Hypertonic Saline for Cerebral Edema and Elevated Intracranial Pressure: A Review

Hypertonic saline is a potential treatment for cerebral edema and elevated intracranial pressure. It offers advantages over current modalities but has associated adverse events. Animal studies demonstrate its efficacy in reducing intracranial pressure, while human studies show promising results in conditions such as stroke, intracranial hemorrhage, and traumatic brain injury. However, further research is needed, and potential adverse effects include rebound edema, BBB disruption, excess neuronal death, and alterations in consciousness.

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Cerebral edema and elevated intracranial
pressure (ICP) are important and frequent
problems in the neurocritically ill patient.
They can both result from various insults
to the brain. Improving cerebral edema and decreas-
ing ICP has been associated with improved out-
come.1 However, all current treatment modalities
are far from perfect and are associated with serious
adverse events:1–4 indiscriminate hyperventilation
can lead to brain ischemia; mannitol can cause
intravascular volume depletion, renal insufficiency,
and rebound ICP elevation; barbiturates are associat-
ed with cardiovascular and respiratory depression
and prolonged coma; and cerebrospinal fluid (CSF)
drainage via intraventricular catheter insertion may
result in intracranial bleeding and infection.
Other treatment modalities have been explored,
and hypertonic saline (HS) solutions particularly
appear to be an appealing addition to the current
therapeutic avenues for cerebral edema. This article
succinctly reviews some of the basic concepts and
mechanisms of action of HS and discusses some of
its possible clinical applications.
■ PHYSIOLOGIC CONTEXT
The blood-brain barrier
The blood-brain barrier (BBB) represents both an
anatomic and a physiologic structure. The BBB is
made up of tight junctions between the endothelial
cells of the cerebral capillaries.5 Various mechanisms
exist for compounds to cross the BBB, including
activetransport,diffusion,and carrier-mediated
movements. Because transport through the BBB is a
selective process, the osmotic gradient that a particle
can create is also dependent on how restricted i
permeability through the barrier is. This restriction is
expressed in the osmotic reflection coefficient, wh
ranges from 0 (for particles that can diffuse freely) to
1.0 (for particles that are excluded the most effe
tively and therefore are osmotically the most active).
The reflection coefficient for sodium chloride is
1.0 (mannitol’s is 0.9), and under normal conditions
sodium (Na+
) has to be transported actively into the
CSF.5,6 Animal studies have shown that in condi-
tions of an intact BBB, CSF Na+ concentrations
increase when an osmotic gradient exists but lag
behind plasma concentrations for 1 to 4 hours.5
Thus, elevations in serum Na+ will create an effec-
tive osmotic gradient and draw water from brain into
the intravascular space.
Cerebral edema and intracranial dynamics
Cerebral edema is defined as an increase in brai
water leading to an increase in total brain mass.7
There are three major categories of brain edema:
• Vasogenic edema, which is caused by increas
permeability of the endothelial cells of brain capil-
laries and is seen in patients with brain neoplasms
• Cytotoxic edema, which results from the influx of
water into cells. This type of edema may be caused
by energy depletion with failure of the ATP-depen-
dent Na+
-K+ pump (ie, cerebral infarction) or low
extracellular Na+ content (ie, hyponatremia).
• Interstitial edema, in which CSF diffuses through
the ependymal lining of the ventricles into the
periventricular white matter. This type of edema
is seen with hydrocephalus.
It is important to point out that different types of
edema can coexist in the same patient. For instance,
brain ischemia is associated with both cytotoxic and
vasogenic edema.
The presence of cerebral edema, with the subse-
Hypertonic saline for cerebral edema
and elevated intracranial pressure
JOSE´ I. SUAREZ, MD
From the Department of Neurology and Neurosurgery, Uni-
versity Hospitals of Cleveland and Case Western Reserve
University, Cleveland, Ohio.
Address: Jose´ I. Suarez, MD, Department of Neurology, Uni-
versity Hospitals of Cleveland,11100 Euclid Avenue,
Cleveland, OH 44106; e-mail:[e-mail].

quent increase in brain mass, alters the intracranial
contents (brain, blood, and CSF). Small increases
in brain volume can be compensated by changes in
CSF volume and venous blood volume. Beyond
that, changes in intracranial volume (ΔICV) will
result in changes in ICP (ΔICP), which has been
termedcompliance(ΔICV/ΔICP). When brain
compliance decreases, such as when intracranial
volume rises, ICP rises.8 However, it is important to
realize that focal cerebral edema can create ICP gra-
dients and cause tissue shifts in the absence of a
global increase in ICP.1
■ HYPERTONIC SALINE: MECHANISMS OF ACTION
HS solutions can possibly affect the volume of the
intracranial structures through various mechanisms.
All or several of them are likely to be interacting to
achieve the end result of HS therapy: reduction of
cerebral edema and elevated ICP. These mecha-
nisms are summarized below:
• Dehydration of brain tissue by creation of an
osmoticgradient,thus drawingwaterfrom the
parenchyma into the intravascular space. As men-
tioned above, this would require an intact BBB.
