Journal of Intensive

Care Medicine
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Hypertonic Saline and Mannitol Therapy in Critical Care Neurology

Holly E. Hinson, Deborah Stein and Kevin N. Sheth
J Intensive Care Med 2013 28: 3 originally published online 24 March 2011
DOI: 10.1177/0885066611400688
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Analytic Reviews

Hypertonic Saline and Mannitol

Therapy in Critical Care Neurology

Journal of Intensive Care Medicine

28(1) 3-11
The Author(s) 2013
Reprints and permission:
sagepub.com/journalsPermissions.nav
DOI: 10.1177/0885066611400688
http://jicm.sagepub.com

Holly E. Hinson, MD1, Deborah Stein, MD, MPH, FACS2, and

Kevin N. Sheth, MD3

Abstract
Osmotic agents play a vital role in the reduction of elevated intracranial pressure and treatment of cerebral edema in Neurologic
critical care. Both mannitol and hypertonic saline reduce cerebral edema in many clinical syndromes, yet there is controversy over
agent selection, timing, and dosing regimens. Despite the lack of randomized, controlled trials, our knowledge base on the
appropriate clinical use of osmotic agents continues to expand. This review will summarize the evidence for the use of
mannitol and hypertonic saline in a variety of disease states causing cerebral edema, as well as outlining monitoring and safety
considerations.
Keywords
mannitol, hypertonic saline, osmotic therapy, cerebral edema
Received July 7, 2010, and in revised form September 20, 2010. Accepted for publication October 12, 2010.

Introduction
Although osmotic agents have been utilized to reduce cerebral
edema for nearly 5 decades, significant controversy regarding
choice of agent and dosing exists. While a variety of agents
have been investigated including hypertonic urea, glycerol, and
sorbitol,1-3 this review will focus on the 2 main agents used in
adult clinical practice today: mannitol and hypertonic saline
(HS). This review will summarize the evidence for the use of
these 2 agents in a variety of disease states causing cerebral
edema, as well as outlining monitoring and safety considerations.

Pharmacologic Properties
Mannitol
Mannitol has long been recognized for its ability to reduce
intracranial pressure (ICP) in animals and entered the clinical
realm in 1960s.4 It is a freely filtered, nonmetabolized solute
that decreases the reabsorption of water and, to a lesser extent,
sodium, across the renal tubule, creating diuresis. Mannitol
works in a biphasic fashion to reduce ICP. Initially, it alters
blood dynamics (rheology), specifically by reducing the
viscosity of blood. Mannitol has been shown to reduce blood
viscosity by reducing red cell rigidity, thereby easing the passage of the red cell through small blood vessels independent
of hematocrit.5 This effect disappears 4 hours after administration. Mannitol also increases intravascular volume due to
increased plasma osmolality, as well as increasing cardiac output.6 In response to reduced viscosity and intravascular volume
expansion, there is compensatory cerebral vasoconstriction

when autoregulatory pathways are intact.7 This may be explained

by Ohms law in which flow (Q) pressure difference
(DP)/resistence (R). If autoregulation is impaired, reduction
in ICP may be modest or absent. Of note, increased cerebral
blood flow (CBF) may be seen in areas of injured brain with
impaired autoregulation, largely due to decreased blood viscosity. The second phase of ICP reduction occurs as mannitol
extracts water from the cerebral extracellular space into the
intravascular compartment via the osmotic gradient between
blood and brain. It is thought that this requires an intact
blood-brain barrier to form an osmotic membrane. Controversy
exists regarding where the volume is removedfrom injured
or uninjured tissue. It appears that both injured and uninjured
tissues contribute to the volume of water lost,8,9 particularly in
the models of both diffuse and focal traumatic brain injury

1
Neurosciences Critical Care, Johns Hopkins Medical Institutions, Baltimore,
MD, USA
2
Department of Surgery, University of Maryland School of Medicine,
Baltimore, MD, USA
3
Division of Stroke and Neuro-Critical Care, Departments of Neurology,
Surgery, Neurosurgery, and Anesthesiology, University of Maryland School
of Medicine, Baltimore, MD, USA

