A Comparison of 3% Hypertonic Saline and Mannitol

for Brain Relaxation During Elective Supratentorial

Brain Tumor Surgery
Ching-Tang Wu, MD,* Liang-Chih Chen, MD,† Chang-Po Kuo, MD,* Da-Tong Ju, MD,‡
Cecil O. Borel, MD,§ Chen-Hwan Cherng, MD, DMSC,* and Chih-Shung Wong, MD, PhD*

BACKGROUND: In this study, we compared the effects of 3% hypertonic saline (HTS) and 20%
mannitol on brain relaxation during supratentorial brain tumor surgery, intensive care unit (ICU)
stays, and hospital days.
METHODS: This prospective, randomized, and double-blind study included patients who were
selected for elective craniotomy for supratentorial brain tumors. Patients received either 160 mL
of 3% HTS (HTS group, n ⫽ 122) or 150 mL of 20% mannitol infusion (M group, n ⫽ 116) for 5
minutes at the start of scalp incision. The PCO2 in arterial blood was maintained within 35 to 40
mm Hg, arterial blood pressure was controlled within baseline values ⫾20%, and positive fluid
balance was maintained intraoperatively at a rate of 2 mL/kg/h. Outcome measures included
fluid input, urine output, arterial blood gases, serum sodium concentration, ICU stays, and
hospital days. Surgeons assessed the condition of the brain as “tight,” “adequate,” or “soft”
immediately after opening the dura.
RESULTS: Brain relaxation conditions in the HTS group (soft/adequate/tight, n ⫽ 58/43/21)
were better than those observed in the M group (soft/adequate/tight, n ⫽ 39/42/35; P ⫽ 0.02).
The levels of serum sodium were higher in the HTS group compared with the M group over time
(P ⬍ 0.001). The average urine output in the M group (707 mL) was higher than it was in the HTS
group (596 mL) (P ⬍ 0.001). There were no significant differences in fluid input, ICU stays, and
hospital days between the 2 groups.
CONCLUSIONS: Our results suggest that HTS provided better brain relaxation than did mannitol
during elective supratentorial brain tumor surgery, whereas it did not affect ICU stays or hospital
days. (Anesth Analg 2010;110:903–7)

H ypertonic saline (HTS) and mannitol are used to

treat intracranial hypertension.1–5 Several prospec-
tive clinical trials that compared the effects of HTS
and mannitol on intracranial pressure (ICP) suggest that
HTS is at least as effective as, if not better than, mannitol in
the treatment of increased ICP.6 –12 However, most studies
included various brain pathologies, and the protocols of
administration of HTS or mannitol and the osmolar load of
the compounds varied among these reports.
The purpose of our study was to compare the effects of
the application of an equiosmolar bolus of HTS with those
of mannitol on intraoperative brain relaxation (as the
primary outcome) and intensive care unit (ICU) stays and
hospital days (as the secondary outcomes) in patients
undergoing elective craniotomy for supratentorial brain
tumors.
From the *Department of Anesthesiology, Tri-Service General Hospital,
National Defense Medical Center, Taipei; †Division of Anesthesiology,
Kaohsiung Armed Forces General Hospital, Kaohsiung; ‡Department of
Neurosurgery, Tri-Service General Hospital, National Defense Medical
Center, Taipei, Taiwan, Republic of China; and §Department of Anesthesi-
ology, Duke University Medical Center, Durham, North Carolina.
Accepted for publication November 8, 2009.
Supported by grants from the Department of Health (DOH95-PA-1053B) of
Taiwan, Republic of China.
Address correspondence and reprint requests to Dr. Ching-Tang Wu,
Department of Anesthesiology, Tri-Service General Hospital, National De-
fense Medical Center, # 325, Section 2, Chenggung Rd., Neihu 114, Taipei,
Taiwan. Address e-mail to wuchingtang@msn.com.
Copyright © 2010 International Anesthesia Research Society
DOI: 10.1213/ANE.0b013e3181cb3f8b
METHODS
After obtaining the approval of the IRB of the National
Defense Medical Center (Taipei, Taiwan) and written in-
formed consent from patients, we performed a power
calculation to determine the ideal sample size before initia-
tion of the study. A minimum of 106 patients was required
in each group to detect a decrease in the incidence of
tight-brain condition from 36% to 18%, with a power of 80%
and a confidence interval of 95%. To compensate for
potential dropouts, we enrolled a minimum of 116 patients
in each group. Two hundred thirty-eight patients who were
scheduled to undergo elective craniotomy for supratento-
rial brain tumors were enrolled in this prospective, ran-
domized, and double-blind study. The data were collected
between January 2005 and January 2009. Exclusion criteria
were age ⬍18 years, Glasgow Coma Scale score ⬍13, ASA
physical status IV–V, signs of increased ICP, perioperative
hypo- or hypernatremia (serum sodium ⬍135 or ⬎150
mEq/L, respectively), history of treatment with any
hyperosmotic fluids (HTS or mannitol) within the 24
hours preceding the surgery, and history of congestive
heart failure or severe renal function impairment. All
patients received 10 mg dexamethasone IV every 6 hours
for 48 hours before brain tumor resection. After random-
ization using sealed envelopes, patients were assigned to
receive IV administration of equiosmolar hyperosmotic
fluids, either 160 mL of 3% HTS (HTS group) or 150 mL
of 20% mannitol (M group) for 5 minutes using an
infusion pump and a central line at the time of scalp
incision. The surgeons and anesthesiologists were
blinded to the identity of the agents under study.

