Emergency Care Journal 2024 volume 20:12310

Comparative efficacy analysis of mannitol and hypertonic saline

in the management of traumatic brain injury: a scientific exploration
of neuroprotective strategies
Nagaraju Kishore, Leema Lobo, Manjari Sharma
Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, PES University, Bangalore, India

While Mannitol has been a longstanding choice, recent attention

Abstract has shifted towards HS due to its reported superiority in ICP reduc-
In the management of severe traumatic brain injuries (TBIs), tion. Concerns associated with mannitol, such as hypotension and
controlling intracranial pressure (ICP) is a pivotal therapeutic goal. rebound ICP, are juxtaposed against the potential advantages
Historically, mannitol has been the recommended first-line osmot- offered by HS. The scarcity of clinical studies focusing on TBI-
ic agent; however, concerns surrounding its use, including related outcomes, such as patient survival and long-term benefits,
hypotension, rebound ICP elevation, and renal toxicity, have is highlighted, underscoring a critical gap in the current knowledge
prompted a quest for alternative strategies. Hypertonic saline (HS) landscape. The review aims to provide a nuanced understanding of
has emerged as a promising substitute, demonstrating efficacy in the comparative effectiveness of Mannitol and Hypertonic Saline,
considering not only ICP control but also broader patient out-

ly
reducing ICP without compromising cerebral perfusion. This com-
prehensive analysis explores the comparative effectiveness of comes. By addressing the suitability of these agents in diverse clin-

on
Mannitol and Hypertonic Saline in the context of severe TBIs. ical settings, this analysis seeks to guide clinicians in making
informed decisions tailored to individual patient needs.

e
Correspondence: Nagaraju Kishore, Department of Pharmacy us
Practice, Faculty of Pharmaceutical Sciences, PES University,
560050 Bangalore, India. Introduction
E-mail: nkishore2468@gmail.com
al
Traumatic Brain Injury (TBI) is on the rise as a leading cause
Key words: traumatic brain injury, mannitol, hypertonic saline, cere- of death and an important contributor to morbidity and mortality.
ci

bral edema, intracranial pressure, brain trauma, osmotherapy, fluid As seen by declining mortality rates, medical treatment for severe
management. TBI has advanced significantly in recent years.1 The “silent epi-
er

demic” of increased ICP is a prevalent life-threatening illness.2

Contributions: NK and LL, conceived and designed this systematic
Most neurological ailments principally traumatic brain injury can
m

review, analyzed the data, and drafted the content accordingly; NK,
LL, and MS performed the literature search; MS, edited and revised
cause cerebral edema which eventually leads to the condition of
om

the drafted content. All authors approved the final version of the Increased Intracranial Pressure (ICP). The main factor that causes
paper. death in patients with acute cerebral edema is thought to be elevat-
ed intracranial pressure also known as Intracranial Hypertension
(IH).3 Intracranial hypertension is one of the commonly seen clin-
-c

Conflict of interest: the authors declare no potential conflict of inter-

est, and all authors confirm accuracy. ical conditions in the intensive care unit which requires instant
on

treatment. The major goal of care is to maintain normal cerebral

Ethics approval and informed consent: not applicable.
perfusion pressure and Intracranial Pressure (ICP) to avoid sec-
ondary brain injury.4 IH is caused by a major Central Nervous
N

Availability of data and materials: all data generated or analyzed

during this study are included in this published article. System (CNS) injury or a side effect of a concurrent systemic ill-
ness. Acute Brain Injury (ABI), which is defined as any condition
Received: 25 January 2024. affecting the central nervous system, consists of two parts: a pri-
Accepted: 29 April 2024. mary brain damage that cannot be restored and a Secondary Brain
Early view: 27 May 2024. Injury (SBI). Any physiological occurrence that can happen min-
utes, hours, or days after the initial insult and causes additional
This work is licensed under a Creative Commons Attribution 4.0
License (by-nc 4.0).
nerve damage is referred to as a SBI. Since it is primarily caused
by elevated ICP, it can be identified through medical evaluation
©Copyright: the Author(s), 2024 and ICP monitoring, and verified by imaging testing.5 Several sig-
Licensee PAGEPress, Italy nificant neurologic disorders share the pathologic state of elevated
Emergency Care Journal 2024; 20:12310 intracranial pressure, which is characterized by the addition of vol-
doi:10.4081/ecj.2024.12310 ume to the cranial vault.5 The brain, cerebrospinal fluid, and blood
are the three basic elements of the stiff structure known as the cra-
Publisher's note: all claims expressed in this article are solely those of
nium. The pressure inside the cranial vault will rise with any
the authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the reviewers.
increase in the volume of its contents.6 The capacity of the human
Any product that may be evaluated in this article or claim that may be skull ranges from 1400 to 1700 mL, and it is a rather unchanging
made by its manufacturer is not guaranteed or endorsed by the publisher. structure. According to biology, it is made up of 80% brain
parenchyma, 10% cerebrospinal fluid, and 10% blood. Since the

