NEUROSURGICAL ANESTHESIA

SECTION EDITOR
DAVID S. WARNER

0.45% Saline and 5% Dextrose in Water, but Not 0.9%

Saline or 5% Dextrose in 0.9% Saline, Worsen Brain Edema
Two Hours After Closed Head Trauma in Rats
Daniel Talmor, MD*, Yoram Shapira, MD, rhw, Alan A. Artru, MD& Boris Gurevich, MD*,
Vladimir Merkind, MDt, Ludmyla Katchko, MDS, and Eli Reichenthal, MDt
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Divisions of *Anesthesiology and tNeurosurgery, Soroka Medical Center and the Faculty of Health Science; *Department
of Anesthesiology, Kaplan Hospital, Ben-Gurion University of the Negev, Beer-Sheva, Israel; and SDepartment of
Anesthesiology, University of Washington, Seattle, Washington

In this study, we examined the effect of four IV fluids respectively). In addition, l/2 NS decreased blood os-
(250 mL/kg) on blood glucose and osmolality and brain molality (248 ? 6 mOsm/L), D5W increased blood glu-
tissue specific gravity after closed head trauma (CHT) cose (1095 t 173 mg/dL), DSNS increased blood osmo-
in rats. CHT was delivered at Time 0; blood was sam- lality (350 + 5 mOsm/L) and glucose (1695 + 76 mg/
pled at 60 min; fluid infusion began at 75 min and ended dL), and NS caused no significant change. We conclude
at 105 mm. Blood was again sampled at 105 and that administering hypoosmolar IV fluids after CHT
120 mm, and brain tissue specific gravity was deter- causes a significant worsening of cerebral edema 2 h
mined at 120 min. Five groups (one control and four after CHT. Implications: We previously reported
fluid-treated groups) received CHT, and five other worse neurological outcome and/or mortality after
groups (one control and four fluid-treated) did not (n = closed head trauma in rats when 5% dextrose in water
9 in each group). 0.45% saline (l/2 NS) and 5% dextrose or 0.45% saline was given IV compared with 0.9% saline
in water (D5W) accentuated the decrease of brain tissue or 5% dextrose in 0.9% saline. The present results and
specific gravity (1.0366 ? 0.0025 and 1.0368 + 0.0028, our previous findings indicate that worsening of out-
respectively; mean -C SD) caused by CHT (1.0395 + come after closed head trauma in rats may be caused
0.0036), but 5% dextrose in 0.9% saline (D5NS) and 0.9% more by edema formation than by hyperglycemia.
saline (NS) did not (1.04312 0.0042 and 1.0389 2 0.0049, (Anesth Analg 1998;86:1225-9)

I
n a model of closed head trauma (CHT) in rats, we Accordingly, we designed another study to examine
reported that the IV administration of 250 mL/kg the effects of the IV administration of 250 mL/kg of
of 5% dextrose in water (D5W) increased the con- 5% dextrose in 0.9% saline (D5NS) and 0.45% saline
centration of glucose in blood, increased brain edema (l/2 NS). We hypothesized that D5NS would increase
in the noncontused hemisphere, and worsened the blood glucose but, being hyperosmolar with respect to
neurological severity score (NSS) and mortality rate blood, would not increase brain edema. Conversely,
four hours after CHT (1). In contrast, the IV adminis- l/2 NS should not increase blood glucose but, being
tration of 250 mL/kg of 0.9% saline (NS) or lactated hypoosmolar with respect to blood, should increase
Ringer’s solution caused no significant change in brain edema. We found that D5NS decreased brain
blood glucose, brain edema, NSS, or mortality rate at edema, increased blood glucose, and caused no signif-
four hours compared with untreated rats (1,2). Based icant change in NSS or mortality rate (3). We also
on these studies, it was not certain whether the wors- found that l/2 NS increased the mortality rate and
ening of NSS and mortality rate seen with D5W re- caused no significant change in blood glucose, brain
sulted from brain edema or from increased glucose. edema, or NSS.
Because both D5W (1) and D5NS (3) increase blood
Accepted for publication February 18, 1998. glucose, but only D5W (1) increases edema and wors-
Address correspondence to Alan A. Artru, MD, Department of ens outcome, we concluded that worsening of out-
Anesthesiology, Box 356540, University of Washington, Seattle, WA come may be caused more by edema formation
98195-6540. Address e-mail to artruaa@u.washington.edu. Address (regardless of whether glucose is concomitantly in-
reprint requests to Yoram Shapira, MD, PhD, Department of Anes-
thesiology, Soroka Medical Center, P.O. Box 151, Beer-Sheva 84101, creased) than by increased glucose per se. An associa-
Israel. tion between hyperglycemia and poor neurological