Corresponding Author:
Kevin N. Sheth, Division of Neuro-Critical Care & Stroke, Neurology/Neurosurgery/Emergency Med/Anesthesiology, University of Maryland School of
Medicine, University of Maryland Medical Center, Adams Cowley Shock
Trauma Center, 110 South Paca Street, 3rd floor, Baltimore, MD 21201, USA
Email: ksheth@som.umaryland.edu

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Journal of Intensive Care Medicine 28(1)

Table 1. Comparison of Osmotic Agents

Solution
Concentration

Sodium Concentration
(mEq/L)

Osmolarity
(mOsm/L)

Ringers lactate
0.009
0.02
0.03
Mannitol 20%
Mannitol 25%
0.075
0.234

130
154
242
513
n/a
n/a
1283
4004

275
308
684
1062
1098
1375
2566
8008

(TBI). Uninjured brain is the main source of water extraction,

especially with repeat dosing in ischemic stroke.10,11
Mannitol is generally dosed 0.25 to 1.0 g/kg.12 The reduction of serum sodium occurs as its resorption across the renal
tubule is inhibited by mannitol. Serum sodium may drop from
9 to 13 mEq/L depending on the patients total body water
content.13 Mannitols excretion is largely governed by the
glomerular filtration rate (GFR); however, in patients with high
amounts of total body water (eg, ascites, severe peripheral
edema) mannitol will be cleared more slowly than predicted
from GFR alone. Assuming normal GFR and total body water,
plasma mannitol concentration should fall to 10% or less of the
initial equilibrium dose after 4 hours, and may be redosed
thereafter.13

Hypertonic Saline
Hypertonic saline gained popularity initially as a volume
expander in acute resuscitation, particularly in hemorrhagic
shock.14 Investigators noted that among patients sustaining
TBI, there was an improved survival rate,15 which was attributed to reduction in cerebral edema and validated in animal
models.16,17 As a result, HS evolved over time as an alternative
to mannitol in treating cerebral edema. Hypertonic saline has
been shown in animal models to produce a biphasic reduction
in ICP, first by way of rheology followed by osmotic activity
across the blood-brain barrier.18,19 Hypertonic saline has the
additional theoretical benefit of being less permeable than
mannitol across the blood-brain barrier due to its higher reflection coefficient. As a consequence, the theoretical potential for
water to follow the solute into the brain worsening cerebral
edema is reduced.20
The majority of inquiry regarding HS has occurred in TBI,
although literature in other forms of cerebral edema exists.
Table 1 compares the concentration and osmolality of several
commonly utilized formulations. As there is no universally
agreed-upon concentration or schedule for administering HS,
comparison between studies is difficult. Additionally, higher
concentrations of HS, particularly 23.4% saline, must be given
via central venous access, making its administration less feasible for patients without a central line catheter.
Continuous infusions as well as bolus dosing of varying
concentrations of HS have been investigated as alternatives

to mannitol for reducing cerebral edema, especially in TBI and

postoperatively. However, the improvements in cerebral edema
seen in TBI have not been observed in patients with ischemic or
hemorrhagic stroke to the same degree, possibly suggesting a
more pronounced effect on vasogenic edema than cytotoxic
edema. Hypertonic saline seems to be safe when given in continuous infusion as an alternative to normal saline. Froelich
et al retrospectively compared patients with varying severe
neurologic injuries, 107 of which received continuous infusions of 3% HS, while 80 received normal saline. Continuous
hypertonic therapy was not associated with an elevated risk
of deep-vein thrombosis, rate of infection, or renal failure compared to the normal saline group.21 In contrast, others have
found continuous hypertonic therapy to be possibly detrimental. Qureshi et al found that continuous infusions of HS
(2% or 3%) did not lessen the need for cerebral edema interventions. In fact, patients receiving continuous HS had higher
in-hospital mortality than patients receiving normal saline.22
These findings lead the authors to recommend bolus dosing
for cerebral edema reduction, which is the preferred practice
in our center.

