Clinical Neurology and Neurosurgery 206 (2021) 106704

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Clinical Neurology and Neurosurgery

journal homepage: www.elsevier.com/locate/clineuro

Hyperosmolar therapy: A century of treating cerebral edema

Aaron Desai, Rahul Damani *
Department of Neurology, Section of Vascular and Neurological Critical Care, Baylor College of Medicine, Houston, TX, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Hyperosmolar therapy is a cornerstone for the management of elevated intracranial pressure in patients with
Cerebral edema devastating neurological injuries. Its discovery and use in various pathologies has become a valuable therapy in
Hyper osmolar therapy modern neurological critical care across the globe. Although hyperosmolar therapy is used routinely, the history
Raised intracranial pressure
of its origin is still elusive to many physicians. Understanding the basis of discovery and use of different
Historical review
hyperosmolar agents lends insight into the complex management of elevated intracranial pressure. There are
very few practices in medicine which has stood the test of time. The discovery of hyperosmolar therapy has not
only provided us a wealth of data for the management of intracranial hypertension but has also allowed us to
develop new treatment strategies by improving our understanding of the molecular mechanisms of cerebral
inflammation, blood-brain permeability, and cerebral edema in all modes of neuronal injury.

1. Introduction
1.1. A serendipitous discovery
At the turn of 18th century, the treatment of brain injured patients
largely consisted of bed rest, morphine and generous amounts of mag­
nesium sulfate, however, since the rationale for the use of the last agent
was not known, it was not popular and soon fell out of favor [1]. It was
during this period that there was a tremendous interest in understanding
the physiology of the brain and cerebrospinal fluid. Alexander Monro
[2] first proposed in 1783 that the volume of blood circulating around
the brain must be constant at all times. This concept was further
advanced in 1824 by Kellie [3] who performed a series of experiments
leading to the Monro-Kellie Doctrine which stated that the sum of vol­
umes of brain, CSF, and intracranial blood is constant. The Monro-Kellie
Doctrine considered the brain to be a fixed incompressible structure, a
belief first challenged by Burrows in 1843 [4]. Burrows’ publication led
to a series of other observations by Kussmaul and Tenner, Donders and
Hill who concluded that the volume of blood in the brain in slightly
variable in different physiological conditions [5]. Around the same time,
Starling [6] discovered the changes in osmolality governing movements
of fluids across membranes, while Dixon and Halliburton [7–9]
advanced the understanding of cerebrospinal fluid (CSF) circulation and
physiology by studying changes in CSF pressure and flow in dogs
anesthetized with ether. However, it was not until March 1919 that two
neurosurgeons, Lewis Weed and Paul McKibben [5,10], discovered that
changes in brain bulk can be caused by osmolar shifts between the
blood, the brain and the CSF. Drs Weed and McKibben were performing
a series of experiments on cats to understand the effects of hyper and
hypo-osmolar solutions on CSF pressure and brain bulk when they
serendipitously discovered that intravenous administration of 30% hy­
pertonic saline resulted in collapse of the lumbar cistern and profound
decrease in brain volume and CSF pressure, whereas intravenous in­
jection of water resulted in significant brain swelling [5,10]. Since the
volume of both intravenous solutions was the same, they concluded that
the change in brain bulk should be secondary to osmolar difference in
solutions and osmolar shifts between the blood, the brain and the CSF.
These remarkable discoveries paved the way for numerous experiments
with a spectrum of hyperosmolar compounds aimed at reducing intra­
cranial pressure (ICP) and brain volume. In September of 1919, Haden
[11] described the use of concentrated intravenous glucose to reduce
swelling in patients with meningitis. This was shortly followed by
similar observations by others in different clinical settings [12]. Cushing
and Foley [13] described the use of hypertonic saline in patients with
herniation secondary to brain tumors after decompression surgeries.
Sachs and Belcher [14] reported the use of saturated salt solution in a
patient with a brain tumor. Ebaugh and Stevenson [15] also described
reduction in brain bulk after administration of hypertonic Ringer’s so­
lution and concentrated glucose. In 1921, Foley [16] also reported on
the use of such solutions to relieve ICP. In 1923, Fay [17] published a
series of patients treated with either magnesium sulfate per rectum or
intravenous hypertonic saline for the same purpose. Fremont-Smith and