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Hypertonic Saline and Brain Relaxation
Anesthetic Management
General anesthesia was induced with 2% lidocaine (1.5
mg/kg), fentanyl (2 ␮g/kg), propofol (2 mg/kg), and
rocuronium (0.6 mg/kg) using a peripheral IV line. In
addition to standard monitoring, we placed a radial arterial
line, a central venous pressure (CVP) catheter, and a
train-of-four stimulator. Anesthetic maintenance included
1% sevoflurane in oxygen combined with IV infusion of
propofol (dose range, 3– 4 mg/kg/h) and an IV bolus of
fentanyl or cisatracurium, if necessary, which were admin-
istered at the attending anesthesiologist’s discretion. ETco2
monitors were calibrated preoperatively and deviation
values between Pco2 in arterial blood (Paco2) and ETco2
were recorded. We adjusted Paco2 between 35 and 40 mm
Hg according to the values of ETco2. Heart rate and arterial
blood pressure (ABP) values were kept within baseline
values ⫾20% using fentanyl and labetalol and by adjusting
the dosage of propofol. Although a CVP catheter was
placed in each patient, we managed the fluid input accord-
ing mainly to urine output (i.e., 100 mL urine output using
100 mL of 0.9% saline or Ringer solution supplement). A
positive fluid balance was maintained at a rate of 2
mL/kg/h, in addition to replacement of urine output
with 0.9% saline or Ringer solution, in turn, throughout
the procedure. Blood loss was compensated using 10%
pentastarch at the ratio of 1:1. The criteria for the
performance of blood transfusion were hemoglobin ⬍10
mg/dL or the presence of other clinical indications.
Estimation of Dural Tension and
Cerebral Swelling
Surgeons blinded to the anesthetic techniques assessed the
degree of brain relaxation using a 3-point scale of “tight”
(1), “adequate” (2), and “soft” (3) immediately after open-
ing the dura. In cases in which surgeons were not satisfied
with the degree of brain relaxation after surgical appraisal,
another bolus of the study fluid was administered, unless
contraindicated, and, if necessary, hyperventilation was
initiated to maintain Paco2 values between 30 and 35 mm
Hg. All patients were tracheally extubated when fully
awake and were then transferred to the neurologic ICU.
The time to transfer to a general ward and discharge were
decided by the attending neurologist, who was also blinded
to the study.
The variables measured included (1) amount of study
agent administered, (2) perioperative fluid input and urine
output, (3) hourly recording of laboratory data, including
blood gases and serum sodium concentration, and (4) ICU
stays and hospital days.
Statistical Analyses
Data are presented as the mean ⫾ sd or as the median with
ranges. One-way analysis of variance with repeated mea-
sures and paired Student t test were used for the analysis of
data within each group (fluid input, urine output, blood
loss, and hospital days). Differences between the HTS and
M groups were analyzed using a ␹2 test (demographic
variables), a Mann-Whitney U test (brain relaxation scores),
and an unpaired Student t test with Bonferroni correction
for multiple measurements (fluid input, urine output,
blood loss, and hospital days). A multivariate analysis of
904 www.anesthesia-analgesia.org
Table 1. Patient Characteristics
Group HTS Group M
(n ⴝ 122) (n ⴝ 116) P
Age (y) 56 (18–80) 54 (18–80) 0.23
Male/female 56/66 56/60 0.82
Height (cm) 162 (144–182) 162 (145–185) 0.67
Weight (kg) 57.9 (43–78) 58.7 (42–76) 0.80
ASA physical status 26/96 28/88 0.54
II/III
Data are presented as median and range.
HTS ⫽ hypertonic saline; M ⫽ mannitol.
