Neurocrit Care (2012) 17:204–210

DOI 10.1007/s12028-011-9574-z

ORIGINAL ARTICLE

Hypertonic Saline Reduces Intracranial Hypertension

in the Presence of High Serum and Cerebrospinal Fluid
Osmolalities
Eduardo Paredes-Andrade • Craig A. Solid •

Sarah B. Rockswold • Rick M. Odland •

Gaylan L. Rockswold

Published online: 2 July 2011

Ó Springer Science+Business Media, LLC 2011

Abstract Methods Forty-two doses of 23.4% saline boluses for

Background Osmotherapy has been the cornerstone in the
management of patients with elevated intracranial pressure
(ICP) following traumatic brain injury (TBI). Several
studies have demonstrated that hypertonic saline (HTS) is a
safe and effective osmotherapy agent. This study evaluated
the effectiveness of HTS in reducing intracranial hyper-
tension in the presence of a wide range of serum and
cerebrospinal fluid (CSF) osmolalities.
E. Paredes-Andrade
S. B. Rockswold
G. L. Rockswold (&)
Division of Neurosurgery, Department of Surgery, Hennepin
County Medical Center, 701 Park Avenue, Minneapolis,
MN 55415, USA
e-mail: gaylan.rockswold@hcmed.org
C. A. Solid
Chronic Disease Research Group, Analytical Services,
Minneapolis Medical Research Foundation, Minneapolis, MN,
USA
S. B. Rockswold
Department of Physical Medicine and Rehabilitation, Hennepin
County Medical Center, Minneapolis, MN, USA
treatment of refractory intracranial hypertension were
reviewed retrospectively. Thirty milliliters of 23.4% NaCl
was infused over 15 min for intracranial hypertension,
defined as ICP >20 mmHg. The CSF and serum osmo-
lalities from frozen stored samples were measured with an
osmometer. The values of serum sodium, hourly ICP,
blood urea nitrogen (BUN), and creatinine were obtained
directly from the medical records.
Results The serum and CSF osmolalities correlated
very closely to serum sodium (r > 0.9, P < 0.0001). The
reduction in ICP from the baseline (measured from either
the mean ICP or the lowest ICP measurement in the first
6 h after bolus HTS treatment) was statistically significant
regardless of serum osmolality. The mean reduction
from baseline to follow-up values was 8.8 mm Hg
(P < 0.0001). The decrease in ICP was as evident with
serum osmolalities >320 as it was at B320.
Conclusion This study demonstrates that 23.4% HTS
bolus is effective for the reduction of elevated ICP in
patients with severe TBI even in the presence of high
serum and CSF osmolalities.

R. M. Odland Keywords Cerebrospinal fluid osmolality

Department of Otolaryngology, Hennepin County Medical
Hypertonic saline
Intracranial pressure
Osmotherapy

Center, Minneapolis, MN, USA
Serum osmolality
Traumatic brain injury
R. M. Odland
Department of Otolaryngology, University of Minnesota,
Minneapolis, MN, USA
Introduction
G. L. Rockswold
Department of Neurosurgery, University of Minnesota, Osmotherapy has been the cornerstone in the management
Minneapolis, MN, USA of patients with elevated intracranial pressure (ICP) fol-
lowing traumatic brain injury (TBI) [1]. In 1919, Weed and
S. B. Rockswold
Department of Physical Medicine and Rehabilitation, University McKibben [2] described the effect of hypertonic saline
of Minnesota, Minneapolis, MN, USA (HTS) in animal models for the first time. They noted that