Clinical Applications
Mannitol Versus HS
Limited head-to-head comparisons exist comparing the
efficacy of mannitol to HS in reduction of ICP. Table 2 lists
5 recent prospective trials comparing the 2 agents. Vialet
et al prospectively examined a series of patients with severe
TBI and elevated ICP, comparing 7.5% saline with 20% mannitol.25 The authors found their patient cohort had fewer episodes and shorter durations of elevated ICP with 2 mL/kg of
7.5% saline compared with 2 mL/kg of body weight of 20%
mannitol. Additionally, episodes of elevated ICP requiring
external ventricular drainage and total CSF drained were fewer
in the saline group.25 However, it is critical to assure that
osmolar loads are dosed in a similar fashion to make a valid
comparison. In the Vialet study, the mannitol group received
a much smaller osmolar load, potentially driving the better
result in the saline group.25 Francony et al compared the effectiveness of a single eqimolar infusion of 20% mannitol with
7.45% HS for ICP reduction in a group of patients with a variety of neurologic injuries. They found that both agents were
equally effective at reducing ICP.24 However, only mannitol
increased cerebral perfusion pressure (CPP) and CBF velocities. Based on these results, the authors recommend mannitol
to be first line in patients with poor cerebral perfusion, and
HS to be considered in patients with hypovolemia or hyponatremia.24 The authors allude to an important clinical concern
when choosing mannitol: vigilant attention to volume status
is essential in order to not disrupt hemodynamics. If not
addressed, this point can be a potential confounder in studies
comparing mannitol with HS. Most recently, Ichai et al
compared 3% sodium lactate with 20% mannitol, both dosed at
1.5 mL/kg in a population of patients with TBI.23 Sodium lactate

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Hinson et al

Table 2. Recent Prospective Trials Comparing Mannitol and Hypertonic Saline

Author (Year)

Type of
Prospective Trial Agent

Ichai et al
(2009)23
Francony et al
(2008)24
Battison
(2005)25
Harutjunyan
(2005)26
Vialet et al
(2003)27

Randomized
controlled
Randomized
controlled
Randomized
controlled
Randomized
controlled
Randomized
controlled

Condition(s)
Treated

3% sodium lactate vs 20% mannitol TBI

7.5% HS vs 20% mannitol

TBI Stroke

20 mL 20% mannitol vs 100 mL 7.5% TBI SAH

HS dextran
7.2% HS 6% HES vs 15% mannitol neurosurgical
patients
7.5% HS vs 20% mannitol
TBI

Number of
Patients?
Outcome
34

HS>Mannitol for #ICP, "GOS

20

Both #ICP similarly

HS > mannitol for #ICP

40

HS > mannitol for #ICP

20

HS > Mannitol for reducing elevated

ICP episodes

Abbreviations: CBF, cerebral blood flow; CPP, cerebral profusion pressure; GOS, Glascow Outcome Score; HES, hydroxyethyl starch; HS, hypertonic saline; ICP,
intracranial pressure; NS, normal saline; TBI, traumatic brain injury; SAH, subarchnoid hemorrhage

Table 3. Avoiding Adverse Effects of Osmotic Agents

Complication

Mannitol

Hypertonic Saline

Renal Failure
Rebound
Metabolic Acidosis
Hypokalemia
Hypovolemia

Avoid continuous infusion, repeat high dosing

Allow clearance prior to repeat dosing
n/a
n/a
Concurrent volume resuscitation

Avoid prolonged hypernatremia >160 mEq/L

Allow clearance prior to repeat dosing
Reduce chloride in admixture
Add potassium to fluids
n/a

was chosen as opposed to sodium chloride because the authors

hypothesized that lactate might provide an advantage as a
fuel for the brain under ischemic-reperfusion injury based
on animal studies. Sodium lactate appeared superior in reducing ICP. The group receiving sodium lactate (either as primary
therapy or as rescue after mannitol) had improved 1-year
Glascow Outcome Scores compared to mannitol alone.23
Kerwin et al retrospectively analyzed 22 patients with severe
TBI who received either mannitol (15 to 75 g) or 30 mL of
23.4% HS for control of ICP >20 sustained for more than
5 minutes. The investigators observed significantly greater
drop in ICP in the HS group in comparison to the mannitol
group, leading them to conclude HS is more efficacious in
reducing elevated ICP in TBI.28 Unfortunately, the authors
do not explain how the dosing of mannitol was determined
(ie, a weight-based protocol), making it unclear if patients in
the mannitol group were underdosed, receiving as little as
15 g in some instances.