variance was used for the comparison of changes in serum
sodium over time between the groups. P ⬍ 0.05 was
considered significant.
RESULTS
There were no significant differences between the 2 groups
regarding age, sex, severity of illness, anesthetic time, and
operation time (Tables 1 and 2). The hemodynamics, Paco2,
ETco2, and CVP levels were not significantly different
between the groups (data not shown). The number of brain
conditions classified as soft, adequate, and tight in the HTS
group was 58, 43, and 21, respectively, whereas it was 39,
42, and 35, respectively, in the M group. Brain relaxation
was significantly better in the HTS group compared with
the M group (P ⫽ 0.02). Twenty-one patients in the HTS
group and 35 patients in the M group required the admin-
istration of additional fluids for brain relaxation (P ⫽ 0.02)
(Table 2). There was no significant difference of additional
hyperventilation (Paco2 maintained within 30 –35 mm Hg)
between the 2 groups (8 vs 15; P ⫽ 0.13) (Table 2).
Compared with mannitol, HTS caused an increase in serum
sodium concentration over time (P ⬍ 0.001, Fig. 1). Urine
output was higher in the M group (707 mL; range, 560 –1100
mL) compared with the HTS group (596 mL; range,
350 –980 mL; P ⬍ 0.001). There were no significant differ-
ences in fluid input before opening of the dura, total fluid
input, ICU stays, and hospital days between the 2 groups
(Table 2).
DISCUSSION
In our randomized study, we demonstrated that (1) 3%
HTS provided a more satisfactory brain relaxation than did
mannitol; (2) 3% HTS was associated with a significantly
higher level of serum sodium compared with mannitol; (3)
compared with 3% HTS, mannitol had a more prominent
diuretic effect; and (4) ICU stays and hospital days were
similar between the 2 groups after elective supratentorial
brain tumor surgery.
The physical effects of HTS and mannitol on the brain of
patients with normal ICP have been investigated.11,13
Gemma et al.11 and De Vivo et al.13 reported that HTS and
mannitol both provided satisfactory brain relaxation in
patients undergoing elective craniotomy. These 2 study
populations with normal ICP were similar to ours; how-
ever, different neurosurgical procedures were involved and
nonequiosmolar HTS or mannitol was delivered.
Administration of HTS or mannitol increases serum
sodium concentration or osmolality and decreases ICP and
brain water content in noninjured brain areas, as shown in
ANESTHESIA & ANALGESIA
 Table 2. Surgical and Anesthetic Data
Group HTS (n ⴝ 122) Group M (n ⴝ 116) P
Brain condition (soft/adequate/tight) 58/43/21 39/42/35 0.02
Anesthetic time (min) 299 (168–696) 286 (196–554) 0.19
Operation time (min) 268 (150–656) 257 (149–520) 0.29
Fluid input before opening of the dural (mL) 395 ⫾ 48 384 ⫾ 49 0.1
0.9% Saline 235 ⫾ 48 234 ⫾ 49 0.97
10% Pentastarch 0 0 1
PRBC 0 0 1
3% Saline 160 0
Mannitol 0 150
Total fluids input (mL) 1294 ⫾ 189 1314 ⫾ 166 0.4
0.9% Saline 438 ⫾ 70 442 ⫾ 79 0.66
Ringer’s solution 361 ⫾ 85 362 ⫾ 91 0.88
10% Pentastarch 293 ⫾ 100 300 ⫾ 85 0.55
PRBC 0 (0–150) 0 (0–150) 0.88
3% Saline 160 (160–320) 0
Mannitol 0 150 (150–300)
Total urine output (mL) 596 (350–980) 707 (560–1100) ⬍0.001
Number of patients required additional doses of 3% 21 35 0.02
saline or mannitol (n)
Number of patients required additional 8 15 0.13
hyperventilation (n)
ICU stays (d) 1 (1–3) 1 (1–3) 0.71
Hospital days (d) 6 (5–8) 6 (5–8) 0.86
Data are presented as number, median (range), or mean (SD). Brain condition was subjectively evaluated by the neurosurgeon.
HTS ⫽ hypertonic saline; M ⫽ mannitol; PRBC ⫽ packed red blood cell; ICU ⫽ intensive care unit.