Experimentalevidencesuggeststhat the brain
water–reducing properties of HS are accomplished
at the expense of the normal hemisphere.
• Reduced viscosity. HS solutions enhance intra-
vascular volume and reduce viscosity.9 The autoreg-
ulatory mechanisms of the brain vasculature have
been shown to respond not only to changes in blood
pressure but also to changes in viscosity.10 Thus, a
decrease in blood viscosity results in vasoconstric-
tion in order to maintain a stable cerebral blood
flow (CBF).
• Increased plasma tonicity. It has been postulated,
based on experimental animal data, that increased
plasma tonicity, such as that seen after HS adminis-
tration, favors more rapid absorption of CSF.11
• Increased regional brain tissue perfusion, possi-
bly secondary to dehydration of cerebral endothelial
cells and erythrocytes, facilitating flow through cap-
illaries.12
• Increased cardiac output and mean arterial blood
pressure, with resultant augmentation of cerebral
perfusion pressure, most likely due to improvement
of plasma volume and a positive inotropic effect.9,13
• Diminishedinflammatoryresponseto brain
injury,which has beendemonstratedwith HS
administration.14
• Restorationof normalmembranepotentials
through normalization of intracellular sodium and
chloride concentrations.13
• Reduction of extravascular lung volume, lead-
ing to improved gas exchange and improved PaO2.15
■ EXPERIMENTAL SUPPORT FOR THE EFFICACY
OF HYPERTONIC SALINE
Animal studies
HS solutions have been studied extensively in a
variety of animal models, as thoroughly detailed in
a recent review.13 The literature suggests that fluid
resuscitation with an HS bolus after hemorrhagic
shock prevents the ICP increase that follows resus-
citation with standard colloid and crystalloid fluids
for 2 hours or less. This effect can be maintained for
longer periods by using a continuous HS infusion.
HS may be superior to colloid solutions with regard
to ICP response during the initial period of resusci-
tation.16,17In animal models of cerebral injury, the
maximal ICP-reducing effect of HS is appreciated
with focal lesions, such as cryogenic injury or intra-
cerebral hemorrhage. Again, the ICP reduction may
be caused by reduction in water content in areas of
the brain with the BBB intact, such as the nonle-
sioned hemisphere and the cerebellum. HS has also
been compared with mannitol and was found to
have equal efficacy in reducing ICP but to have a
longerdurationof action and to yield greater
improvement in cerebral perfusion pressure.13
Human studies
Despite the numerous studies in animal models,
most of the evidence in humans is based on the pub-
lication of case series and a few randomized studies.
Some of the published studies are briefly reviewed
here. Readers are referred to a recent review13 for a
more detailed description.
Acute ischemic stroke. HS in two different con-
centrations, 7.5% and 10%, has been used to reduce
ICP in patientsafter largecerebralinfarcts.18,19
Schwarz et al18 compared the effect of 100 mL of
7.5% HS hydroxyethyl starch (osmolarity 2,570
mosm/L) and 200 mL of 20% mannitol (osmolarity
1,100 mosm/L) in 9 patients with stroke randomized
to one of the two treatments. HS hydroxyethyl
starch caused a greater and earlier peak reduction in
ICP, although mannitol caused more improvement
in cerebral perfusion pressure.These same
researchers studied the effect of 10% saline bolu
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infusionsin 8 patientsin whom mannitolhad
failed.19 HS reduced ICP by at least 10% in all the
instances it was used, and the maximal effect was
noted at 20 minutes after the end of the infusion.
Even though ICP rose subsequently, it did not reach
pretreatment values during the 4 hours of data
recording.
Intracranial hemorrhage.There has been one
report of 2 patients with nontraumatic (presumably
hypertensive) intracranial hemorrhage who were
treatedwith continuousHS infusion.20 Both
patients improved clinically after 24 hours of treat-
ment but deteriorated at 48 and 96 hours despite
continuedHS infusion. RepeatCT scanning
showed extension of edema. These findings were
attributedto a reboundeffectsimilarto that
described with mannitol.
Subarachnoidhemorrhage.Two studieshave
been published on the effect of HS on clinical
improvement and CBF in patients with subarach-
noid hemorrhage.9,21 Suarez et al21 retrospectively
studied 29 patients with symptomatic vasospasm
and hyponatremia who received continuous infu-
sions of 3% saline. They found that a positive fluid
balance was achieved, and there was short-term
clinical improvement without adverse effects. Tseng
et al9 studied the effect of 23.5% saline bolus infu-
sions on CBF, ICP, and cerebral perfusion pressure
in 10 patients with poor-grade subarachnoid hemor-
rhage. They found that HS caused a significant
decrease in ICP and a significant rise in blood pres-
sure with a subsequent increase in cerebral perfusion
pressure. These effects were accompanied by a sig-
nificant elevation in CBF as determined by trans-
cranial Doppler ultrasonography and xenon CT.