Traumatic Brain Injury

Hyperosmolar agents role in neurologic injury is probably best
understood in TBI, despite the fact that the evidence even in
TBI ranges from class II to III. Several insights have been
gained about mannitol in this population. Continuous infusion
seems to be no better, if not worse, than bolus dosing. Mannitol
becomes less effective with repeat dosing. Fast infusion seems
to be best. Mannitol works best when autoregulation is intact.
Lastly, mannitol consistently improves MAP, CPP, and CBF
while lowering ICP.29-31

More recently, HS has come to fore as an alternative to

mannitol in TBI. Initially, continuous infusions of hyertonic
saline were investigated. Qureshi et al found that a continuous
infusion of 3% saline exerted a beneficial effect on ICP as well
as improving lateral displacement of brain due to edema in
patients with head injury, spontaneous intracranial hemorrhage
(ICH) or postoperatively (after tumor resection or aneurysm
clipping).31 Like mannitol, bolus dosing of HS has shown more
promise than continuous infusions for ICP management.22
Bolus dosing for both agents might be more effective than continuous osmotic agents because continuous infusions of osmotic agents allow more time for the reestablishment of a new
osmotic set point, such that the intracellular and extracellular
compartments reequilibrate. No further water extraction can
occur once this reequilibration occurs. Several case series have
shown the effectiveness of boluses of HS for the reduction of
ICP in TBI, both as an alternative and as an adjuvant to mannitol.27,33-35 Bolus dosing regimens vary within the literature.
Some authors advocate the use of 2 mL/kg of 7.5%27 for the
control of elevated ICP, while others have used 250 mL boluses
of 3%36 or 30 mL of 23.4%.37 To date, there are no direct
comparison studies between these dosing regimens. Hypertonic
saline also appears to increase levels of brain tissue oxygenation (PbtO2) and improve hemodynamics (higher CPP and
cardiac output) when used as a Tier II therapy after mannitol
administration for elevated ICP. Mannitol had no measurable
effect on PbtO2 in this study.38 Again, these results should be
interpreted with caution as equi-osmolar doses of each agent
were not used. The HS group received a larger osmolar load
(250 mL of 7.5% saline versus 0.75 g/kg of 25% mannitol;

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Journal of Intensive Care Medicine 28(1)

Table 1). There is also a suggestion that use of HS may improve

biomarker profiles. Baker et al measured levels of S100B,
neuron-specific enolase (NSE), and myelin basic protein in
patients with severe TBI receiving either normal saline or
7.5% HS with 6% dextran for resuscitation, as opposed to cerebral edema. They found the lowest levels of these biomarkers
in survivors resuscitated with HS; whereas the highest levels
were seen in nonsurvivors. The link between these biomarkers
and survival benefit has not yet been definitively shown.39
As of 2007, the Brain Trauma Foundation Guidelines do not
provide guidance on administration of either mannitol or HS
for elevated ICP in TBI other than to indicate that both agents
may lower ICP.40