* Correspondence to: Baylor College of Medicine, MS NB 120, One Baylor Plaza, Houston, TX 77030, USA.
E-mail address: Rahul.damani@bcm.edu (R. Damani).

https://doi.org/10.1016/j.clineuro.2021.106704
Received 14 April 2021; Received in revised form 16 May 2021; Accepted 17 May 2021
Available online 20 May 2021
0303-8467/© 2021 Elsevier B.V. All rights reserved.
A. Desai and R. Damani
Forbes in 1927 [18] further demonstrated that intraperitoneal injection
of hyperosmolar agents leads to a reduction in ICP and intraocular
pressure.
The early enthusiasm for the use of hyperosmolar agents (50%
glucose, sucrose, magnesium sulfate, 25% sodium chloride etc.) for the
treatment of brain edema and increased ICP, however, was short lived.
In fact, it became evident that the effects of these agents in clinical
practice was transient and sub-optimal. There was also concern for
rebound intracranial hypertension. Hence these agents went quickly out
of favor [19] and by 1930s hyperosmolar agents were no longer used in
clinical practice for elevated ICP and brain edema [20]. It took almost
two decades for researchers to realize the hyperosmolar quality of urea
to treat elevated ICP [21]. The discovery of urea’s effect on ICP coupled
with the lack of side effects that prior agents had re-invigorated
enthusiasm for hyperosmolar therapy in the treatment of increased
ICP and brain edema [22].
2. Rise and fall of urea
The earliest use of urea as a hyperosmolar agent was described in
1914 by Hertel, who injected urea intravenously to lower intra-ocular
pressure in animals [18]. However, urea effect on ICP was unknown
till 1927 when Fremont and Smith performed experiments where they
injected 50% urea intraperitoneally to study the relationship between
intracranial and intraocular pressure and reported reduction in CSF
pressure with its use [18]. This discovery was corroborated in 1950 by
the work of Smythe et al. who performed experiments injecting 17%
urea intravenously in monkeys [21] and reported that on an
equi-osmolar basis, urea was actually more effective than glucose or
sucrose in reducing CSF pressure. The use of urea as a hyperosmolar
agent in clinical practice was pioneered by Javid and Settlage between
1954 and 1958. They described the use of urea in different neurosurgical
setting to lower ICP [23–28]. Following their work, the use of urea was
studied for different clinical application. Spector [29] in 1961 described
the beneficial effect of urea in anoxic brain injury in rats. In 1963,
Joyner and Freeman [30] described its use in spinal cord injury, and
Clasen et al. in 1965 [30] showed its efficacy in reducing brain volume,
ICP and areas of focal hemorrhagic necrosis. Further, Mann and Travaini
[31] showed that urea lead to reduction in cerebral edema at the his­
tological level. These studies paved the way for urea to become the first
hyperosmolar compound to be used widely [22,32].
2.1. Mechanism of action
To understand the mechanism of action of urea it is important to
understand the basic principles behind the movement of water and the
concept of osmotic equilibrium. Briefly, if two solutions of different
concentrations are separated by a semipermeable membrane, in order to
maintain osmotic equilibrium, there will be movement of water from the
area at higher to the area at lower solute concentration. The use of
osmolar therapy for the management of cerebral edema and intracranial
pressure depends on one other important factor which is unique to the
brain, the blood brain barrier (BBB). Since the BBB is relatively imper­
meable, any solute of higher concentration will tend to stay within the
intravascular compartment of the brain and will tend to draw water
from the brain into the intravascular compartment, thereby decreasing
the cerebral volume. This factor which determines if a solute is imper­
meable and thereby will stay within the intravascular compartment is
known as reflection coefficient [33]. Its value ranges between 0 (freely
permeable) to 1 (impermeable). The most effective hyperosmolar agents
are those whose reflection coefficients approach 1 [34]. The reflection
coefficient of urea is 0.59 which means it does have a tendency diffuse
out of the intravascular space [35]. Urea works as an osmotic diuretic
and itself is excreted renally. However, its role as a diuretic to decrease
cerebral edema has been disputed since changes in brain volume are