[page 31] [Emergency Care Journal 2024; 20:12310]

 Review

skull is thought to be an immutable volume, any rise in the volume endothelium barrier. The edematous fluid will eventually be
of its constituent parts or the inclusion of a pathologic component pushed into blood vessels and significantly aid in decreasing ICP.16
will lead to an increase in pressure inside the skull.7 Increased ICP However, major adverse effects are becoming more and more evi-
may result from cerebral edema or mass lesions in patients with dent, like rebound cerebral edema and acute renal failure. The
Traumatic Brain Injury (TBI). Ischemia and subsequent brain dam- potential negative effects of the hyperosmolar drug are to be taken
age may result from elevated ICP because it lowers Cerebral into account while deciding whether to administer it. Strong diuret-
Perfusion Pressure (CPP) to the point where Cerebral Blood Flow ics like mannitol can increase the potential of injury to the kidneys
(CBF) may deteriorate significantly.8 TBI, stroke, intracranial in hypovolemic patients. mannitol causes osmotic diuresis, the ini-
hemorrhage, intracranial infection, hydrocephalus, brain tumor, as tial quick rise in intravascular volume paradoxically has the poten-
well as other neurological diseases, can all result in raised ICP as tial to lead to acute hypervolemia and, can cause cardiac failure or
a consequence.9 The location and degree of brain damage due to pulmonary edema in vulnerable patients.17 In the aftermath of brain
increased ICP are related to the neurological outcome, although damage, mannitol is frequently administered to lower elevated
edema or infarction of the perilesional tissue are also causally intracranial pressure. Initially, mannitol reduces the swelling, but
related to permanent deterioration and death.10 there is proof that continued use over time can eventually make the
pressure worse. When it comes to the pre-operative treatment of
patients with acute cerebral hemorrhages, high-dose mannitol
seems to be preferred to conventional-dose mannitol. The use of
Management of the intracranial hypertension mannitol as a continuous infusion in patients with elevated
After supportive care, which is crucial for neuroprotection, intracranial pressure who do not have an operative cerebral hemor-
hyperosmolar treatment is the medical standard for treating ICH. rhage is, however, not well supported by the available research.
Mannitol and hypertonic saline are the two osmotic agents current- The ideal administration of mannitol after an acute traumatic brain

ly
ly used for this purpose.11 The application of hyperosmolar solu- injury is still a subject of much debate. Mannitol’s present
widespread use and the dearth of knowledge when compared with

on
tions has been one of the main medical treatments for cerebral
edema. Over the past century, there has been a significant evolu- other medicines that lower intracranial pressure still require appro-
tion in the therapeutic targets, the medicines utilized, and how they priate investigation.18
are administered. The first to describe the ability of hyperosmolar

e
liquids to reduce nerve tissue was Weed and McKibbens in 1919. us
They discovered that administering free water caused brain
swelling while infusing a 30% saline solution significantly reduced Hypertonic saline
brain volume.12 Several substances, including 50% glucose, 50% To lower intracranial pressure after traumatic brain injury,
al
sucrose, 25% sodium chloride, 25% urea, 50% magnesium sulfate, hypertonic saline is utilized as a hyperosmolar treatment. It is still
ci

glycerol, concentrated albumin, and concentrated plasma, were debatable whether hypertonic saline is more successful than other
examined for the purpose. The warning that “most of these dehy- intracranial pressure-lowering medications in the short- and long-
er

drating substances have only a transient effect, which may be fol- term therapy of acute traumatic brain injury.19 Still, there are sev-
lowed by a “rebound phenomenon” during which the intracranial eral potential ways for how intracranial hypertension may be treat-
m

pressure can rise above that which existed before their administra- ed with Hypertonic Saline (HS). By establishing a pressure gradi-
tion” was included in the literature used to temper its use.13 ent within the intracellular and intravascular spaces and by exhibit-
om