01998 by the International Anesthesia Research Society

0003-2999/98/$5.00 Anesth Analg 1998;86:1225-9 1225
1226 NEUROSURGICAL ANESTHESIA TALMOR
EDEMA 2 HOURS AFTER HEAD INJURY
outcome has been reported in both adult and pediatric
head-injured patients and experimental models of is-
chemia (4). Regarding the comparison between NS
and l/2 NS in our earlier studies (l-3), because l/2
NS worsened the mortality rate but did not cause
cerebral edema at four hours as expected, these data
did not address the question of whether an increase in
blood glucose is required to worsen the NSS and
mortality rate associated with cerebral edema forma-
tion after the IV administration of D5W after CHT.
In a study designed to examine the time of occur-
rence of the greatest change in the NSS, brain edema,
and blood-brain barrier permeability after CHT in rats
in the absence of IV fluid administration, we meas-
ured brain tissue specific gravity and water content
before CHT and 15 minutes; 1, 2,4,10, and 24 hours;
and 2, 4, and 7 days after CHT (5). The graph of the
data gives the appearance of an initial increase in
brain edema at 2-4 hours, followed by a second larger
increase in brain edema at 24 hours. Thus, it is possible
that although brain edema was not demonstrable at
four hours when l/2 NS was administered IV after
CHT, brain edema may be demonstrable at two hours.
Accordingly, the present study was designed to exam-
ine brain edema two hours after CHT when each of
the four above-mentioned IV fluids was administered.
Methods
This study was approved by the animal care commit-
tee of the Ben-Gurion University of the Negev, Beer-
Sheva, Israel. Ninety adult Sprague-Dawley rats,
238 +- 32 g (mean t SD), were used in this study. By
random assignment, 45 rats were allocated to the
groups undergoing scalp incision (Groups l-5) and 45
rats were allocated to the groups undergoing scalp
incision followed by CHT (Groups 6-10). Experimen-
tal conditions for the 10 groups are summarized in
Table 1. This model has been previously described
Table 1. Experimental Design
Group Cranial blow
1 No
2 No
3 No
4 No
5 No
6 Yes
7 Yes
8 Yes
9 Yes
10 Yes
All rats were killed at 2 h.
n = 9 in each group.
l/2 NS = 0.45% saline, D5NS = 5% dextrose in 0.9% saline, D5W
dextrose in water, NS = 0.9% saline.
a All IV fluids were administered in the amount
ET AL. ANESTH ANALG
1998;86:1225-9
(1,2,6,7). Briefly, 1.5%-2.0% halothane in oxygen was
administered in concentrations sufficient to abolish
cornea1 reflexes. A midline scalp incision was made,
and the scalp and underlying muscles were reflected
laterally. A cranial blow was then delivered (in the
appropriate groups) at a prefixed point over the left
hemisphere l-2 mm lateral to the midline on the skull
convexity. The blow was delivered by a free-falling
plate, from the center of which protruded a silicone-
tipped rod that impacted the skull. Settings on the
frame controlled the distance of the fall of the plat-
form. The energy imparted to the skull by the ster-
eotaxically guided plate is directly and linearly related
to the distance of the fall, and the nonpenetrating blow
causes reproducible brain injury and deterioration of
neurologic status (1,2,6,7). After scalp incision with or
without CHT, anesthesia was discontinued, and ani-
mals were returned to their cages and supplied with
unlimited food and water.
One hour after CHT or scalp incision, the NSS was
determined. Rats were then reanesthetized with halo-
thane and placed in the supine position. The femoral
region was infiltrated with 2% lidocaine, and 23-gauge
catheters were inserted into a femoral artery and vein.
A 300-PL sample of arterial blood was obtained, and
continuous measurement of blood pressure was be-
gun. At 75 min after CHT or scalp incision, IV fluid
infusion was begun as appropriate. No IV fluids were
given to Groups 1 and 6. The other eight groups
received 250 mL/kg of IV fluid over 30 min. At
105 min after CHT or scalp incision, IV fluid infusion
was discontinued and a blood sample was obtained.
Two hours after CHT or scalp incision (i.e., 15 min
after completion of IV fluid infusion), a blood sample
again was obtained, and all rats were killed.
The NSS was developed to assessthe clinical con-
dition of the rats after CHT (1,2,6,7). Points are as-
signed for motor function and behavior. The detailed
criteria for scoring have been published previously
(1,2,6,7). The NSS directly measures the deterioration
of observable neurological status so that a low score
IV fluids” represents nearly intact neurological status (minimum
0) and a high score represents severe neurological
None
l/2 NS dysfunction (maximum 25). The NSS was measured
D5NS 1 h after CHT or scalp incision by a blind observer.
D5W Rats were decapitated 2 h after CHT or scalp inci-
NS sion, and the entire brain was immediately removed
None and placed on a frozen plate. In the CHT groups, brain
l/2 NS
D5NS tissue samples weighing up to 50 mg were cut from
D5W areas adjacent to the zone of maximal macroscopic
NS damage in the left hemisphere and from the corre-
sponding area in the right hemisphere. In groups with
no CHT, brain tissue samples were taken from the
= 5%
corresponding left and right hemisphere areas. These
of 250 mL/kg. small brain tissue samples were used to determine
ANESTH ANALG NEUROSURGICAL ANESTHESIA TALMOR ET AL. 1227
1998;86:1225-9 EDEMA 2 HOURS AFTER HEAD INJURY