Ischemic Stroke
Unlike TBI, controversy exists regarding the utility of hyperosmolar agents in ischemic stroke. First, the lack of intact bloodbrain barrier in ischemic stroke is worrisome, based on the fear
that osmotic agents may leak across the compromised
membrane bringing water with the solute. This phenomenon
has been reported in animals, but may not apply to humans.41
Second, mannitol seems to reduce the water content of the
uninjured hemisphere,11 which could worsen midline shift if
present. To address these concerns, Manno et al examined a
group of patients with complete middle cerebral artery (MCA)
infarctions with cerebral edema and administered boluses of
mannitol. They found that a single, large dose of mannitol
(1.5 g/kg of body weight) did not worsen midline shift nor
precipitate neurologic decline in the first hour after administration.9 From a global outcomes perspective, a large retrospective observational study failed to find any effect of routine
mannitol use on outcome at 1 month or 1 year. Of greater concern, depending on the variables entered into the authors
regression model, mannitol appeared either to have no effect
or to be harmful, rendering the authors unable to make any recommendation on the use of mannitol in ischemic stroke.42
However, it is difficult to interpret these results as the treatment
groups were not homogenous enough to be directly comparable, and routine mannitol use is not a common clinical practiceits use usually being reserved for malignant cerebral
edema. The literature does suggest bolus dosing of mannitol
and HS can reduce ICP, but long-term outcomes in these studies were not addressed.43,44 It may be appropriate not to address
long-term outcomes, as patients requiring osmotic therapy for
cerebral edema are usually critically ill. Critical illness entails
many confounders affecting outcome such as ICU-acquired
infections, requiring large numbers of patients to account for
these confounders. Thus, ICP may be the more appropriate
measure of efficacy.
Continuous infusions of osmotic agents have shown less
promise than bolus dosing. Bhardwaj et al found hypertonic
agents might actually increase infarct volume. Utilizing an
MCA occlusion model of stroke in rats, the investigators initiated osmolar therapy with 20% mannitol, 0.9% normal saline,
3% HS, or 7.5% HS at the onset of reperfusion. The group

observed that continuous infusion hypertonic therapy initiated

at the onset of reperfusion did not reduce infarct volume, thus
may not represent an effective resuscitation strategy after
ischemic stroke. It should be noted, that reperfusion time in
humans is rarely available as a clinical parameter, thus caution
should be employed when generalizing to humans. Surprisingly, the group randomized to 7.5% saline had a statistically
significant increase in infarct volume over the other groups,
causing the authors to caution its use in ischemic stroke.45
Indeed, there has been no randomized, controlled trial addressing the use of mannitol or HS in ischemic stroke. In the
absence of definitive evidence in humans, mannitol rescue
therapy for malignant cerebral edema is the most common
clinical practice. The American Stroke Association guidelines
advise treatment of stroke-related edema and elevated ICP
with mannitol as a bridge to more definitive therapy, such as
decompressive craniectomy.46

Subarchnoid Hemorrhage
Both mannitol and HS significantly lower ICP in the animal
model of subarchnoid hemorrhage (SAH).47,48 A recent
Norwegian study compared 30-minute infusions of 2 mL/kg
of 7.2% HS or 0.9% saline (placebo) and measured ICP in
stable SAH patients. The group observed a reduction in ICP
of 3 mm Hg on average compared with 0.3 mm Hg in the
placebo group, as well as an increase in CPP of 5.6 mm Hg
compared with negligible change in CPP in the placebo group.
The authors favored HS over mannitol in the SAH patient population due to the risks of diuresis-induced hypovolemia and
the inherent risks of vasospasm. Additionally, the authors
hypothesize that SAH patients might be more suitable for the
osmotic effect of HS given a relatively intact blood-brain
barrier.49 Cerebral blood flow was of particular interest to
Tseng et al. Their group showed that infusions of 23.5% HS not
only reduced ICP but also increased CBF as evidenced by
continuous transcranial dopplar and Xenon-enhanced computed
tomography scans. Patients with the greatest increases in CBF in
response to HS seemed to also have the most favorable outcomes
as measured by discharge modified Rankin scores.50

Intracerebral Hemorrhage
Investigation of ICP management in intracerebral hemorrhage
with osmotic agents is less robust than in other disease states
like TBI. From the scant human clinical trials, it appears that
scheduled, low dose mannitol (100 mL of 20% dosed every
4 hours) did not improve outcome in ICH patients or change
CBF.51,52 While no clinical trials of HS in the setting of ICH
have been conducted, animal models suggest bolus dosing of
23.4% HS reverses transtentorial herniation and restores
regional CBF.53 In the same animal model, Quereshi et al also
compared bolus 20% mannitol, bolus 23.4% HS, and continuous 3% HS. While all 3 groups showed an initial drop in ICP
values, the investigators noted that only in the 3% group did
the animals have sustained lower ICP.54 This observation

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Hinson et al

represents one of the few accounts in the literature of continuous

osmotic therapy being superior to bolus dosing. This may be
related to the continuous HS group benefiting from longer term
intravascular volume expansion in the intracranial vasculature.
Studies comparing bolus doing versus continuous infusions of
lower concentration HS (2%-3%) are needed to resolve this
issue.