123
Neurocrit Care (2012) 17:204–210 205

the intravenous injection of 30% HTS was followed by

18 patients
a marked decrease in the size of the brain. However,
42 23.4% dosesa
mannitol has been widely used in clinical practice for
osmotherapy since the 1960s and has been the traditional
osmotic agent of choice for the control of elevated ICP 1 23.4% doseb 5 23.4% dosesc
excluded excluded
[3, 4]. Recently, HTS has emerged as a potential alternative
to mannitol [5–10]. 18 patients
Osmotic agents elevate serum osmolality which creates 36 23.4% dosesd
an osmotic gradient that pulls water out of the brain into
the capillaries. This mechanism largely depends on an
intact blood brain barrier (BBB) [11, 12]. Mannitol can be
associated with the development of acute tubular necrosis
and renal failure. The risk is increased if serum osmolality 35 CSF osmolalities 31 Serum osmolalities
exceeds 320 mOsm/l or if patients have other predisposing correlated with ICP correlated with ICP
risk factors for renal failure (e.g., arterial hypotension, values values
preexisting renal disease, sepsis) [13, 14]. It is recom-
mended that during mannitol therapy the serum osmolality Fig. 1 Flow chart illustrating the number of 23.4% HTS doses and
be maintained below 320 mOsm/l [15]. Mannitol can also CSF and serum osmolalities excluded from the analysis in 18 patients
with severe TBI. aNumber of patients and doses of HTS on which the
accumulate in the brain tissue in areas with disrupted BBB correlations between the serum sodium, serum osmolality and serum
after multiple administrations, reversing osmotic gradients CSF were done. bNumber of doses of HTS excluded because neither
and exacerbating cerebral edema [16]. CSF or serum osmolalities were available. cNumber of doses of HTS
Several clinical investigations have indicated that HTS excluded because they were administrated less than 6 h after the last
dose. dNumber of patients and doses of HTS on which the correlations
appears effective and safe at serum osmolalities of up to between the serum and CSF osmolalities and reduction in ICP were
365 mOsm/kg and serum sodium levels of 170 mEq/l done
[8, 17, 18]. Accordingly, osmolality and sodium levels in
serum and cerebrospinal fluid (CSF) osmolalities from
patients with severe TBI, receiving 23.4% saline for received 23.4% HTS at serum osmolalities B320 and
intracranial hypertension were evaluated. The study was >320). The ICP, mean arterial pressure (MAP), and
designed to test the hypothesis that HTS therapy creates an cerebral perfusion pressure (CPP) were recorded hourly.
osmotic gradient which is equally effective in decreasing The lowest measurement of ICP and the mean ICP calcu-
ICP at both normal or high serum and CSF osmolalities. lated for the first 6 h after the bolus HTS were used in the
analysis.
The patients’ clinical characteristics are summarized in
Clinical Materials and Methods Table 1. The mean age of patients was 35 years, and the
majority (88%) was males. The median Glasgow Coma
A retrospective chart review of 18 patients was undertaken
to analyze the correlation between the serum sodium and
serum/CSF osmolality to the response of elevated ICP to Table 1 Demographic characteristics in 18 patients with TBI who
bolus HTS. The protocol for this study was approved by the received 23.4% saline
Human Subjects Research Committee at our institution. Characteristics Value
Patients were selected because a CSF osmolality value was
Mean age in years (range) 35 (17–67)
available at approximately the time when at least one HTS
Gender (female/male) 2/16
dose was administered to that particular patient (Fig. 1).
Post-resuscitation GCS score (median) 6
A total of 42 doses of 23.4% of HTS were given to the 18
patients for refractory intracranial hypertension. Five doses Multiple trauma (%) 10 (56)
were excluded because boluses of HTS were administrated Total number of bolus HTS doses (range) 42 (1–7)
less than 6 h after the last dose. Of the remaining 37 23.4% Days (mean) of bolus HTS treatment (range) 3 (1–5)
HTS doses, two were missing CSF osmolalities, four were Outcome (GOS) at 6 months (%)
missing serum osmolalities, and in one dose, both the CSF Death 6 (35)
and serum osmolalities values were not available (Fig. 1). Favorable outcomea 9 (53)
Thirteen out of 18 patients received 22 23.4% HTS boluses GOS Glasgow Outcome Scale
at serum osmolalities B320 mOsm and 6 patients received a
Favorable outcome is defined by good recovery and moderate
9 doses at serum osmolalities >320 mOsm (One patient disability on the GOS