specific gravity. Specific gravity was determined us- Table 2. Brain Tissue Specific Gravity
ing linear gradient columns of kerosene and bromo- Left (injured) Right (uninjured)
benzene (1). A calibrated curve was generated for each Group hemisphere hemisphere
column using anhydrous K2S04 solutions of known
1 1.0449 + 0.0009 1.0451 + 0.0009
specific gravity (1.045, 1.040, 1.035, and 1.025). 1.0425 t 0.001211 1.0427 2 0.0007~~
2
Systolic and diastolic arterial blood pressures were 3 1.0500 f 0.0010 1.0493 t 0.0013
measured via the 23-gauge catheter in the femoral 4 1.0404 + 0.000711 1.0404 2 0.0007~~
artery. Mean arterial blood pressure (MAP) was de- 5 1.0445 + 0.0004 1.0442 ? 0.0006
termined by electronic integration of the systolic and 6 1.0395 + O.O036*t 1.0441 2 0.0026
diastolic arterial blood pressures. Blood pressure mea- 7 1.0366 + O.O025t$ 1.0422 t- 0.0013
8 1.0431 2 o.o042*t 1.0487 2 0.00225
surement began 1 h after CHT or scalp incision and
9 1.0368 ? O.O028*tS 1.0428 2 0.0017
was discontinued 2 h after CHT or scalp incision. 10 1.0389 ? O.O049*t 1.0435 -c 0.0037
Blood was sampled from the arterial catheter at 1,1.75,
and 2 h to determine plasma osmolality and blood gas Values are mean ? SD.
* Significant difference within the group (P < 0.05).
tensions and concentrations of urea, glucose, sodium, t Significant difference compared with the same condition without closed
and potassium. head trauma, either hemisphere (P < 0.05 for Groups 6-8 and 10, and P <
0.001 for Group 9).
Blood pressure, brain tissue specific gravity, and $ Significant difference compared with the same hemisphere in Group 8
laboratory results are expressed as the mean ? SD. (P < 0.001) and Group 6 (P < 0.05).
§ Significant difference compared with the same hemisphere in Groups 6,
These data were compared using analysis of variance 7, 9, and 10 (I’ < 0.001).
followed by post hoc evaluation using the Student- I/ Significant difference compared with the same hemisphere in Groups 1
and 5 (P i 0.05) and Group 3 (P < 0.001).
Newman-Keuls test. The NSS values were tabulated
as median (range) and were compared using the
Kruskal-Wallis test with post hoc evaluation using the In Groups 1-5, the MAP was 91 + 11 mm Hg (com-
Mann-Whitney U-test. Mortality rates were compared bined value for all groups). In Groups 6-10, the MAP
using Fisher’s exact test. A probability value of co.05 increased to 104 IfI 11 mm Hg (combined value for all
was considered significant. groups).
Values from blood sampled after initial insertion of
Results the femoral artery catheter were: plasma osmolality
280 + 7 mOsm/kg; blood concentrations of glucose
Table 2 summarizes the specific gravity of cortical 130 ? 5 mg/dL, sodium 135 + 6 mEq/L, potassium
slices taken from the injured and the corresponding 3.1 + 0.1 mEq/L, and urea 25.8 + 2.6 mg/dL; and
contralateral hemisphere in the 10 experimental hematocrit 40% + 2%. Plasma osmolality was de-
groups. Within-group comparisons indicated that in creased by l/2 NS and increased by D5NS. Blood
all groups with CHT, the specific gravity was de- glucose was increased by D5NS and D5W; blood so-
creased (water content was increased) in the injured dium was decreased by l/2 NS, D5NS, and D5W; and
hemisphere compared with the specific gravity in the blood potassium was decreased by l/2 NS and D5NS
noninjured (right) hemisphere. Between-group com- (Table 3).
parisons indicated that specific gravity of the injured The NSS 1 h after CHT was 18 (15-21) with no IV
hemispheres was decreased compared with that in fluid administration (Group 6), 18 (14-21) with l/2
both hemispheres in rats with no CHT. Among the NS (Group 7), 20 (17-22) with D5NS (Group B), 16
groups with CHT, specific gravity in the injured (14-19) with D5W (Group 9), and 17 (15-19) with NS
hemispheres of rats given l/2 NS (Group 7) or D5W (Group 10). The NSS did not differ significantly
(Group 9) was significantly decreased compared with among groups.
the injured hemispheres of rats given D5NS (Group 8)
or no IV fluid (Group 6). Specific gravity in the unin-
jured hemispheres of CHT rats given D5NS (Group 8)
was significantly increased compared with the unin- Discussion
jured hemispheres of the other groups of CHT rats. The principal finding of the present study is that the
Among the groups with CHT, the specific gravity in IV administration of 250 mL/kg of l/2 NS or D5W
both hemispheres of rats given l/2 NS (Group 2) or after CHT caused significantly greater cerebral edema,
D5W (Group 4) was significantly decreased compared as indicated by a significantly greater decrease of
with that in rats given D5NS (Group 3), NS (Group 5), brain tissue specific gravity in the injured hemisphere,
or no IV fluid (Group 1). than did the IV administration of D5NS or NS or no
There was no significant difference in blood pres- fluid administration. The finding of greater cerebral
sure among the five groups with no (Groups l-5). edema at two hours with l/2 NS and D5W permits a
There was also no significant difference in blood pres- more complete interpretation of our previous studies
sure among the five groups with CHT (Groups 6-10). (l-3) and addresses the question of whether outcome
1228 NEUROSURGICAL ANESTHESIA TALMOR ET AL ANESTH ANALG
EDEMA 2 HOURS AFTER HEAD INJURY 1998;86:1225-9