However, during neurosurgery or critical care unit admissions, ing some rheological effects, the HS has demonstrated a biphasic
hyperosmolar solutions are frequently used to lower ICP and brain reduction in ICP. Fluid moves osmotically from the intracellular
volume.14 into the interstitial and intravascular area as a result of this gradi-
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ent. The hypertonic saline administered must remain in the

on

intravascular area and not penetrate the blood-brain barrier to sus-

tain this osmotic gradient.20 HS serves as a plasma volume
Mannitol expander and has an osmotic impact on the cerebral interstitium.
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Brain edema can be caused by a variety of neurosurgical con- There is proof that hypertonic saline has neurohumoral and
ditions, most notably craniocerebral trauma, which can then vasoregulatory effects as well. In the context of vasospasm, it may
increase ICP. The main factor that causes mortality among individ- also operate as a cerebral vasodilator.21 With the administration of
uals with acute cerebral edema is thought to be elevated pressure. HTS, ICP reduction is safe to achieve. In those who have therapy-
Mannitol’s usefulness as a regularly used medication to lower ICP resistant rise of ICP, repeated bolus administration of HTS may
has long been acknowledged.15 1,2,3,4,5,6-hexanehexol, often result in a considerable reduction in ICP. A proper ICP reduction
known as mannitol (C6H8(OH)6), is a naturally occurring polyol can prevent subsequent damage and potentially life-threatening
that is largely employed for its osmotic diuretic characteristics. consequences.22 When utilized for patients with head injuries com-
Mannitol decreases ICP by raising intravascular osmotic pressure, pounded by hemorrhagic shock, the benefit of improved survival
which draws extracellular fluid into the intravascular compartment was noted, leading to the initial recognition of HTS as a potentially
since it cannot cross the endothelium membrane. By increasing more successful alternative for hemorrhagic shock resuscitation.
plasma volume, mannitol initially reduces blood viscosity while HTS is typically administered as a bolus or continuous infusion at
also increasing microvascular flow and tissue oxygenation. dosages of 1.0 to 4.0 mL/kg, with a concentration range of 3.0% to
Increased tissue perfusion causes a vasoconstriction reflex, which 23.4%.23 The administration of HS needs to be taken into account,
reduces blood flow to the brain and lowers ICP. Meanwhile, man- it may result in demyelination syndrome in patients with a chronic
nitol causes a rise in intravascular osmotic pressure, widening the condition of hypernatremia and hyponatremia.24 To prevent the
osmotic gradient between the intravascular and extravascular com- negative effects, a periodic electrolyte serum check may be
partments due to its size and difficulty in permeating through the required. Because HS has a higher coefficient to cross the brain

[Emergency Care Journal 2024; 20:12310] [page 32]

Review

barrier than mannitol, the rebound phenomenon is less frequent the urine together with an excess of free water, which may lead to
when administered with HS.21 hypernatremia because of the induced diuresis.37 Mannitol also
worsens the cerebral edema. It partially penetrates the vessel wall,
despite its limited cross-sectional area, in individuals with cerebral
hemorrhage, mannitol crosses the vascular wall more readily.
Intracranial pressure monitoring Mannitol can penetrate the blood-brain barrier when taken
For most healthcare workers, including neurological surgeons fequently, which can exacerbate cerebral edema because the man-
and physicians, ICP is equivalent to a numerical figure. It might be nitol draws water into the brain rather than out of it. Mannitol treat-
the amount of fluid in an irrigation system or the value displayed ment may cause patients’ cerebral edema to deteriorate, particular-
on the display of the computer in millimeters of mercury ly in children with cerebral hyperemia.38 Hypertonic Saline
(mmHg).25 ICP is much more than just a number. To enhance clin- Solution (HSS) restores intracranial compliance, extracts fluid
ical decision-making, a variety of ICP ratings and ICP-derived from the interstitial space, and lowers intracranial pressure, mostly
assessments have been investigated.26 Normal mean ICP readings by preventing the buildup of extracellular osmolytes in the brain
have not been determined since ICP assessments in individuals in that is associated with blood-brain barrier malfunction.39 For the
good health cannot be justified ethically. Only indirect evidence treatment of increased ICP, mannitol remains the cornerstone of
concerning ICP from people who are “as normal as possible” is hyperosmolar therapy, however, a bolus infusion of HSS is more
available. The aim, by TBI guidelines, is to keep mean ICP under effective.40 Thus in TBI patients without ICH, continuous HSS
20 mmHg.27 The mean ICP values don’t seem to alter between the infusion enhanced Cerebral Perfusion Pressure (CPP), raised
hours of day and night.28 The average mean ICP values, on the natremia and osmolarity, and reduced the likelihood of ICH.41
other hand, are significantly dependent on body posture. The mean
ICP decreases when a person stands up straight. reported that the