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206
Score (GCS) score was 6 in this group after resuscitation.
Bolus HTS treatment was administered over a mean of
3 days (range 1–5 days). All 18 patients with severe TBI
were evaluated and stabilized in the Emergency Depart-
ment and admitted to the Surgical Intensive Care Unit
(SICU) at Hennepin County Medical Center. Severe TBI
was defined as a GCS B8 after resuscitation. This score
was determined when no effects from paralytic agents,
sedation, alcohol, and/or street drugs were present. Medical
management of the intracranial hypertension involved a
coordinated, stepwise approach including head elevation,
mild hyperventilation, CSF drainage, analgesia, and seda-
tion [15]. The HTS solutions have routinely been used in
our patients with severe TBI to treat intracranial hyper-
tension [8]. If the ICP remained >20 mmHg for more than
20 min in the absence of noxious stimulation, a 30 ml of
23.4% saline bolus was administered intravenously over
15 min via a central line. Serum osmolality, blood urea
nitrogen (BUN), and creatinine were measured daily.
Sodium and potassium were measured every 6 h.
The CSF samples were taken from the buretrol of the
ventriculostomy and immediately chilled at 4°C, processed
within 15 min of collection and centrifuged to remove
cells, and aliquoted. The CSF was frozen at -80°C and
stored. The CSF samples were taken 2–3 times a day for 3
days following injury. The same process was carried out
with serum samples taken at the same time as the CSF. The
serum and CSF samples were thawed, and their osmolali-
ties were measured in our research laboratory with a Vapro
Vapor Pressure Osmometer Model 5520 (Wescor, Inc.,
Logan, Utah). The measurements were made in triplicate,
and the values were averaged to obtain the representative
osmolality in each case. The values of serum sodium used
for the analysis were obtained from medical records. Three
serum osmolalities that were not measured directly in our
Fig. 2 Scatterplot showing the 360
relationship between the serum
osmolality and CSF osmolality. 350
There is a significant direct
340
CSF Osm (mOsm/kg)
correlation (r = 0.95882,
P < 0.0001)
330
320
310
300
290
280
270
270
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Neurocrit Care (2012) 17:204–210
research laboratory were calculated based on serum levels
of sodium, potassium, glucose, and urea of those patients.
The mean time of administration of HTS was 2.5 ±
17.3 min after the CSF was taken.
In order to assess the linear relationship between pairs of
variables without adjusting for confounding factors, a
simple correlation coefficient provided the necessary
information. Therefore, the correlation coefficients were
calculated and variables were considered to have a statis-
tically significant linear association if the P value
corresponding to the correlation was <0.05. In general,
correlations the absolute values of which are <0.3 are
considered weak, while those between 0.3 and 0.7 are
considered intermediate, and those above 0.7 are consid-
ered strong. This principle was not necessary to apply to
our data since calculated correlations indicated either a
very weak (absolute value <0.1) or a very strong (absolute
value >0.9) linear association between variables. To
compare the mean change in ICP from baseline between
the two osmolality groups (B320 mOsm or >320 mOsm)
a two-sample t test was used. All statistical calculations
were done using SAS v9.1 (Cary, NC).
Results
Cerebrospinal osmolality correlated very closely with
serum osmolality (r = 0.96, P < 0.0001) (Fig. 2). Serum
sodium correlated with both serum osmolality (r = 0.94,
P < 0.0001), and CSF osmolality (r = 0.92, P < 0.0001).
When analyzing the change in ICP against the level of
either serum osmolality or CSF osmolality, no appreciable
pattern could be identified, demonstrating that the reduc-
tion in ICP from the baseline (whether it was the lowest
280 290 300 310 320 330 340 350 360
Ser. Osm at time of CSF (mOsm/kg)
Neurocrit Care (2012) 17:204–210 207