The ICP-lowering effect occurred immediately after
the infusion and continued for more than 200 min-
utes. The increase in blood flow velocities lasted
175 to 450 minutes.
Traumatic brain injury. Most of the human stud-
ies have been in patients with traumatic brain
injury. Although there is no agreement on the
appropriateconcentration,dose,or durationof
treatment, HS has been reported to have a benefi-
cial effect on elevated ICP in patients after trau-
matic brain injury.22–33Most of the reported studies
are limited by small sample size and the use of vari-
ous concentrations of HS. The use of HS in patients
with traumatic brain injury deserves more atten-
tion, and well-designed studies are needed.
Miscellaneous conditions.Other investigators
have reported on the use of HS in patients with var-
ious intracranial pathologies.34–37
Gemma et al34 performed a prospective, random-
ized comparison of 2.5 mL/kg of 20% mannitol and
7.5% saline in patients undergoing elective supra-
tentorial procedures. They found that the two treat-
ments had similar effects on CSF pressure and o
clinical assessment of brain bulk. However, the
administered solutions used were not equiosmolar.
In a retrospective study, Qureshi et al35determined
the effect of continuous 3% saline/acetate infusio
on ICP and lateral displacement of the brain in
patients with cerebral edema and a variety of under-
lying cerebral lesions. The authors found a reduction
in mean ICP within the first 12 hours, correlating
with an increase in serum sodium concentration, in
patients with traumatic brain injury and postopera-
tive edema, but not in patients with nontraumatic
intracranial hemorrhage or cerebral infarction. This
beneficial effect was not apparent at later intervals.
In a retrospectivereviewof 8 patientswith
intracranial hypertension refractory to hyperventi-
lation, mannitol, and furosemide, Suarez et al36
showed that bolus administration of 23.4% saline
was effective in reducing ICP and raising cerebra
perfusion pressure. The effect was still present at 3
hours after administration of the HS solution.
Horn et al37 reported on the administration of
7.5% saline boluses in patients with subarachnoid
hemorrhage or traumatic brain injury and refractory
intracranial hypertension. The authors demonstrat-
ed an increase in cerebral perfusion pressure and a
decrease in ICP. The maximal drop in ICP was
observed at a mean of 100 minutes after the bolus
was given.
■ ADVERSE EFFECTS
The administration of HS has been associated with
potential adverse effects, both theoretical and real,
as summarized below.
Intracranial complications
• Rebound edema can occur as a result of continu-
ous infusion.
• Disruption of the BBB (“osmotic opening”) may
be due to the shrinking of endothelial cells and a
loosening of the tight junctions that form the
BBB,38or to an increase in pinocytotic activity and
possibly an opening of transendothelial channels.39
• The possibility of excess neuronal death has been
postulatedafter continuousinfusionof 7.5%
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saline in a rat model of transient ischemia.40 This
has not been proven.
• Alterations in the level of consciousness associat-
ed with hypernatremia.6 Also, other intracranial
alterations have been reported in children with
fatal hypernatremia,includingcapillaryand
venous congestion; intracerebral, subdural, and
subarachnoid bleeding; and sagittal sinus and cor-
tical vein thrombosis with hemorrhagic infarction.
Severe hypernatremia (> 375 mosm/L) has been
found to cause similar changes in animal models.6
• Central pontine myelinolysis is a syndrome typi-
cally associated with too-rapid correction of (in
most cases chronic) hyponatremia.41 Such grave
complications have not been reported in associa-
tion with the use of HS in humans.
Systemic complications
• Congestive heart failure can be precipitated sec-
ondary to volume expansion.35
• Transient hypotension is possible after rapid intra-
venous infusions, but it is followed by an elevation
in blood pressure and cardiac contractility.42
• Decreasedplateletaggregationand prolonged
prothrombin times and partial thromboplastin
times have been reported with large-volume infu-
sion of HS.43
• Hypokalemia and hyperchloremic metabolic acido-
sis can be seen with infusion of large quantities of
HS solutions but can be avoided by adding potas-
sium and acetate, respectively, to the infusion.36
• Phlebitis can be avoided by infusing HS solutions
through a central venous catheter
• Renal failure was reportedto occur with
increased incidence in a single study.44
■ SUMMARY
The use of HS solutions has been shown to reduce
ICP both in animal models and in human studies in
a variety of underlying disorders, even in cases
refractory to treatment with hyperventilation and
mannitol. There are several possible mechanisms of
action, and important complications such as central
pontine myelinolysis and intracranial hemorrhage
have not beenreportedin the humanstudies.
Different types of HS solutions with different meth-
ods of infusion (bolus and continuous) have been
used in the past, and so far there are not enough
data to recommend one concentration over anoth-
er. Many issues remain to be clarified, including the
exact mechanism of action of HS, the best mode of
administration and HS concentration to be given,
and the relative efficacy of HS vis-a`-vis available
treatments, particularly mannitol.
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