Open Journal of Vet eri nary M e dici ne , 2011, 1, 1-7
doi:10.4236/ojvm.2011.11001 Published Online December 2011 (http://www.SciRP.org/journal/ojvm)
Comparison between Hypertonic Saline with Dextran
and Mannitol on Vasodilatation of Encephalic Vessels
Using a Magnetic Resonance Imaging in the Dogs
Miki Akaishizawa1, Reiko Tabata1, Kazuyuki Suzuki1,2, Ryuji Asano1
1Department of Veterinary Medicine, College of Bioresourse Sciences, Nihon University, Kanagawa, Japan
2Department of Lar ge Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University,
Hokkaido, Japan
Received November 8, 2011; revised November 20, 2011; accepted December 13, 2011
Abstract
This study aimed to investigate whether a small volume of 7.2% hypertonic saline solution with 6% dextran 70 (HSD)
is superior to mannitol in vasodilatation of encephalic vessels in the dogs using magnetic resonance imaging (MRI).
Fifteen healthy 2.4 ± 0.9 year-old purpose-bred male Beagle dogs were assigned to receive 5 mL/kg of isotonic saline
solution (ISS) as control, 20% mannitol or HSD infusion at a flow rate of 20 mL/kg/hours via right cephalic
vein.Venous blood samples were collected immediately before fluid infusion (pre) and ev ery 15 minutes until 120 min-
utes after the initiation of fluid infusion. Immediately after collectio n of each blood sample, T1 and T2-weighted mag-
netic resonance imaging recordings were undergone. Immediately after HSD infusion, the area of the cross-section of
superior sagittal sinus was significantly greater than th at of beagles in the other groups (p < 0.001), reaching the 2.09 ±
0.25 times pre-value. During the 120 minutes period of observation after the initiation of fluid infusion, HSD infusion
significantly reduced the area of the cross-section of CSF compared with the mannitol group (p < 0.001). Our results
indicate that HSD induced a rapid and strong reduction in the area of the cross-section of CSF more than mannitol did.
Therefore, it is suggested that 5 mL/kg of HSD might be superior to isovolume of mannitol in inducing vasodilatation in
the dog.
Keywords: Canine, Hypertonic Saline, Magnetic Resonance Imaging, Mannitol, Superior Sagittal Sinus
1. Introduction
Hypertonic mannitol is commonly used to treat compro-
mised encephalic circulation associated with neurologic
disorders since mannitol is known to improve brain
edema, intracranial hypertension, and encephalic blood
flow [1,2]. Standard pre-hospital and initial room treat-
ment of patients with clinical evidence of elevated in-
tracranial pressure (ICP) includes intravenous admini-
stration of a hypertonic mannitol [3-5]. This was pre-
sumed to be secondary to a dehydrating effect or direct
reduction of white matter water content [4]. However, it
is associated with profound diuresis, itself a potential
cause of morbidity, and also acute renal failure [6], and
tending to decrease the blood pressure [7].
The effects of hypertonic saline solution (HSS) in the
resuscitation of animals in hemorrhagic and endotoxic
shock have been documented in a variety of laboratory
and clinical studies [8-11]. Recently, investigative inter-
est has focused on the intracranial effects of HSS resus-
citation [12-15]. The administration of 7.5%-HSS with
cryogenic encephalic regions causes a prompt and sub-
stantial decrease in encephalic water content in rabbits as
assessed by spine-echo T2-weighted magnetic resonance
imaging (MRI) [16]. Therefore, HSS may prove to be
more beneficial than osmotic diuretics because they
augment intravascular volume and cardiovascular per-
formance in addition to improving intracranial elastance
[17].
The use of HSS alone, however, had a transient effect
on encephalic circulation [18,19]. The addition of a hy-
peroncotic agent, such as dextran, has been shown to
prolong the cardiovascular resuscitative effect of HSS in
the treatment of hemorrhag ic shock [7,19-21]. Therefore,
there has been a clinical interest in HSS with 6% dextran
70 (HSD) for the treatment of cerebral hypertension and
cardiovascular resuscitation [13,19]. Thus, Battison et al.