Liver Failure
Cerebral edema may occur as a consequence of acute,
fulminant liver failure. The presumed mechanism of cerebral
edema relates to ammonia and glutamine causing cytotoxic
injury combined with cerebral vasodilation from the loss of
autoregulation.55,56 Although the definitive therapy for fulminant hepatic failure is liver transplantation, the cerebral edema
may be imminently life-threatening. In the 1980s, mannitol
proved to be more effective than dexamethasone for reducing
cerebral edema and improving outcome in liver failure.57
More recently, interest has shifted to HS. Murphy et al induced
moderate hypernatremia (145-155 mmol/L) with a 24-hour
infusion of 30% saline at 10 mL/hour in a group of liver failure
patients with acute liver failure and Grade III or IV encephalopathy, and measured ICP. The group found that moderate
hypernatremia along with the standard of care interventions
significantly reduced ICP from baseline levels when compared
with standard of care alone. Standard of care was provided to
both patient groups, and included standardized ventilation
management, head of bed elevation, ICP monitoring, N-acetylcystine aministration, hemodynamic monitoring with intervention for hypotension, enteral feeding, prophylactic antibiotics,
and hemoglobin goals.58

Transtentorial Herniation
Mannitol, in combination with hyperventilation, has been
shown to reverse transtentorial herniation in a cohort of
28 patients with a variety of underlying illnesses causing cerebral edema (including neoplasm, ICH, TBI, and ischemic
stroke).59 Hypertonic saline has also shown promise in reversing transtentorial brain herniation. A retrospective analysis
of boluses (30-60 mL) of 23.4% HS reversed 75% of clinical
herniation events in a cohort of patients with a variety of
neurologic illnesses.60

Monitoring
Intracranial Pressure
Hyperosmolar agents are frequently used to reduce ICP and/or
reverse brain herniation events. Thus, it is recommended to
have an ICP monitor in place to aid titration.

Serum Sodium Osmolarity

Generally, fluid balance should be monitored closely as mannitol
may cause significant diuresis, while HS expands intravascular

volume. Serum sodium concentrations and plasma osmolality

are usually measured in a serial fashion after the administration
of either HS or mannitol. Target serum sodium and osmolality
values are controversial, but clinicians often strive for serum
sodium concentrations of 150 to 160 mEq/L and plasma osmolality between 300 and 320 mOsm.32 In general, an infusion of
1 mL/kg of 3% saline will raise the serum sodium by approximately 1 mEq/L, regardless of baseline serum sodium concentration.61 The literature suggests an increased risk of acute
renal failure and metabolic acidosis when plasma osmolality
>320 mOsm,12,30 however, this threshold is not absolute.62
Diringer and Zazulia explain well in their review article,
Osmotic Therapy Fact and Fiction,62 that the value of
320 mOsm was arrived at in patients receiving continuous,
high-dose mannitol infusions (0.25-0.5 g/kg per h). None of the
patients in this study developed renal failure with a serum
osmolality below 400 mOsm.63 In fact, a serum sodium of
160 mEq/L and a plasma osmolality of 340 mOsm might be a
safe upper limit.64

Osmolar Gap
Unfortunately, a test for serum mannitol concentration is not
commercially available. Despite its frequent clinical use, serum
osmolality is a poor surrogate for serum mannitol concentrations.65 To surmount this issue, some authors have advocated
the use of osmolar gap (OG) as a method of monitoring mannitol concentrations to avoid complications such as renal failure.
Osmolar gap is the difference between osmolality and osmolarity, which is used to detect the presence of unmeasured osmoles
such as mannitol.62 If the OG falls within the normal range
(varying by formula and patient population), Garcia-Morales
et al assert a patient has sufficiently cleared the mannitol,
and may be redosed.66 It has been suggested that maintaining
an OG below 55 mmol/kg of H2O will help to prevent renal
failure.67 OG may be calculated by several different formulas;
Diringer et al report utilizing 1.86 (Na K) (blood urea
nitrogen/2.8) (glucose/18) 10 provided the best correlation
to measured mannitol levels.62