ly
positional variation in mean ICP might distinguish healthy persons
from CSF disturbance patients. In our clinical practice, mean ICP Comparison of hypertonic saline and mannitol

on
in a standing position of less than 5 mmHg is considered Intracranial pressure is a key indicator of decline in neurolog-
abnormal.29,30 To add clinical significance to mean ICP alone, it has ical function in patients with traumatic brain injury.42 It has also
been coupled with additional variables to form multiple indices.

e
been demonstrated that when cerebral perfusion pressure is severe-
CPP, which is the variation between average arterial BP and aver- ly low (50 mm Hg), intracranial pressure becomes an indicator of
us
age ICP (CPP = mean arterial BP-mean ICP), is probably the most undesirable outcome, and maintaining intracranial pressure in the
well-known ICP-derived measure.31 Other indicators employed in range of 18 to 23 mmHg verifies that cerebral perfusion pressure
certain centers include the RAP, which stands for the relationship remains constant for a longer period.43 Mannitol has been utilized
al
between amplitude and pressure, and the pressure reactivity for years to treat elevated intracranial pressure. Recommendations
index(PRx).32 A RAP greater than 0.6 has been regarded as indicat-
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recently suggested that mannitol is more efficient than barbiturates

ing a deteriorated pressure-volume reserve.33 The PRx (moving in lowering intracranial pressure in people with traumatic brain
er

association of average ICP and average arterial BP) is thought to injury.44 Mannitol, causes a decrease in cerebral perfusion pressure
be an indicator of auto-regulatory status or a measure of cere- due to its diuretic mechanism of action, which can cause the devel-
m

brovascular responsiveness.34 opment of several adverse effects, including edema in the lungs,
acute kidney dysfunction, and arterial hypotension, which causes a
om

decrease in cerebral perfusion pressure due to its diuretic impact.45

In a Randomised prospective trial conducted by Vialet et al., the
Hyponatremia: an emergency in traumatic brain patients were randomly assigned to one of the two groups: one that
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injury received 7.5% hypertonic Saline (361 mOsm) and one that
on

The primary electrolyte imbalance seen in individuals with received 20% mannitol (175 mOsm) in the same amount (2
TBI is hyponatremia and is considered as most emergency, which mL/kg). In comparison to hypertonic saline, the mannitol group
is defined as serum sodium <135 meq/L. Hyponatremia has been had greater total and duration of daily periods of ICP > 25 mmHg
N