[22] demonstrated that treatments reduced ICP with both

2 M. AKAISHIZAWA ET AL.
mannitol (median decrease, 7.5 mm Hg) and HSD (me-
dian decrease, 13 mm Hg). In addition, HSD caused a
significantly greater decrease in intracranial pressure and
had a longer duration of effect than equimolar dose of
mannitol in human with brain injury [22]. Future HSD
research needs to be performed in several areas with re-
gard to cerebral edema, hypertension and brain injury in
the dogs. Thus, studies comparing HSD and mannitol as
primary agents to lower ICP are needed to explore their
relative safety and efficacy. Therefore, this study aimed
to investigate, using MRI, whether a small volume of
HSD is superior to mannitol, when infused at the same
volume, in the vasodilatation of encephalic vessels in the
dogs.
2. Materials and Methods
The work was carried out at the Veterinary teaching hos-
pital, Department of Veterinary Medicine, College of
Bioresourse Sciences, Nihon University, Kanagawa, Ja-
pan. All procedures were in accordance with the College
of Bioresource Sciences, Nihon University on the Code
for the Care and Use of Laboratory Animals (approval
number: 079) and the National Research Council on
Guide for the Care and Use of Laboratory Animals [23].
The experiments were performed on 15 healthy 2.4 ± 0.9
year-old purpose-bred male Beagle dog s weigh ing 12.4 ±
1.4 kg (mean ± standard deviation). Dogs were deemed
healthy on the basis of physical examination, biochemi-
cal profile, electrocardiography, thoracic radiography
and echocardiography analysis. A complete, balanced
diet consisting of rationed concentrated pellet was pro-
vided, and the dogs had unlimited access to fresh water.
Food was removed 16 hours and water 1 hour prior to
anesthesia.
An isotonic saline solution (ISS, 300 mOsm/L., Nihon
Zenyaku Kogyo, Fukushima, Japan) and 20% mannitol
solution (1200 mOsm/L, Nikken Kagaku Co., Ltd., Tokyo,
Japan) were purchased. A 7.2%-HSD (2400 mOsm/L)
were kindly prepared and provided by Dr. S. Iwabuchi
(Nihon Zenyaku Kogyo Co., Ltd).
The cross-sections of superior sagittal sinus, which is
represented by area of cerebral falx, in the axial trans-
verse section of pituitary (Figure 1(A)), and facial vein at
the axial transverse section of epencephalic limbic (Fig-
ure 1(B)) were measured by spin-echo T1-weighted MRI
using a 0.5 tesla-superconducting MRI system (Flexart
MRT-50GP, Toshiba Medical Systems, Tokyo, Japan)
set at TR/TE = 375/15 milliseconds, field of view = 14 ×
14 cm, image matrix 192 × 256 pixels in T1- weighted
image with 4-mm-thick slices. Changes in cross-section
of superior sagittal sinus and facial vein were analyzed
using image analysis software (Toshiba Med ical Systems).
Figure 1. Measurement of cross-section of superior sagittal
sinus and facial vein. A: sagittal transverse section views in
the beagle and open rectangle indicates the location for the
axial transverse section of pituitary; A-1: the axial T1
weighted images at the pituitary section. Arrowhead shows
the area of the cerebral falx. The area of the superior sagit-
tal sinus is represented by area of cerebral falx in the axial
transverse section of pituitary; B: sagittal transverse section
views in the beagle and open rectangle indicates the location
for the axial transverse section of epencephalic limbic; B-1:
the axial T1 weighted images at the epencephalic limbic.
Arrowhead shows the cross-section of facial vein.
Each region of interests (ROI), which traced by manually
using an ROI tool kit (Toshiba Medical Systems), un-
derwent triplicate measurement and then used the aver-
age. A detailed description of the procedure to measure
the area of superior sagittal sinus and facial vein using
MRI are described elsewhere [24].
The dogs were anesthetized with intravenous infusion
of thiopental sodium (Ravonal for Injection, Tanabe
Seiyaku Co., Osaka, Japan) at a dose of 18 mg/kg before
being orotracheally intubated with a cuffed endotracheal
tube and positioned in supine position. After tracheal
intubations, each dog was put under general anesthesia
and maintained in oxygen throughout the experiment
using a 1.5 - 2.0 times the minimum alveolar concentra-
tion of isoflurane (Forane, Abbott Japan Co, Osaka, Ja-
pan).
