Clinical Neurology and Neurosurgery 200 (2021) 106359

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Clinical Neurology and Neurosurgery

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

Comparison of equiosmolar doses of 10% hypertonic saline and 20%

mannitol for controlling intracranial hypertention in patients with large
hemispheric infarction
Yingying Su *, Yifei Liu , Zhongyun Chen , Lili Cui
Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing 100053, China

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

Keywords: Objective: We conducted this prospective self-crossover controlled trial to compare the efficacy and safety of 10 %
Hypertonic saline hypertonic saline (HS) and 20 % mannitol in doses of similar osmotic burden for the treatment of increased
Mannitol intracranial pressure (ICP) in patients with large hemispheric infarction (LHI).
Intracranial pressure
Patients and Methods: Patients with LHI were enrolled from January 2017 to January 2018. We used an alter­
Large hemispheric infarction
nating treatment protocol to compare the effects of HS with mannitol given for episodes of increased ICP in
patients with LHI. Indicators such as ICP, mean arterial pressure (MAP) and cerebral perfusion pressure (CPP)
were continuously monitored at regular intervals for 240 min after initiation of infusion. Electrolytes, plasma
osmolality and renal functions were measured before and 240 min after initiation of infusion to compare the
efficacy and safety of the two drugs.
Results: A total of 49 episodes of increased ICP occurred in 14 patients with LHI, of which 24 were infused with 10
% HS and 25 with 20 % mannitol. Both the treatments were equally effective in reducing ICP (P < 0.01). The
differences in the duration and degree of reduction were not significant between the groups (P > 0.05). Although
both the osmolar agents decreased MAP, the degree was greater in the mannitol group (P < 0.05) at T120. The
increase in CPP was greater in the HS group compared with the mannitol group (P < 0.05) at T120. However, HS
was associated with faster heart rate (HR) and higher serum chloride levels (P < 0.05). Changes in serum sodium
levels and osmolality were not significant between the groups in spite of being higher in the HS group.
Conclusions: Both the drugs can serve as first-line agents for treating intracranial hypertension caused by LHI and
should be selected rationally according to the differences in efficacy and adverse effects.

1. Introduction
Large hemispheric infarction (LHI), also known as malignant middle
cerebral infarction, is a devastating disease with the mortality rate as
high as 80 % [1]. Death mainly is caused by severe post-ischemic brain
edema leading to increased intracranial pressure (ICP), clinical deteri­
oration, coma, and death [2,3]. Reducing ICP and improving cerebral
perfusion pressure (CPP) have, thus, become important goals for saving
lives and improving prognosis. Although decompressive craniectomy
(DC) can reduce the mortality rate to 38 % [4,5], intravenous hypertonic
injection is still an important non-invasive option for non-surgical pa­
tients to help them pass through the most dangerous period or
pre-operative choice for patients with DC to gain operation time and
opportunity.
Mannitol is a most commonly used osmotic agent and has served as
the recommended first-line agent for years [6]. However, hypertonic
saline (HS) has attracted increasing attention in recent years, with
several studies showing its enhanced potency over mannitol. A
meta-analysis in 2015 showed that HS reduced ICP more effectively and
for a longer duration than mannitol in traumatic brain injury (TBI) [7].
A major flaw in all these studies was the use of varying and
non-equiosmolar concentrations making it difficult to find the most
appropriate osmolar agent with salutary effect on ICP. Besides, clinical
studies have shown that continuous intravenous infusion of HS,
precipitated in rapid elevation in sodium, increased burden of cardio­
pulmonary and renal dysfunction, coagulation disorder and even
life-threatening events [8]. Therefore, the safety, effectiveness and scope
of application of HS deserve further study. It is still not clear whether HS

* Corresponding author at: Department of Neurology, Xuan Wu Hospital, Capital Medical University, No. 45, Changchun Street, Xicheng District, Beijing, China.
E-mail address: suyingying@xwh.ccmu.edu.cn (Y. Su).