documented to occur in 9.6% to 51% of TBI patients, and it is and needed more CSF fluid drainage. This study also found that
well-known that hyponatremia independently predicts a poor neu- treatment failure was 70% higher in the mannitol group compared
rologic prognosis in TBI patients. The Syndrome of Inappropriate to 10% in the hypertonic saline group. There was no significant
Antidiuretic Hormone Secretion (SIADH), hypopituitarism, difference in mortality or neurological improvement after 90 days.
Cerebral Salt Wasting Syndrome (CSW), and insufficient salt con- It was noted that the study used both fluids with different osmolar-
sumption in the diet are the major causes of hyponatremia in TBI ities.46 The optimum therapeutic agent for controlling intracranial
patients.35 Following traumatic brain injury, dysregulation of the pressure should reduce intracranial pressure while maintaining
neuroendocrine system is a common consequence (TBI). These cerebral perfusion. Hypertonic saline boosts serum sodium and
hormone imbalances often have mild symptoms that are simple to osmolality considerably. Excessive salt levels and osmolarity pro-
overlook. Usually, hyponatremia is a sign of underlying illnesses duce an overload of volume, edema of the lungs, and heart failure,
that interfere with fluid homeostasis. Hyponatremia is a character- or they might begin coagulopathy and hyperchloremic metabolic
istic of the SIADH following brain injury in the majority of TBI acidosis. Thus, hypertonic solutions should be administered with
patients, which is caused by pituitary failure. Hyponatremia linked caution and under constant cardiac surveillance in individuals with
to traumatic brain injury is often temporary and curable.36 When impaired cardiac function.47-48 In patients with head trauma
mannitol is administered to reduce intracranial pressure in traumat- (whether single or numerous injuries), it is important to avoid
ic brain injury intravascular free water content is first raised, which hypotension, since it boosts the incidence of mortality in this con-
might exacerbate electrolyte imbalances, such as hyponatremia. text.49 In contrast to mannitol, an osmotic diuretic, HTS preserves
The second phase of action involves the excretion of mannitol in and even improves the mean arterial blood pressure in various

[page 33] [Emergency Care Journal 2024; 20:12310]

 Review

kinds of shock.50 Isotonic resuscitation using fluids in the trauma tran, restores intravascular volume with less volume,58 raises CPP,
circumstance, necessitates a large amount of fluid, which can raise decreases ICP,59 and regulates the inflammatory response.60-67 The
ICP. The significant benefit of HTS in this context is that blood beneficial effect of HTS over mannitol in terms of potential long-
pressure is maintained with minimal volume resuscitation, pre- term neurological consequences is still unknown. To solve this
venting possible iatrogenic ICP elevations.51 Intravenous adminis- topic, a substantial prospective randomized investigation is
tration of hypertonic saline increased cerebral perfusion and shift- required. Many of the issues have yet to be resolved, necessitating
ed the oxygen dissociation curve, thus boosting the availability of more studies to reach a firm judgment on the supremacy of these
oxygen and brain responsiveness while decreasing intracranial hyperosmolar drugs.
pressure and cerebral edema.52 HTS may have a role in brain cell
immune system regulation, perhaps leading to beneficial effects on
inflammation and a better prognosis for TBI patients. The inflam-
matory cascade is activated by severe trauma, resulting in systemic Evidence linking management of cerebral edema
allergic reaction syndrome. Furthermore, cerebral leukocytes in traumatic brain injury
move to wounded regions in response to TBI, resulting in peroxi-
There have been few research that compare mannitol with HTS
dase- and protease-mediated cell death.53 The study conducted by
in the context of pure cerebral relaxation in tumors. De Vivo et al.
Battison et al. in 2005 discovered that both mannitol and hyperton-
undertook a prospective, randomized comparative analysis of
ic saline considerably lowered ICP, however hypertonic saline dra-
supratentorial tumors. The study concluded that HTS is an efficient
matically reduced ICP more strongly and for an extended period
way to reduce ICP in people without affecting CVP or serum
than mannitol. The usage of the identical osmolarity between the
osmolality. It is unlikely to cause anaphylaxis or spread infectious
two fluids is the study’s key strength.54 In the final analysis, man-
agents, and serum Na levels can readily regulate it. It is a viable
nitol is regarded as the “standard of care” treatment for TBI-
alternative to mannitol in intracranial surgery.68 Several investiga-

ly
induced intracranial hypertension because of its historical use
tions have examined the cerebral effects of mannitol and HTS in
rather than its efficacy against HTS. HTS offers numerous theoret-

on
patients with normal ICP. Gemma et al. found that HTS and man-
ical benefits over mannitol in terms of physiology. In clinical
nitol produce acceptable cerebral relaxation in individuals under-
terms, HTS appears to be more effective than mannitol in lowering
ICP, both in terms of degree and duration of decrease. Ultimately, going elective craniotomy. This investigation was carried out using

e
HTS appears to promote brain tissue oxygenation more than man- several neurosurgical techniques and non-equimolar dosages of
nitol. All of these benefits imply that HTS should be thoroughly HTS and mannitol.69
us
researched so that it might potentially be utilized as an alternative The clinical evidence comparing hypertonic saline and manni-
to mannitol as a first-line treatment for the management of elevat- tol is discussed in the Supplementary Materials, Table 1.70-77
A summary of the comparison of safety efficacy profile of
al
ed ICP in TBI patients. It is uncertain if a bolus dosage or an infu-
sion is required. The bolus dosage was administered at various pro- mannitol and hypertonic saline is available in the Supplementary
ci

portions with no indication of superiority of any concentration in materials, Table 2.