The end-tidal con centration of isoflurane and en d-tidal
partial pressure of carbon dioxide were continuously
monitored using an airway gas monitor (Datex Instru-
ment Co., Helsinki, Finland). The animals were allowed
to breathe spontaneously throughout the experiments.
Fifteen dogs were randomly allocated one of three
groups as follows: ISS, mannitol and HSD groups (n = 5

M. AKAISHIZAWA ET AL.
3
per group). The dogs in the ISS, mannitol and HSD
groups were received 5 mL/kg of ISS as control, 20%
mannitol and HSD infusion at a flow rate of 20 mL/
kg/hours via right cephalic vein over 15 minutes, respec-
tively. Venous blood samples were collected immedi-
ately before fluid infusion (pre) and 15, 30, 45, 60, 75,
105 and 120 minutes after the in itiation of fluid infusion.
Immediately after collection of each blood sample,
T1-weighted MR images recordings were started. Ve-
nous samples were analyzed for partial pressure of car-
bon dioxide and sodium concentration with an automatic
analyzer (Bayer 348, Bayer Medical Japan, Tokyo, Ja-
pan). Some blood samples were used to determine he-
moglobin concentrations and hematocrit values by an
automatic cell counter (Celltac Alfa, Nihon Kohden Co.,
Tokyo Japan). Changes in relative plasma volume (rPV)
were calculated from hemoglobin concentrations and
hematocrit values, using the following formulas [25].
pre samp
samp pre
Hb100 Hct
rPV (%)100
Hb100 Hct

 

where Hbpre and Htpre were Hb and Ht befo re saline infu-
sion, and Hbsamp and Htsamp were Hb and Ht at each sam-
pling point.
Data are expressed as mean ± standard deviation. All
data recorded in this study were continuous measures
with normal distributions. Statistical evaluatio n of data is
conducted by a two-way repeated measures analysis of
variance (ANOVA), with treatment group and time as
the two factors, followed by use of a post hoc test that
depended on multiple comparisons versus pre-value
(Bon-ferroni test). We used ANOVA for repeated meas-
ures, followed by Tukey’s Studentized range test, to as-
sess the differences between the three study groups at
each sample point. Those statistical analyses were per-
formed using a software package (Stat View Japanese
Edition Ver.5, Hulinks Japan, Tokyo). The level of sta-
tistical significance was set at p < 0.05.
3. Results
The end-tidal concentration of isoflurane (1.9 ± 0.1%)
was remained unchanged throughout the experiment. The
end-tidal partial pressures of carbon dioxide in the ISS,
mannitol and HSD groups were maintained at 39.2 ± 6.7,
39.0 ± 11.8 and 42.3 ± 10.1 mmHg, respectively. No
significant differences in the end-tidal concentration of
isoflurane and end-tidal partial pressure of carbon diox-
ide were observed among groups. Figure 2 shows se-
quential changes in rPV and venous sodium concentra-
tion in dogs received either mannitol or HSD. There was
a slight decrease in the rPV of the mannitol group,
reaching 93.4 ± 7.8% during the rest of the experiment,
Figure 2. Sequential changes in the relative plasma volume
(upper) and serum sodium concentration (bottom) in dogs
received either mannitol or HSD. Significant differences
from pre-values: *p < 0.05 by Bonferroni test; from ISS and
mannitol groups: ap < 0.05 and bp < 0.05 by Tukey’s Stu-
dentized range test , res pectively.
whereas ISS infusion induced a transient increase in rPV,
reaching 113.9 ± 2.8% at the completion of fluid infusion.
In contrast, rPV in the HSD group increased markedly,
reaching 128.2 ± 0.9% at the completion of fluid infusion,
and it remained high throughout the experimental period
(p < 0.001). The rPV was higher in the HSD group 90
minutes following infu sion than that in ISS and mannitol
groups (p < 0.001). Venous sodium concentration in the
HSD group increased significantly and markedly from
149.6 ± 1.2 mM at pre to 162.4 ± 2.1 mM at the comple-
tion of fluid infusion (p < 0.001), and it was higher 2
hours following infusion than that in control and manni-
tol groups (p < 0.001).