from CHT is worsened by cerebral edema only when

blood glucose is concomitantly increased. In our pre-
vious studies, both D5W and D5NS increased blood
glucose, but only D5W increased edema and wors-
ened outcome after CHT (l-3). Although we specu-
lated that worsening of outcome may be caused more
by edema formation (regardless of whether glucose is
concomitantly increased) than by increased glucose
per se, that conclusion could not be confirmed because
l/2 NS worsened the mortality rate but did not cause
cerebral edema at four hours as expected. The finding
in the present study that l/2 NS caused cerebral
edema at 2 hours confirms that the worsened outcome
after CHT (mortality rate 50%) previously reported at
24 hours may relate to postraumatic cerebral edema
without a concomitant increase in blood glucose (3).
The present study also provides information about
changes in factors two hours after CHT that may affect
edema formation. This two-hour data complements
previously reported data on changes in factors four
hours after CHT that may affect edema formation
(l-3). We previously reported that at four hours, D5W
caused no significant change in blood osmolality and
decreased the blood sodium concentration; NS caused
no change in osmolality or sodium; D5NS increased
osmolality and decreased sodium; and l/2 NS de-
creased osmolality and sodium. In the present study,
we found that at two hours, all four IV fluids pro-
duced the same changes in osmolality and sodium as
at four hours. Our findings of worsening cerebral
edema two hours after CHT when D5W or l/2 NS
were administered are consistent with previous re-
9 ports that edema formation is inversely related to the
d
V increase or decrease from normal values of blood os-
c molality and sodium concentration (8).
‘as Several of the findings of the present study are
z consistent with previously reported results and sup-
:g port the validity of this model. In the present study,
4 the lower brain tissue specific gravity in rats given l/2
a NS or D5W but not subjected to CHT is consistent
E with the time course of equilibration of hypoosmolar
solutions across the blood-brain barrier (5,9). The
2
5 greater brain tissue specific gravity in the uninjured
3 hemisphere of rats with CHT that received D5NS is
%5 consistent with the well known effect of hyperosmolar
BG
solutions to decrease brain water content (9,lO). The
08
lol lower brain tissue specific gravity in the injured hemi-
jg sphere of all groups of rats with CHT is consistent
$E with previous reports of rapidly developing cerebral
II $
kg2 edema after cranial impact (5). The NSS at one hour
+,oc: %E are consistent with values previously reported for this
5 ‘5 3 model and indicate that an adequate cranial blow was
UOh
E%- delivered (l-3,11,12).
WE 2
-almu Limitations of the present study are that the rats
m-c%
3 II 6 breathed spontaneously during and after CHT, that
753 systemic arterial blood pressure was not measured
L-Z*
during the 0- to 60-minute period after CHT, and that
ANESTH ANALG NEUROSURGICAL ANESTHESIA TALMOR ET AL. 1229
1998;86:1225-9 EDEMA 2 HOURS AFTER HEAD INJURY