particular, although total osmolar load must be considered.
er

Infusions with 3% HTS at a rate of 0.1-2mL/kg/h have been

m

proven to be successful, with step-wise titration of the dosage to a

goal of 145-155mEq/L NA+ (maximum 160mEq/L) and an osmo-
Conclusions
om

lality of 320-330mOsm/L (maximum 360mEq/L). According to The significance of Intracranial Pressure (ICP) in managing
the literature, HTS infusion decreases ICP over 72 hours, however, conditions like traumatic head injuries and various neurologic dis-
this effect cannot be sustained with continued treatment. The bolus eases cannot be overstated. It is crucial to recognize that the prima-
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dosage can be administered alone or in conjunction with continu- ry objective of ICP management is to optimize cerebral perfusion
ous infusion treatment. It is also used to reduce ICP in people who pressure (CPP) for the preservation of cerebral metabolism and
on

have not had surgery.55 In the study conducted by De Vivo et al. the neurologic function. Solely concentrating on ICP, without consid-
first group received mannitol, the following one received ering other relevant physiologic variables such as CPP, oxygen uti-
Mannitol+HTS, and the third group received solely HTS and the lization, and clinical outcomes, is a notable flaw in numerous pub-
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treatment continued for 72 hours, utilizing boluses three times each lished randomized controlled trials (RCTs) focusing on hyperos-
day. They concluded that HTS is a viable option for decreasing ICP molar therapy. Regardless of the specific hyperosmolar agent
in humans without affecting CVP or serum osmolality. It is unlike- employed, the efficacy of hyperosmolar therapy for acute ICP
ly to cause allergic responses or to transfer infectious agents, and management has been substantiated by both clinical experience
it is readily managed by serum Na levels. In intracranial surgery, it and RCTs. Mannitol and HS are the most commonly used hyper-
is an acceptable substitution for mannitol.56 Following elective osmolar agents, each with distinct physiologic properties affecting
craniotomy, mannitol, and HTS enhance CSF osmolality and are blood rheology, inflammation, neurochemistry, and hemodynamic
associated with comparable levels of cerebral relaxation, arteriove- regulation. While the idea of a universally applicable, single opti-
nous O2 differential, and lactate. They propose that HTS should be mal agent is appealing, it is more plausible that different hyperos-
employed instead of mannitol to reduce brain size in patients with molar agents may exert optimal therapeutic effects in diverse clin-
and without subarachnoid hemorrhage, especially if they are ical contexts. For example, the relative merit of using HS, which
hemodynamically unstable.57 Resuscitation with fluids is crucial in expands systemic volume status, versus mannitol, which depletes
TBI patients because it prevents hypotension and subsequent brain it, needs exploration in patients with congestive heart failure expe-
damage, both of which increase mortality. The Brain Trauma riencing elevated intracranial hypertension. Trials should consider
Foundation’s care recommendations for TBI state unequivocally testing equimolar agents infused over the same period to mitigate
that hypotension must be avoided since it is an independent char- the effects of molarity and infusion time, a consideration often
acteristic of poor prognosis. The administration of fluids in this absent in existing literature. In conclusion, a thoughtful analysis of
patient, particularly with HTS alone or in combination with dex- individual clinical scenarios, coupled with a rigorous interpretation

[Emergency Care Journal 2024; 20:12310] [page 34]

Review

of existing literature, is essential for providing optimal patient 19. Chen H, Song Z, Dennis JA. Hypertonic saline versus other
care. intracranial pressure–lowering agents for people with acute
traumatic brain injury. Cochrane Database Syst Rev
2020;1:CD010904.
20. Surani S, Lockwood G, Macias MY, et al. Hypertonic saline in
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Online supplementary material:

Table 1. Clinical evidence comparing hypertonic saline and mannitol.
Table 2. Summarising the comparison of safety efficacy profile of mannitol and hypertonic saline.

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