Figure 3 shows sequential changes in cross-section of
superior sagittal sinus and facial vein in the dogs re-
ceived either mannitol or HSD. The cross-sections of
superior sagittal sinus in the ISS and mannitol groups
were not altered from the pre-value. Immediately after
fluid infusion, the cross-section of superior sagittal sinus
in HSD group increased its size and markedly, from
0.054 ± 0.009 cm2 at pre to 0.112 ± 0.015 cm2 at 30 min-
utes after the initiation of fluid infusion (2.09 ± 0.25

4 M. AKAISHIZAWA ET AL.
Figure 3. Sequential changes in areas of superior sagittal
sinus (upper) and facial vain (bottom) in dogs received ei-
ther mannitol or HSD. See Figure 2 for remainder of sym-
bols.
times pre-value), and remained constant throughout the
experimental period (p < 0.001). The size of the cross-
section of superior sagittal sinus was significantly reach-
ing 128.2 ± 0.9% at the co mpletion of fluid in fusion, and
it remained high throughout th e experimental period (p <
0.001).
The changes in cross-section of facial vein in the HSD
group were induced significantly, from 0.559 ± 0.101
cm2 at pre to 0.923 ± 0.111 cm2 at 30 minutes after the
initiation of fluid infusion (1.68 ± 0.27 times pre-value),
and it was significantly higher than that in the ISS and
mannitol groups (p < 0.001).
4. Discussion
In the present study, the superior efficacy of 5 mL/kg of
HSD over equal volumes of 20% mannitol was implied
by the fact that vasodilatation of encephalic vessels such
as superior sagittal sinus was more rapid and stronger in
the HSD group than in the mannitol group. In addition,
HSD had a longer duration of eff ect than mannitol
Aggressive ICP management is considered a corner-
stone in the treatment of dogs with severe head injures.
Hypertonic mannitol is commo nly used to treat critically
ill patients with compromised encephalic circulation as-
sociated with various neurologic disorders, although its
mechanism is not fully understood. Two differential
mechanisms by which mannitol reduce ICP have been
established. Improvement of blood rheology leading to
an increased encephalic blood flow and compensatory
encephalic vasoconstriction may cause an early drop in
ICP, which was observed shortly after infusion [3,26]. A
delayed decrease in ICP following 30 minutes to 6 hours
after infusion is attributed to an osmotic gradient pro-
duced between plasma and parenchyma cells [21]. The
osmotic effect of mannitol is delayed for 15 - 30 minutes
until gradients are established between plasma and cells.
Its effect persists for a variable period ranging from 90
minutes to 6 hours or more, depending on the clinical
conditions [27]. However, Arai et al. [1] demonstrated
that the administration of hypertonic mannitol failed to
improve and even worsened encephalic blood flow, but it
did decrease ICP for several hours, most likely due to the
excessive urine losses it caused. In our study, mannitol
induced a slight decrease in the systemic circulation
volume, reaching 93.4 ± 10.0%, whereas the rPV re-
mained high in the HSD group 2 hours following infu-
sion. This result supports the report by Arai et al [1].
One of the primary mechanisms by which HSD exerts
its action on the encephalic circulation is via its osmotic
effects [13]. By dehydrating tissues, HSD can simulta-
neously improve perfusion by pulling fluid into the in-
travascular compartment and decrease edema in critical
areas such as the brain [13,28]. Several animal models of
traumatic brain injury have demonstrated a decrease in
encephalic water content with use of HSD, often through
dehydration of the uninjured hemisphere [16,28,29]. The
cranial vault is a fixed space consisting of 3 compart-
ments such as parenchyma, cerebrospinal fluid (CSF)
and encephalic blood within calvaria by Monroe-Kellie
doctrine. Therefore, increases in encephalic blood results
in a compensatory decrease in CSF in order to maintain
ICP in normovolemic dogs. In this study, HSD infusion
induced a greater and faster vasodilatation of superior
sagittal sinus than mannitol did. Therefore, this result
suggests that HSD might be superior to mannitol in ini-
tial treatment of cerebral hypertension in dogs with ele-
vated ICP.