ICP measurement or mean ICP) had no association with Table 3 Comparison of ICP reductions by serum osm. level and
the level of osmolality reached. Similar results were BUN, creatinine and GFR values after 23.4% HTS bolus
found when using serum sodium instead of osmolality. Serum osmolality (mOsm/kg) B320 >320 P value
Bolus HTS was effective in reducing intracranial hyper-
N patients 13a 6a
tension in the presence of the highest serum and CSF
osmolalities achieved (348 and 349 mOsm, respectively). N doses 22 9
Correlation coefficients reinforce this finding with values Reduction to mean ICP
ranging from 0.01 to 0.47, all with non-significant Mean (mmHg) -8.50 -9.56 0.6090
P values (Table 2). Standard error 1.03 1.97
The mean reductions of both the lowest ICP measure- P value <0.0001 0.0013
ment and the mean ICP over the 6-h posttreatment were Reduction to lowest ICP measurement
statistically significant, regardless of baseline serum Mean (mmHg) -11.82 -13.0 0.6384
osmolality (Table 3). Thirty-six of the baseline ICP values Standard error 1.28 2.32
were between 20 and 29 mmHg and 6 of the baseline ICP P value <0.0001 0.0005
values were between 30 and 42 mmHg. For patients with BUN (mg/dl) (range) 5–16 3–23
serum osmolalities B320, the mean reduction of the mean Creatinine (mg/dl) (range) 0.5–1.0 0.7–1.2
follow-up ICP was 8.5 mmHg (P < 0.0001), and the mean GFR (ml/min/1.73 m2) (range) 83–143 66–127
reduction of the lowest ICP measurement was 11.8 mmHg a
One patient received 23.4% HTS at serum osmolalities B320
(P < 0.0001); for patients with serum osmolalities >320, and >320
those reductions were 9.6 mmHg (P = 0.0013) and
13.0 mmHg (P 0.0005), respectively. Further statistical
tests on these data reveal that the mean reductions from Discussion
baseline ICP experienced by each group were similar
(mean ICP for serum osmolalities B320 vs. serum osmo- To our knowledge, this is the first clinical study correlating
lalities >320, P = 0.6090; as well as the lowest ICP serum sodium levels, as well as serum and CSF osmolali-
measurement for serum osmolalities B320 vs. serum ties, with the reduction in ICP achieved by bolus HTS in
osmolalities >320, P = 0.6384). Therefore, the reduction patients with severe TBI. The results of our study dem-
of ICP with bolus 23.4% HTS was as robust in the presence onstrated that serum and CSF osmolalities vary directly
of serum osmolalities >320 mOsm as it was at B to with the serum sodium level, and the CSF osmolality varies
320 mOsm. directly with the serum osmolality. This finding was true
Nine patients reached serum osmolalities above even in patients who received 23.4% boluses for up to
320 mOsm, and their creatinine levels were within normal 5 days. This study also demonstrated the effectiveness of
limits after 23.4% HTS boluses were administrated. Using 23.4% HTS in reducing ICP at a wide range of serum
the values of creatinine and demographic data, glomerular osmolalities, from slightly elevated to values close to
filtration rate (GFR) was estimated using the Chronic 350 mOsm/kg. There was no correlation between serum
Kidney Disease Epidemiology Collaboration (CKD-EPI) osmolality level and the incidence of intracranial
equation [19]. The values found were above 60 ml/min/ hypertension.
1.73 m2. None of the patients had evidence of previous Cerebral edema is defined as an increase in cerebral water
kidney disease. One patient developed renal failure sec- content [20]. The aim of osmotherapy for cerebral edema is
ondary to sepsis before his death. No patients developed to create an osmotic gradient between the blood and brain
hyperchloremic metabolic acidosis. The overall mortality tissue to cause egress of water into the vascular compart-
at 6 months was 35%, and a favorable Glasgow Outcome ment. The osmotic effectiveness across the BBB can be
Scale (GOS) score was achieved in 53% of patients. A expressed by the osmotic reflection coefficient of a given
favorable outcome is defined by good recovery or moderate solute. The reflection coefficient gives a measure of a sol-
disability on the GOS (Table 1). ute’s permeability to the BBB and varies between 0 (freely
permeable) and 1 (completely impermeable) [1]. Mannitol
Table 2 Correlation coefficients for the association of ICP reduction has a reflection coefficient of 0.9 while sodium chloride has
to osmolality a reflection coefficient of 1, making it theoretically an ideal
Variable 1 Variable 2 Correlation P value osmotic agent and more effective than mannitol. The more
permeable an osmotic agent is to the BBB, the greater the
Serum osmolality ICP baseline to mean ICP 0.03103 0.8595
risk of the rebound phenomenon [12, 21].
CSF osmolality ICP baseline to mean ICP 0.470 0.7887
Sodium is the major extracellular cation and is the
Serum sodium ICP baseline to mean ICP 0.01825 0.9171
most important determinant of both plasma osmolality

