 1962;
41:1591-1598
5. Harrison MJG, Kendall BE, Pollock S, Marshall J: Effect of
hematocrit on carotid stenosis and cerebral infarction. Lancet 1981;2:114-115
6. Kannel WB, Gordon T, Wolf PA, McNamara P: Hemoglobin and the risk of cerebral infarction: The Framingham
Study. Stroke 1972;3:409-420
7. Tohgi H, Yamanouchi H, Murakami M, Kameyama M:
Importance of the hematocrit as a risk factor in cerebral
infarction. Stroke 1978;9:369-374
8. Cyrus AE, Close AS, Foster LL, Brown DH, Ellison EH:
Effects of low molecular weight dextran on infarction after
experimental occlusion of the middle cerebral artery. Surgery 1982;52:25-31
9. Gelin LE, Ingelman B: Rheomacrodex—A new dextran
solution for rheological treatment of impaired capillary flow.
Ada Chir Scand 1961;122:294-302
10. Haggendal E, Norback B: Effect of viscosity on cerebral
blood flow. Ada Chir Scand (Suppl) 1966;364:13-22
11. Henriksen L, Paulson OB, Smith RJ: Cerebral blood flow
following normovolemic hemodilution in patients with high
hematocrit. Ann Neurol 1981;9:454-457
12. Sundt TM, Waltz AG, Sayre GP: Experimental cerebral
infarction: Modification by treatment with hemodiluting and
dehydration agents. / Neurosurg 1967;26:46-56
13. Wood JH, Simeone FA, Fink EA, Golden MA: Hypervolemic hemodilution in experimental focal cerebral ischemia.
J Neurosurg 1981;59:500-509
14. Wood JH, Simeone FA, Kron RE, Snyder LL: Experimental
hypervolemic hemodilution: Physiological correlations of
cortical blood flow, cardiac output and intracranial pressure
with fresh blood viscosity and plasma volume. Neurosurgery
1984;14:709-723
15. Hint H: The pharmacology of dextran and the physiological
background for the clinical use of Rheomacrodex and Macrodex. Ada Anaesthesiol Belg 1968;19:119-138
16. Sunder-Plassman L, Klovekorn WP, Holper K, Hase U,
Messmer K: The physiological significance of acutely induced
hemodilution, in Sixth European Conference on Microcirculation, Aalburg, 1970. Basel, Karger, 1971, pp 23-28
17. Fein JM: Comment on Wood JH, Simeone FA, Kron RE,
Snyder LL: Experimental hypovolemic hemodilution: Physiological correlations of cortical blood flow, cardiac output,
and intracranial pressure with fresh blood viscosity and
plasma volume. Neurosurgery 1984;14:722-725
18. Strand T, Aspiund K, Eriksson S, Hagg E, Lithner F,
Wester P-O: A randomized controlled trial of hemodilution
therapy in acute ischemic stroke. Stroke 1984;15:980-989
19. Honda K, Hoshino S, Shoji M, Usuba A, Motoki R, Tsuboi
M, Inoue H, Iwaya F: Clinical use of a blood substitute
(letter). N EnglJMed 1980;303:391-392
20. Peerless SJ, Ishikawa R, Hunter IG, Peerless MJ: Protective
effect of Fluosol-DA in acute cerebral ischemia. Stroke 1981;
12:558-563
21. Oda Y, Handa H, Nagasawa S, Naruo Y, Asato R, Yonekawa
Y: Efficacy of a blood substitute (Fluosol-DA 20%) on
cerebral ischemia. J Neurol Res 1982;4:35-45
22. Handa H, Nagasawa S, Yonekawa Y: New treatment of
cerebral vasospasm with Fluosol-DA 20%: Protective effect
on cerebral ischemia and change of cerebral blood flow
Downloaded from http://stroke.ahajournals.org/ by guest on March 4, 2014
1246
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
Stroke Vol 20, No 9, September 1989
(CBF), in Handa H, Nagasawa S, Yonekawa Y, Naruo Y,
Oda Y (eds): Advances in Blood Substitute Research. New
York, Alan R Liss Inc, 1983, pp 299-306
Knize DM, Weatherley-White RCA, Paton BC: Use of
antisludging agents in experimental cold injuries. Surg Gynecol Obstet 1969;129:1019-1026
Weatherley-White RCA, Knize DM, Geisterfer DJ, Paton
BC: Experimental studies in cold injury. V. Circulatory
hemodynamics. Surgery 1969;66:208-214
Hymes AC, Safavian MH, Gunther T: The influence of an
industrial surfactant Pluronic F-68, in the treatment of
hemorrhagic shock. / Surg Res 1971;11:191-197
Grover FL, Amundsen D, Warden JL, Fosburg RG, Paton
BL: The effect of Pluronic F-68 on circulatory dynamics and
renal and carotid artery flow during hemorrhagic shock. J
Surg Res 1974;17:30-35
Sloviter HA: Perfusion of the brain and other isolated organs
with dispersed perfluoro compounds, in Jamieson GA, Greenwait TJ (eds): Blood Substitutes and Plasma Expanders.