noticed even before the increase in urine output, thereby suggesting
2
Clinical Neurology and Neurosurgery 206 (2021) 106704
there are other factors at play as well [36,37].
2.2. Drawbacks of urea
The rise in the popularity and routine use of urea in clinical practice
also meant that its drawbacks became more evident. One of the major
drawbacks was the instability of the agent itself. Urea is a very sensitive
to heat, needs a cool environment (cannot be stored on shelf) and needs
to be mixed just before its use. This required specialized training and at
time preparation times rendered it futile during emergent use [38]. Also,
extravasation of even small quantities of urea during administration led
to skin necrosis [27,32,36]. Other important drawback was its tendency
to cause platelet dysfunction which made its use difficult in patients with
hemorrhage, traumatic brain injury and recent neurosurgery. Urea is
also associated with hemolysis and related hemoglobinuria due the
diffusion of urea into erythrocytes causing cellular swelling and even­
tually lysis [39,40]. Since urea is renally excreted, it cannot be used in
patients with renal insufficiency [35]. Other systemic side effects
included electrocardiographic changes such as ST elevation, inversion of
T wave, distortion of QRS, and increased PR interval [41].
The above drawbacks coupled with availability of better hyper­
osmolar agents (see below) caused decline in the clinical use of urea and
an eventual cessation of its production. At the same time, significant
progress in our understanding of cerebral edema and elevated ICP in the
setting of different pathologies was being made around the 1950s and
1960s. The view that there should only be one type of treatment for the
management of cerebral edema seemed antithetical. This concept was
further highlighted by Galicich, French, and Melby [42–44] who
demonstrated the efficacy of steroids to reduce peritumoral edema. The
use of steroids was not only relatively safe, but it was also associated
with a significant reduction in operative mortality and morbidity.
3. Dawn of mannitol
In 1940, Smith et al. [45] first demonstrated the safety of hexitol
solutions in animals which led to an interest in understanding the renal
physiology and the concept of osmotic diuresis for the treatment of
edema [46]. Almost two decades after, Burton Wise and Norman Chater
in 1961 [47,48], first reported the use of mannitol in direct comparison
to urea. These authors showed that mannitol was not only effective in
lowering ICP, but it was also longer acting and not associated with
rebound rise in ICP, as seen for urea. This led to a new era: mannitol
became one of the mainstays for the treatment of cerebral edema and
elevated ICP.
Mannitol is a six carbon hexahydric alcohol with a molecular weight
of 182 daltons and a half-life of 2–4 h [49]. Since it is a large molecule
compared to urea, it has a tendency to stay in the intravascular
compartment longer and has a higher reflection coefficient of 0.9,
compared to 0.59 for urea [50]. These molecular properties explain why
mannitol has a greater therapeutic effect than urea. Mannitol is not only
a potent diuretic but it also has a rheological effect (reduces blood vis­
cosity, and promotes plasma expansion and cerebral oxygen delivery)
which is responsible for the reduction in ICP even before the diuresis sets
in [51]. Given the ease of preparation, stable shelf life and lack of toxic
effects after extravasation in the skin, mannitol took over the use of urea.
However, for about a decade it was debated that urea was still a faster
agent to lower ICP and that it was a better agent in the perioperative and
post-operative settings [52,53]. Furthermore, the fact that mannitol was
not associated with a rebound rise in intracranial pressure was also
cause of discussion [54]. The drawbacks of mannitol as compared to
urea included a more significant decrease in plasma protein and he­
moglobin values upon administration and a more potent diuresis, which
limited its use in patients with volume deficiency [55].
As with any other pharmacological agent, mannitol is not devoid of
side effects. Given its molecular size and high reflection coefficient, it
has potential of triggering transient increased intravascular volume,
A. Desai and R. Damani Clinical Neurology and Neurosurgery 206 (2021) 106704