0 means an ideally permeable solute. HTS may present a

Figure 1. Sodium (Na) concentration in arterial blood. Hypertonic
saline (HTS) administration caused an increase in serum Na concen-
tration at points 0, 1, 2, 3, 4, and 5 compared with the baseline
(point ⫺1) and mannitol (#P ⬍ 0.001). In the presence of mannitol,
Na concentration decreased at points 0, 1, and 2 compared with
point ⫺1 (*P ⬍ 0.001). Point ⫺1 indicates the onset of hyperos-
motic solution infusion; point 0 indicates the time of dural opening;
point 1 indicates 1 hour after the end of the infusion; points 2, 3,
and 4 indicate 2, 3, and 4 hours after the end of the infusion; and
point 5 indicates the end of surgery. M ⫽ mannitol.
human and animal studies.1– 4,14 –17 The principal mecha-
nism underlying these effects is the induction of a water
shift from brain tissues to the intravascular space by the
hyperosmolarity of HTS and mannitol because the blood-
brain barrier (BBB) is impermeable to sodium and manni-
tol. The effectiveness of the hyperosmolar solute depends
on its “reflection coefficient” (RC), which determines the
relative impermeability of an intact BBB to the solute. An
RC of 1 means an absolutely impermeable solute and an RC of
theoretical advantage over mannitol because sodium has a
higher osmotic RC than does mannitol (1.0 vs 0.9). A lower
solute leakage may evoke a greater increase in serum
osmolality, and a higher transendothelial osmotic gradient
in the vascular compartment may lead to increased brain
water extraction into the intravascular space. In addition, a
lower RC contributes to lower incidence of rebound cere-
bral edema. In this regard, our data revealed a more
effective brain-bulk reduction associated with HTS versus
mannitol, which is consistent with the classic theory of
hyperosmotic therapy.
Our study showed that 3% HTS was associated with
significantly higher levels of serum sodium and a de-
creased diuretic effect compared with mannitol, which is
compatible with the results of Rozet et al.12 The increase in
serum sodium stimulates the release of antidiuretic hor-
mones, leading to the absorption of free water from the
kidney,18 which may explain the lower diuretic effect of
HTS compared with mannitol. In addition, Rozet et al.12
reported that mannitol had a more prominent diuretic
effect and a less positive or even negative fluid balance,
which was associated with an increase in blood lactate over
time, whereas no changes in blood lactate were observed
after HTS administration. The negative fluid balance in-
duced by mannitol suggests that the increase in lactate
concentration may be secondary to effective hypovolemia.
Because hypovolemia is considered detrimental after brain
injury, HTS solutions have gained renewed interest and,
recently, are administered more frequently in neurocriti-
cally ill patients.19 –25
Together with the hyperosmotic mechanism, the im-
proved blood rheology with shrinkage of erythrocytes, the
decreased cerebrospinal fluid production, and the antiin-
flammatory and other lesser properties associated with
both HTS and mannitol are believed to play a role in their