Complications
Renal Failure
Of particular interest is avoiding renal failure. Mannitol may
become nephrotoxic by several mechanisms, including dosedependent vasoconstriction of the renal artery and intravascular
volume depletion from osmotic diuresis.68,69 In one study, the
mean total dose of mannitol that precipitated acute renal failure
in healthy kidneys was 626 + 270 g over 2 to 5 days.70 There is
an association between prolonged hypernatremia (serum
sodium concentration >160 mEq/L) and oliguric acute renal
failure observed in burn patients receiving HS as resuscitation
fluid.71 Observations of renal failure associated with HS in neurological patients is limited;72,73 however, close monitoring of
renal function is advised. Patients that already require intermittent or continuous renal replacement pose a special challenge to

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Journal of Intensive Care Medicine 28(1)

the use of osmotic agents. If mannitol is to be used when renal

failure is already present, the smallest effective dose possible
should be used (consider 0.5 g/kg). Use of hemodialysis to
remove mannitol will expedite the half-life of the drug to
6 hours versus 5 or more days with GFR <50 mL/min. With
regard to sodium balance, the standard sodium concentration
of dialysate is 140 mEq/L. Serum sodium levels will trend
toward 140 mEq/L as dialysis is applied, particularly for continuous renal replacement therapy (CRRT).74 In the authors
experience, frequent redosing of HS is often needed to maintain
hypernatremic goals.

Osmotic Demyelinating Syndrome

Osmotic demyelinating syndrome or more specifically central
pontine myelinolysis (CPM) may occur when sodium levels are
rapidly increased with HS, causing demyelination of white
matter in the CNS or specifically in the pons. Patients are most
at risk when hyponateremia exists at baseline. To date, there are
no case reports of CPM occurring after the administration of
HS for elevated ICP60 nor has CPM been reported in any of the
trials using HS for elevated ICP.72,73

Conclusion
Nearly a century after mannitol was noted to reduce cerebral
edema, osmotic agents including mannitol still play an important role in the medical management of both cerebral edema
and elevated ICP. Despite the lack of randomized, controlled
trials, our knowledge base on the appropriate clinical use of
osmotic agents continues to expand. While not definitively
superior to mannitol, HS shows promise in not only reducing
ICP but also in reversing neurologic deterioration and improving hemodynamics. Future work will further define agent
selection and dosing regimen. The disease state as well as the
type of edema encountered (vasogenic versus cytotoxic) will
likely guide agent selection as clinical practice evolves.
Authors Note
KNS is supported by an American Academy of Neurology Clinical
Research Award

Declaration of Conflicting Interests

The authors declared no potential conflicts of interests with respect to
the authorship and/or publication of this article.

Rebound Phenomenon
After exposure to osmotic agents, ICP may precipitously rise
back to an elevated level after an initial response. This is
termed the rebound phenomenon and occurs particularly
after mannitol administration. Previously rebound was feared
as a consequence of the osmotic agent leaking into injured tissue across a damaged blood-brain barrier, and pulling water
with it, promoting swelling in the injured area. However, observations of mannitol exiting the brain down its concentration
gradient make this explanation less compelling.62 Rebound is
more likely related to osmotic compensation within the central
nervous system, allowing for increased intracellular concentrations of electrolytes. Repeated administration of osmotic
agents, especially in the setting of poor CNS compliance where
small volemic changes result in dramatic changes in ICP,
promote the rebound phenomenon.75 Additionally, repeat
dosing or continuous infusions of these agents without time
allotted for the osmotic agent to clear might also contribute
to this phenomenon.

Metabolic Acidosis
Hypertonic saline inhibits the resorption of bicarbonate from
the proximal renal tubules. It may also produce hyperchloremic
metabolic acidosis from the large amount of chloride delivered
in the fluid. One possible solution to this problem is to change
the fluid admixture to 50:50 sodium chloride-sodium acetate.76

Hypokalemia
Hypokalemia might also be encountered as the kidney
exchanges potassium for sodium in the distal tubule. Addition
of potassium to maintenance fluids may correct this.

Funding
The authors received no financial support for the research and/or
authorship of this article.

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