New York, Alan R Liss Inc, 1978, pp 27-39
Grover FL, Kahn RS, Heron MW, Paton BC: A nonionic
surfactant and blood viscosity. Arch Surg 1973;106:307-310
Meyer FB, Anderson RE, Sundt TM Jr, Yaksh TL: Intracellular brain pH, indicator tissue perfusion, electroencephalography, and histology in severe and moderate focal
cortical ischemia in the rabbit. J Cereb Blood Flow Metab
1986;6:71-78
Downs H, Litt M, Kron RE: Low shear rate viscosity of
fresh blood. J Biorheology 1980;17:25-35
Seybert J, Kron S, Litt M, Kron RE: Design considerations
for a transient capillary viscometer. Presented at the 35th
Annual Conference on Engineering in Medicine and Biology.
Philadelphia, Pennsylvania, Sept. 22-24, 1982
Shug A, Noonan J, Plehn S, Subramanian R, Hunter R,
Schafer T: The effect of RheothRx™ copolymer and streptokinase on recovery from ischemia in the isolated perfused
rat heart (abstract). Fibrinolysis 1988;2(suppl 1):5
BASF Wyandotte Corporation, Central Research and Development. Pluronic® Polyols. Toxicity and irritation studies
and data. Wyandotte, Michigan, December 1975
34. Wright ES, Sarkozy E, Dobell ARC, Murphy DR: Fat
globulemia in extracorporeal circulation. Surgery 1963;
53:500-504
35. Wells R, Bygdeman MS, Shahriari AA, Matloff JM, Harken
DE: Use of a polyol in the prevention of hemolysis due to an
antifoam agent in pump oxygenators. Circulation 1968;
37-38(suppl II):II-168-IM72
36. Wells R, Bygdeman MS, Shahriari AA, Matloff JM: Influence of a defoaming agent upon the hematological complications of pump oxygenators. Circulation 1968;37:638-647
37. Danielson GK, Dubilier LD, Bryant LR: Use of Pluronic
F-68 to diminish fat emboli and hemolysis during cardiopulmonary bypass. A controlled clinical study. / Thorac Cardiovasc Surg 1970;59:178-184
38. Ceresa RJ: Block and Graft Copolymerization. New York,
John Wiley & Sons, 1976, vol 2
39. Waddell WR, Geyer RP, Olsen FR, Stare FJ: Clinical
observations on the use of nonphosphatide (pluronic) fat
emulsions. Metabolism 1957;6:815-821
40. Pelham LD: Rational use of intravenous fat emulsions. Am J
HospPharm 1981;38:198-208
41. Mitsuno T, Ohyanagi H, Naito R: Clinical studies of a
perfluorochemical whole blood substitute (Fluosol-DA). Summary of 186 cases. Ann Surg 1982;195:60-69
42. Vercellotti GM, Hammerschmidt DE, Craddock PR, Jacob
HS: Activation of plasma complement by perfluorocarbon
artificial blood: Probable mechanism of adverse pulmonary
reactions in treated patients and rationale for corticosteroid
prophylaxis. Blood 1982;59:1299-1304
43. Hunter RL, Bennett B, Kidd MR: Enhancement of t-PA
mediated fibrinolysis in vitro by RheothRx™ (abstract).
Fibrinolysis 1988;2(suppl 1):72
44. Papadea C, Hunter R: Effect of RheothRx™ copolymer on
blood viscosity related to fibrin(ogen) concentration
(abstract). Fed Am Soc Exp BiolJ 1988;2:A384
45. Safar P, Takaori M, Kirimli B, Kampschulte S, Nemoto E:
Plasma substitutes for resuscitation, in Jamieson GA, Greenwait TJ (eds): Blood Substitutes and Plasma Expanders.
New York, Alan R Liss Inc, 1978, pp 91-104
46. Adamson AW: Physical Chemistry of Surfaces, ed 4. New
York, John Wiley & Sons, 1982
KEY WORDS
rabbits
cerebral blood flow
Downloaded from http://stroke.ahajournals.org/ by guest on March 4, 2014
cerebral ischemia