Table 1
Hypertonic saline.
Concentration of Administration IV access requirements Monitoring Points to consider
hypertonic saline parameters

2% As a continuous infusion
3% As a continuous infusion or 150 ml
bolus infusion every 4–6 h
23.4% 30 ml IV push over 10 min
Peripheral IV or a central Serum The rate of infusion can be titrated to goal sodium levels
venous catheter (preferred) electrolytes (145–155)
Central venous catheter Serum Prefer to use a 50:50 solution of sodium chloride and
electrolytes sodium acetate to avoid hyperchloremic metabolic acidosis
Central Venous Catheter Serum Mostly used in emergencies for managing intracranial
electrolytes pressure crisis and to prevent brain herniation

however, diuresis is more sustained than the former effect, hence

Table 2
intravascular volume depletion and hypotension can ensue [56]. Further
Mannitol vs. hypertonic saline.
mannitol is excreted via kidney and can precipitate acute kidney injury
especially at higher osmolar gap [56]. One of commonly held belief is to Mannitol Hypertonic saline

avoid using mannitol if the serum osmolarity is above 320 or the serum Dosing Used as bolus doses of Available in different
osmolar gap is greater than 20. This is due to few isolated reports of 0.25–1.5 g/kg every 4–6 h concentrations, can be used as
continuous infusions or bolus
mannitol causing renal injury if used in these situations, however, these
doses to reach desired sodium
reports are anecdotal as indicated by Diringer et al. [50]. Despite these goals (see table)
limitations, mannitol administered in boluses continues to be one of the Monitoring Serum osmolarity and serum Serum electrolytes
mainstays for the treatment of increased ICP. osmolar gap (not to exceed
20)
Advantages - Can be used in emergencies - Can be used in
4. Dimethyl sulfoxide (DMSO) via peripheral access. hemodynamically unstable
- Used in patients in heart patients
Due to the widespread use of mannitol, there was a renewed interest failure due to its diuretic - Reflection coefficient of 1
in agents for the treatment of cerebral edema. One such agent which was property
Disadvantages Effects are mediated via Requires central access so might
studied in the 1970 by de la Torre and his colleagues was dimethyl
osmolar diuresis minimizing not be readily used in
sulfoxide (DMSO) [57,58]. DMSO showed efficacy similar to other os­ efficacy in patients with emergencies if patients do not
motic agents and had a similar mechanism of action along with some renal failure have central venous access.
neuroprotective qualities. However, it was difficult to store and
administer, and was associated with intravascular hemolysis due to its
osmotic effect on red blood cells. One of the non-serious but bothersome as compared to patients who received saline and it was also associated
side effect of DMSO was the garlic breath due to pulmonary excretion of with greater use of interventions to control ICP and maintain cerebral
its breakdown product dimethyl sulfide [59]. perfusion pressure (CPP).