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Hypertonic Saline and Brain Relaxation
therapeutic action on healthy and injured brains.23,26 How-
ever, it has become popular to view HTS as having some
advantages over mannitol. Oddo et al.27 examined the
effects of mannitol (25%, 0.75 g/kg) and HTS (7.5%, 250
mL) on brain tissue oxygen tension in 12 patients with
refractory intracranial hypertension. They showed that if
these patients exhibited a poor response to previous man-
nitol treatment, the administration of 7.5% HTS as the
second-tier therapy was associated with a significant in-
crease in brain oxygenation and improved cerebral and
systemic hemodynamics. Heimann et al.28 showed HTS
improved cerebral blood flow and reduced the area of
infarction by using a laser Doppler approach in a rat
cerebral ischemia model. Moreover, Taylor et al.29 used a
near-infrared spectrophotometer to show that cerebral ox-
ygenation was restored more rapidly in the HTS-treated
group in a pediatric animal model of head injury and
hemorrhagic shock. The comparison of HTS and mannitol
revealed that the former seems to favor ICP reduction,
brain circulation, cerebral oxygenation, and hemodynamic
stability. In addition, HTS was associated with more pro-
nounced increase in osmolarity30 and decrease in ICP,30,31
which improve brain swelling and cerebral perfusion and
attenuate the progression of secondary brain injury. There-
fore, it was reasonable to presume that the HTS group
would exhibit improved outcomes. However, we did not
detect any significant differences in ICU stays and hospital
days between the 2 groups.
In this study, surgery was performed by 1 of the 3 senior
neurosurgeons. Although serious complications were not
observed, the prognosis of brain tumor surgery was influ-
enced by many factors, including the size and the location
of the tumor, the severity of the adjacent tissue damage, the
residual function after tumor excision, and the immune or
inflammatory responses to the procedure. The results of
ICU stays and hospital days in the 2 groups were similar,
perhaps because (1) these 2 study outcomes were affected
mainly by the factors described above, rather than by the
different effects of HTS and mannitol on brain relaxation;
(2) significant differences may have been present mainly at
the cellular level or at the cognitive function level, which
was beyond the scope of our study; (3) even though HTS
yielded a greater effect on brain relaxation, it is very
important to note that a reduction in brain volume does not
necessarily translate into a better cerebral outcome32; and
(4) the median ICU stays and hospital days was just 1 and
6 days, respectively. Thus, it is possible that the obvious
effects of HTS would be apparent in patients who were
more seriously ill.
Throughout the procedure, we maintained Paco2 be-
tween 35 and 40 mm Hg and ABP within baseline values
⫾20% to avoid the effect of CO2 and ABP on brain bulk
until assessment by the surgeon. It is possible that ABP
fluctuations were manipulated by the blinded anesthesiolo-
gist; however, this is unlikely because no specific hemody-
namic pattern emerged before the surgical appraisal. We
did not measure ICP routinely during elective supratento-
rial brain tumor surgery in clinical practice. Although brain
relaxation can be influenced by ICP, patients with signs of
increased ICP were excluded from the study.
906 www.anesthesia-analgesia.org
HTS solutions have evolved as an alternative to manni-
tol or may be used to manage otherwise refractory intra-
cranial hypertension. Caution is advised for high osmolar
fluid loads because they are associated with an increased
risk of the potentially deleterious consequences of hyper-
natremia or may induce osmotic BBB opening, with pos-
sible harmful extravasation of the hypertonic solution into
the brain tissue.32 However, if administered via an appro-
priate route and at an appropriate dose, it is no more
dangerous than other similar drugs, including mannitol.
Therefore, randomized outcome trials comparing mannitol
with HTS in various subpopulations of patients with neu-
rologic injury would provide valuable information and a
basis for the establishment of the most adequate clinical
applications.
To the best of our knowledge, this is the largest prospec-
tive, double-blind, randomized human study performed to
date that demonstrates the differential effects of HTS and
mannitol on intraoperative brain relaxation. This study is
also unique for using a design that correlates drug admin-
istration with ICU stays and hospital days. We think that
this study design provides an opportunity to test the effect
of equiosmolar 3% HTS and 20% mannitol on brain relax-
ation under a uniform type of intracranial surgery. Within
the limitations of this study, these data allowed us to
conclude that equiosmolar 3% HTS provided more satis-
factory brain relaxation (compared with 20% mannitol)
during elective supratentorial brain tumor surgery.
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