brain temperature was not measured. Two conse- 2. Feldman Z, Zachari S, Reichenthal E, et al. Brain edema and
neurological status with rapid infusion of lactate Ringer’s or 5%
quences of spontaneous ventilation that might affect
dextrose solution following head trauma. J Neurosurg 1995;83:
the present outcome measures are hypoxemia and 1060-6.
hypercapnia. Because Pao2, Paco2, and blood pressure 3. Gurevich 8, Talmor D, Artru AA, et al. Brain edema, hemor-
were not measured during the 0- to 60-minute period rhagic necrosis volume, and neurological status with rapid in-
after CHT, there are no data to prove that hypoxemia, fusion of 0.45% saline or 5% dextrose in 0.9% saline following
closed head trauma in rats. Anesth Analg 1997;84:554-9.
hypercapnia, and hypotension did not occur. How- 4. Avellino AM, Lam AM, Winn HR. Management of acute head
ever, hypoxemia, hypercapnia, and hypotension se- injury. In: Albin MS, ed. Textbook of neuroanesthesia: with
vere enough to affect outcome measures might also be neurosurgical and neuroscience perspectives. New York:
expected to have affected the NSS one hour after CHT. McGraw-Hill, 19971137-75.
In the present study, the NSS at one hour did not 5. Shapira Y, Setton D, Artru AA, Shohami E. Blood-brain barrier
permeability, cerebral edema, and neurological function after
differ among groups. Pao2, Paco2, and MAP values closed head injury in rats. Anesth Analg 1993;77:141-8.
did not differ among groups during the 60- to 120- 6. Shapira Y, Artru AA, Cotev S, et al. Brain edema and neurolog-
minute period after CHT. In a later study using this ical status following head trauma in the rat. Anesthesiology
same model, MAP was monitored during CHT and 1992;77:79-85.
7. Shapira Y, Shohami E, Sidi A, et al. Experimental closed head
the 0- to 60-minute period after CHT and did not differ
injury in rats: mechanical, pathophysiologic, and neurologic
between groups (13). In another subsequent study properties. Crit Care Med 1988;16:258-65.
using this same model, temporalis muscle tempera- 8. Zornow MH, McQuitty C, Prough DS. Perioperative fluid man-
ture (and rectal temperature) were measured during agement of the neurosurgical patient. In: Albin MS, ed. Text-
CHT and 1,4,24, and 48 hours after CHT and did not book of neuroanesthesia: with neurosurgical and neuroscience
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differ between groups (14).
9. Zomow MH, Scheller MS. Intraoperative fluid management
In summary, in our previous studies, both D5W and during craniotomy. In: Cottrell JE, Smith DS, eds. Anesthesia
D5NS increased blood glucose, but only D5W in- and neurosurgery. St. Louis: Mosby-Year Book, 1994:247-59.
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suggested, but did not prove, that worsening of out- volemic hemodilution with a hypertonic saline solution. J Neu-
rosurg 1985;63:944-8.
come after CHT may be caused more by edema for-
11. Feldman A, Gurevich 8, Artru AA, et al. Magnesium given one
mation than by increased glucose per se. The results of hour following head trauma decreases brain edema and im-
the present study and those of our previous studies proves neurological outcome. J Neurosurg 1996;85:131-7.
indicate that l/2 NS given after CHT increases edema 12. Shapira Y, Gurevich 8, Artru AA, et al. Influence of closed head
and worsens outcome without altering blood glucose. injury on isoflurane MAC in the rat. J Neurosurg Anesthesiol
1997;9:51-7.
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edema, blood glucose, or outcome. The present results neurological outcome after head trauma [abstract]. J Neurosurg
support the proposal that edema is a greater risk factor Anesthesiol 1997;9:390.
for worsening of outcome after CHT than is increased 14. Gurevich B, Artru AA, Lam AM, et al. Effects of a new NMDA
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