6. Re-emergence of hypertonic saline

5. Albumin

Mannitol enjoyed the status of hyperosmolar agent of choice for

The use of albumin came into light during the second world war,
decades in the United States. Initially hypertonic saline was only used to
after the attack on Pearl Harbor, when seven patients with severe burns
treat mannitol refractory patients [64]. However, 1980s saw a renewed
were treated with this agent [60]. Shortly thereafter, interest sprang for
interest for the use of hypertonic saline as a first line agent especially in
the use of albumin for fluid resuscitation in various diseases. In the
patients in whom mannitol might not be an ideal agent (hypovolemic,
1990s, due to increased attention to cost/benefit analyses of medical
acute kidney injury). By 1990s hypertonic saline gained a broad
treatments, there was a real outburst of research on this subject. In 1998,
acceptance as a first line agent for the treatment of cerebral edema and
a Cochrane meta-analysis report suggested the potentially harmful effect
elevated intracranial pressure [65]. The reflection coefficient of sodium
of albumin administration as compared to other fluids for volume
and by extension, hypertonic saline approached almost 1 which makes it
replacement [61]. The meta-analysis included 32 clinical trials
an ideal hyperosmolar agent [66]. This property allows it to remain in
involving a total of 1419 patients, and showed, among patients with
the intravascular space, drawing water from the intracellular compart­
surgery- or trauma-induced hypovolemia, no differences in mortality
ment with an intact BBB.
between those treated with albumin and those treated with crystalloids.
The mechanism of action of hypertonic saline is similar to that of
In contrast, patients with burns who were treated with albumin
mannitol in a broader sense, however unlike mannitol it doesn’t induce
appeared to have a higher mortality rate as compared to those treated
diuresis or cause hypovolemia, but rather it raises the intravascular
with crystalloids. To resolve the contradictory findings obtained from
volume, and can improve mean arterial blood pressure, cardiac output
these meta-analyses, 16 ICUs in Australia and New Zealand conducted a
and stroke volume. This property made it an hyperosmolar agent of
prospective, randomized, double-blind study, the Saline vs. Albumin
choice in conditions where maintaining intravascular volume is critical
Evaluation (SAFE) study, comparing the effects of the infusion of 4%
such as septic shock, traumatic brain injury and subarachnoid hemor­
albumin and saline solution (0.9% NaCl) for volume replacement in
rhage [56]. In addition to its high reflection coefficient, hypertonic sa­
critically ill patients with hypovolemia [62]. The authors concluded that
line also has a rheological effect which means that it can decrease blood
albumin use was associated with higher mortality. They suggested that
viscosity by modifying the red blood cells [67,68]. This allows for a
contrary to expectations of less cerebral edema due to better intravas­
compensatory vasoconstriction thereby reducing ICP, while still main­
cular oncotic pressure, there may have been albumin outflow through
taining adequate blood flow to the brain [69]. Moreover, it is also a
the damaged BBB, paradoxically leading to greater net efflux of fluid
faster acting agent, with an onset of action similar to mannitol, begin­
from the cerebral intravascular to interstitial spaces in patients who
ning within minutes, reaching a peak between 15 and 120 min, and
received albumin. They later performed a post hoc analysis of 321 pa­
lasting up to 4–6 h [68].
tients in whom intracranial pressure (ICP) was monitored [63]. 51.1%
A matter of frequent debate is the optimal dosing and administering
patients received 4% albumin and 48.9% patients received 0.9% saline.
strategy for achieving hypernatremia. There have been many studies
The authors found that patients who received albumin had higher ICPs