The principal physiological mechanism underlying the
efficacy of HSD, mannitol, and other osmotically active
agents in decreasing ICP is believed to be an osmotic
gradient-induced shift of extra- to intra-vascular water
across the blood-brain-barrier (BBB) [30]. The BBB
consists of tight junctions between encephalic endothe-
lial cells that allow free passage to water but are not
permeable to osmotically active substances such as so-
dium and low molecular weight compounds [31]. The
reason why the HSD is superior to mannitol on im-
provement of encephalic circulation is that the BBB is

M. AKAISHIZAWA ET AL.
5
better able to exclude HSD because of tight gap junctions
and its higher polarity, resulting in a reflection coeffi-
cient of 1.0 for NaCl as compared with 0.9 for mannitol
[13,14]. In the short term, hypertonic solutions expand
plasma volume and reduce brain edema. It is known that
the mannitol turn toward filtratio n and in time result in a
net increase tissue volume [32]. However, HSS is the
only hypertonic solution that did not induce a rebound
effect. One explanation may be that sodium ion pumps
prevent intracellular accumulation of sodium and chlo-
ride, whereas mannitol shows transient accumulation in
the intracellular space. This hypothesis is consistent that
fluid microvascular permeability was increased by HSD
but was not influenced by mannitol [32].
There are more than 300 studies published in which a
small-volume solution of 7.2% to 7.5% NaCl is com-
bined with 6% to 10% dextran. Interestingly, the original
HSD choice of 7.2% NaCl with 6% dextran 70 by Smith
et al. [5] was entirely arbitrary [9]. A few studies have
evaluated variations in concentration or total dose [9].
These studies show that it is not a specific concentration
of the crystalloid or the colloid component that contrib-
utes to a particular efficacy. Clinical studies support its
efficacy, and to our knowledge there has not been a sin-
gle adverse event reported with HSD in more than 1,000
patients treated to date in published clinical trials [9].
HSS and HSD are given as a rapid IV bolus (1 mL/kg
per minutes) at a dose of 4 to 6 mL/kg in the veterinary
practice [33]. In the sev eral literatures, however, in fusion
period for HSD of 10 to 20 minutes is recommended for
the initial resuscitation of animals with hypotensive
trauma [8,9,34]. A continuous infusion of 7.5%-HSS
with splenectomy resulted in minimal blood loss and
improved survival in rat [34]. Based on new data that
show the possibility of vasodilatation and/or cardiac ar-
rhythmia, and concerns regarding increased bleeding,
several researchers suggest that a 10- to 20-miniute in fu-
sion of 4- to 5-mL/kg of HSD be recommende d for criti-
cal care [8,9,34]. Mannitol has become popular as “a
small volume resuscitation fluid” and has often been
compared with HSS and HSD. Several literatures rec-
ommended that a 20% or 25% mannitol at a dose from
0.25 to 1.0 g/kg be given intravenously over 10 to 15
minutes to treat head injury in human [2,30,35]. There-
fore, 15 minutes continuous 20% mannitol and HSD at a
dose of 5 mL/kg was adopted in this study. MRI offers
an opportunity for repeated, noninvasive in vivo deter-
minations of the cross-section of encephalic vessel and
encephalic water content [16,36]. Therefore, we com-
pared HSD with mannitol on CSF in anesthetized dog
using the noninvasive and serial spin-echo T1-weighted
MRI from ethical consideration.
The present study demonstrated that 5 mL/kg of HSD
induced a rapid and strong vasodilatation of superior
sagittal sinus more than isovolu me of 20% mannitol did.
Based on these results, the question may be raised
whether HSD is a better choice to improve an encephalic
circulation and to treat brain edema than mannitol.
Clinical research is necessary before definitive recom-
mendations of HSD can be made regarding the optimal
fluid for use in the treatment of cerebral hypertension in
the dog with elevated ICP.
5. Acknowledgements
This study was supported by a grant-in-aid for Science
Research from the Ministry of Education, Culture and
Sciences of Japan (18580319 and 21580393) to Suzuki
K.
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