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208
(approximately 95%) and CSF osmolality [11, 22]. The
CSF sodium concentrations are usually slightly higher than
those of serum and correlate with serum sodium concen-
tration fluctuations [23, 24]. The CSF and the interstitial
fluid (ISF) that surrounds the cells of the brain comprise the
total extracellular fluid of the brain. Both CSF and ISF
have similar chemical composition [25, 26]. The osmotic
concentrations of intracellular and extracellular fluids are
also equal under steady state conditions [27]. Changes in
intracellular or extracellular solute concentrations generate
a transmembrane osmotic gradient. Because cell mem-
branes are permeable to water, any such gradient change
results in the immediate flow of water into or out of the cell
until osmotic equilibrium is restored [27].
The guidelines for the management of severe TBI
published by the Brain Trauma Foundation recommend
caution in the use of mannitol in patients with severe TBI if
the serum osmolality exceeds 320 mOsm because of the
risk of renal failure [15]. The mechanism of acute renal
failure is probably due to severe vasoconstriction of renal
afferent arterioles as a consequence of mannitol accumu-
lation in the extracellular space [14]. Becker and Vries [13]
found in their study using mannitol that 7 of 9 patients who
required a serum osmolality over 320 mOsm to reduce ICP
below 25 mmHg died. The main cause of death in those
patients was increased ICP because osmotherapy could not
be continued because of renal failure in three cases and
systemic acidosis in five cases.
There are a limited number of studies on the efficacy
and safety of HTS relative to the serum sodium levels and
serum osmolalities achieved in patients with intracra-
nial hypertension secondary to severe TBI. Recently,
Rockswold et al. reported the beneficial effects following
treatment with 23.4% HTS in patients with severe TBI with
intracranial hypertension. In that study, 23 of 25 patient’s
serum osmolality levels were C320 mOsm/kg, and in 10 of
25 patients, serum osmolality reached C340 mOsm/kg. No
renal failure developed in any of the patients treated with
23.4% HTS. The ICP levels >20 mmHg were consistently
reduced by a mean >8 mmHg [8]. Previous studies in
pediatric patients with severe TBI using continuous infu-
sions of 3% HTS demonstrated that the serum sodium and
serum osmolality levels significantly correlated with the
decrease in ICP [17, 18, 28]. Simma et al. performed a
randomized prospective study in 35 children with severe
TBI using HTS versus lactated Ringer’s over the first
3 days after injury. They found that patients treated with
HTS required fewer interventions to control ICP than those
treated with lactated Ringer’s. They concluded that an
increase in serum sodium concentrations up to 160 mEq/l
significantly correlates with lower ICP and higher CPP
[28]. Peterson et al. reported a retrospective study on the
use of continuous infusion of 3% HTS in 68 children with
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Neurocrit Care (2012) 17:204–210
closed TBI. The mean serum sodium concentration for all
patients was 160 mEq/l (range of 140–182 mEq/l), and the
mean serum osmolality was 331 (range of 278–382 mOsm/l).
The ICP was decreased to <20 mmHg for a majority of
the time [18]. Khanna et al. reported a prospective study
using 3% HTS in 10 children with increased ICP resistant
to conventional therapy. The mean highest serum sodium
was 170.7 mEq/l (range of 157–187 mEq/l), and the mean
highest serum osmolarity was 364.8 mOsm/l (range of
330–431 mOsm/l). A statistically significant decrease in
ICP and CPP occurred. Two patients developed acute renal
failure. However, there were concurrent episodes of sepsis
and multiple system organ dysfunction. Both recovered full
renal function [17].
It is known that the administration of 23.4% HTS cre-
ates a marked osmotic gradient between the blood and the
brain tissue. This gradient produces the movement of water
from the brain interstitial space and/or intracellular space
into the intravascular spaces in the intact or even injured
areas of the brain [29]. In our study, there was no corre-
lation between the degree of decrease of ICP from bolus
HTS and the level of serum and CSF osmolalities. This
finding implies that bolus HTS is capable of producing an
osmotic gradient across the BBB even in the presence of
high serum and CSF osmolalities. Bolus infusions of HTS
have proved to be effective in controlling intracranial
hypertension even after repeated (up to 17) administrations
[8]. The ongoing efficacy of HTS may be due to the
presence of elimination pathways in the brain for sodium
and chloride which are not available for mannitol. Thus,
passive and active transport across the BBB, glial uptake,
redistribution mechanisms, and resorption into the CSF
compartment may effectively counteract accumulation of
HTS in brain tissue [30, 31]. Our findings suggest that there
is no relative accumulation of sodium in the brain relative
to the intravascular space.
In contrast, in a study of humans, Palma et al. [32] found
a considerably higher peritumoral white matter mannitol
concentration relative to the plasma in patients with glio-
mas. Sankar et al. [33] reported the first case of mannitol
accumulation within a meningioma and within the brain
parenchyma around the tumor using in vivo magnetic
resonance spectroscopy. Owing to its reflection coefficient,
mannitol accumulates in brain tissue with time in patients
with a normal BBB [34]. In the presence of BBB damage,
higher quantities of mannitol enter the brain tissue and
CSF. There is pharmacological evidence that mannitol is
not metabolized by the brain, and it possesses a slow
elimination from CSF [35]. When mannitol is acutely
discontinued, serum osmolality decreases much faster than
CSF osmolality reversing the osmotic gradient between the
serum and CSF [36]. The consequent accumulation of
mannitol in the brain tissue and CSF, after repeated doses,
Neurocrit Care (2012) 17:204–210
elucidates the ineffectiveness of mannitol in lowering ICP
over time and the subsequent exacerbation of cerebral
edema [16].
Conclusion
In this study, intracranial hypertension reduction by bolus
23.4% HTS administration appeared as effective at high
serum and CSF osmolalities as at more normal levels.
Clinically, this finding means HTS continues to be effec-
tive in reducing ICP at relatively high serum and CSF
osmolality levels. Confirmation of this result is required in
a larger group of patients. The rate of favorable outcome in
this group of patients was good, considering the patients
had intracranial hypertension. This study is another con-
tribution to the growing evidence of the beneficial effects
of HTS.
Disclosure The authors have no personal financial or institutional
interest in any of the drugs, materials, or devices described in this
article.
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