3
A. Desai and R. Damani
1920 Cushing
and Foley
showed
concentrated
glucose 1930s
1898 Starling reduced hyperosmolar
discovered swelling in agents fell out
changes in paent with of favor due to
osmolarity meningis side effects
1919 Weed and 1923 Fay
McKibben first published a
demonstrated series on
the changes in paents
brain volume treated with
with hyper and hyperosmolar
hypo-osmolar agents
soluons
Fig. 1. Timeline of discovery.
which used either bolus dosing or continuous infusion [70–72]of hy­
pertonic saline for treatment of cerebral edema (Table 1), however,
there has been only one study by Maguigan et al. [73] which compared
the two strategies which showed no difference in CPP, ICP, length of stay
and mortality. Recent guidelines from Neurocritical Care society [74]
concluded that it is not clear whether continuous or bolus dosing is
preferable when targeting a goal serum sodium concentration, given the
lack of evidence comparing these dosing strategies. Also, the panel
suggested that there is a significant gap in the literature regarding the
value of targeting a specific serum sodium concentration in patients with
cerebral edema, and whether targeting specific serum sodium concen­
tration is efficacious [74].
Hypertonic saline has many advantages, but it is also not devoid of
complications. One concern with the use of hypertonic saline is myeli­
nolysis which is associated with overcorrection of preexisting hypona­
tremia. The use of hypertonic saline can also cause encephalopathy,
lethargy and hallucinations due to rapid sodium and plasma osmolality
changes, however, these side effects are typically short lived. Other
drawbacks include hyperchloremic metabolic acidemia (using chloride
solutions only), coagulopathy, hemolysis, and ventilation failure sec­
ondary to pulmonary edema [50,75,76].
7. Hypertonic saline or mannitol, which is better? (Table 2)
Since the widespread use of hypertonic saline and mannitol for
treatment of intracranial hypertension, there has been eagerness to
determine relative efficacy of these two forms of hyperosmolar therapy.
A recent Cochrane review sought to compare hypertonic saline against
other ICP lowering agents especially mannitol [77]. The authors
concluded that in patients with acute traumatic brain injury there is a
weak evidence that hypertonic saline is better than mannitol in terms of
efficacy or safety. A meta-analysis comparing equi-osmolar dose of hy­
pertonic saline to mannitol showed relative risk of intracranial pressure
control was 1.16 (CI 1.00–1.33) and difference of mean ICP reduction
was 2.0 mmHg (CI 1.6–5.7) in favor of hypertonic saline, however
meta-analysis only had 112 patients with 184 episodes of elevated ICP
from 5 small randomized controlled trials [78]. A systematic review of
36 studies (11 prospective randomized, 15 prospective observational
and 10 retrospective trials) by Mortazavi et al. [79] reported that hy­
pertonic saline is more effective in reducing elevated ICP per the larger
portion of the studies however given heterogeneity of the data,
meta-analysis could not be performed and it would be imprudent to
draw any conclusion. Another systematic review of seven studies in the
setting of traumatic brain injury by Boone et al. [56] found that both
mannitol and hypertonic saline were effective in reducing ICP; however
had same issue as other systematic review making it impossible to draw
definite conclusions. A systematic review and meta-analysis by Lazaridis
Clinical Neurology and Neurosurgery 206 (2021) 106704
1954-1958
Javid and
Selage used
Urea in 1980s
different Hypertonic
Neurosurgical Saline re-
sengs emerged
1950 Smythe 1960s Urea fell 1990s
used IV urea in out of favor Hypertonic
monkeys due to side saline
effects aer its surpassed
wide use and Mannitol owing
was replaced by to its less side
Mannitol effect profile
et al. [68] found that highly concentrated hypertonic saline such as
23.4% saline provides a small volume solution with exceedingly high
osmolarity capable of resulting in an over 50% reduction effect on raised
ICP; however, there is no adequate data to compare the effect of 23.4%
saline to that of equi-osmolar doses of mannitol.
Limitation of above clinical trials precludes us from making prefer­
ential recommendation of one agent over another. A large randomized
controlled trial is needed to make any concrete recommendations. While
we wait for such clinical evidence there are numerous biochemical,
physiological and side-effect consideration that clinicians need to
consider while selecting hyperosmolar therapy for their patients. An
online survey of the Neurocritical Care Society members found that 90%
of members used hyperosmolar agents as needed for intracranial hy­
pertension, though a minority reported initiating treatment prophylac­
tically. Further, practitioners were fairly evenly split between those who
preferred hypertonic saline (54.9%) and those who preferred mannitol
(45.1%), with some respondents reserving hypertonic saline for patients
with refractory intracranial hypertension [80].
8. Conclusions
From a serendipitous discovery, hyperosmolar therapy has become a
core component of medical management of cerebral edema and intra­
cranial hypertension and is widely used in the neurocritical care units
across the world (Fig. 1). While there has been evolution in management
of intracranial hypertension over years, the fruits of the original work
done by Weed and McKibben still finds its place in practice even after a
century from its original report in 1919 [10]. There are very few prac­
tices in medicine which has stood the test of time. The discovery of
hyperosmolar therapy has not only provided us a wealth of data for the
management of intracranial hypertension but has also allowed us to
develop new treatment strategies by improving our understanding of the
molecular mechanisms of cerebral inflammation, blood-brain perme­
ability, and cerebral edema in all modes of neuronal injury [35,81]. Our
knowledge on the pathophysiology of cerebral edema and intracranial
hypertension is still evolving, in the meanwhile, we will continue to
carry on the legacy left behind by Weed and McKibben.
Declaration of Competing Interest
None
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