https://doi.org/10.1016/j.clineuro.2020.106359
Received 24 October 2020; Received in revised form 4 November 2020; Accepted 5 November 2020
Available online 11 November 2020
0303-8467/© 2020 Elsevier B.V. All rights reserved.
Y. Su et al.
is effective and safe for treating LHI with intracranial hypertension.
Therefore, this randomized controlled crossover study was designed to
compare the efficacy of equi-osmolar solutions of HS (10 %) and
mannitol (20 %) and on ICP, systemic hemodynamics and short-term
adverse effects in LHI patients with increased ICP.
2. Material and methods
2.1. General design
This prospective self-crossover controlled trial was conducted at the
Neurointensive Care Unit of Xuanwu Hospital. The design of this study
was approved by the Medical Ethics Committee of Xuanwu Hospital of
Capital Medical University (Approved No. of ethic committee: [2016]
024) and informed consents were obtained from patients’ relatives. The
trial was registered in the Chinese Clinical Trial Registry (ChiCTR-IPR-
17010545).
2.2. Patients population
Patients with LHI- confirmed by cranial computed tomography (CT)/
magnetic resonance imaging (MRI)-admitted to the neurological inten­
sive care unit of Xuanwu Hospital of Capital Medical University from
January 2017 to January 2018 were enrolled in the study. Eligibility
criteria were as follows: (1) age between 18 and 80 years; (2) diagnosed
within 3 days of onset; (3)infarction involving at least two-thirds of the
MCA territory, with or without additional infarction in the territory of
the ipsilateral anterior or posterior cerebral artery on cranial CT or MRI;
(4) a National Institute of Health Stroke Scale score (NIHSS) ≥15 if the
nondominant hemisphere was affected or ≥20 if the dominant hemi­
sphere was affected; (5) somnolence, or full outline of unresponsiveness
(FOUR) score of ≦ 14 points, or a Glasgow Coma Scale (GCS) score of ≦
12 points..
Exclusion criteria included: (1) congestive heart failure, (2) acute
myocardial infarction, (3) shock (systolic blood pressure of <90 mmHg),
(4) respiratory failure (PaO2 of <60 mmHg, PaCO2 of >50 mmHg), (5)
renal failure (Cr of >2 mg/dL), (6) hypoproteinemia (white Protein of
<25 g/L); (7) electrolyte disorders (blood sodium of >160 mmol/L,
serum potassium of > 5.0 mmol/L, (8) abnormal blood coagulation
(PLT < 100,000/mm3 or INR > 1.3), (9) increased plasma osmolality
(>340mOsm/L), (10) other serious complications that could not be
corrected in a short time; (11) anisocoria/ bilateral dilated pupil with no
light reaction; (12) pregnancy or postpartum perioperative period; (13)
severe scalp tissue infection that is not suitable for ICP monitoring.
2.3. Standard medical treatment
All patients received standard medical treatment, including head-of-
bed elevation at 30 degrees or higher, core body temperature was
maintained between 36.5 and 37.5℃. Other vitals were as follows:
systolic blood pressure of <220 mmHg, mean arterial pressure (MAP) of
≥ 90 mmHg, blood oxygen saturation of > 93 %, PO2 of 75–100 mmHg,
PCO2 of 35–45 mmHg, blood sugar of 7.8–10 mmol/L, maintaining
water, electrolyte and acid-base balance, infection control, early initia­
tion of intestinal nutrition (within 48 h). All enrolled patients underwent
ICP monitoring (Codman Microsensor ICP Monitoring System). ICP was
measured with an intraparenchymal sensor and sensors were placed in
frontal of ipsilateral infarction(2.5 cm lateral to the median sagittal line
and 2.5 cm posterior to the hairline).
2.4. Study protocol
Using a computerized random number generator, patients were
randomized either to the mannitol or the HS group.Osmolarity of 20 %
mannitol is 1110 mOsm/l and that of 10 % HS is 3422 mOsm/l, hence,
200 ml of 20 % mannitol and 65 ml of HS will have equal osmolality
2
Clinical Neurology and Neurosurgery 200 (2021) 106359
(220 mOsm/L vs. 222 mOsm/L). Patients in the mannitol group received
20 % mannitol at the rate of 400 ml/h followed by HS. In the HS group,
patients received10 % HS at the speed of 130 ml/h followed by 20 %
mannitol.
In the episodes of ICP ≥ 15 mmHg lasting for more than 5 min (not
related to short-term external stimuli), or pupillary changes (anisocoria
or slow light reflex), osmotic agents was infused through the central
vein.
The osmotic agent was considered effective if the decrease in ICP was
more than 10 % of baseline value or improvement in pupillary abnor­
mality occurred within 60 min of infusion [9]. Otherwise, it was
considered ineffective. The next osmotic agent could be given immedi­
ately if the previous osmotic agent was ineffective. The experiment was
terminated if both osmotic agents were ineffective and other measures
were taken to reduce ICP. No other ICP-lowering measures such as over
ventilation, barbiturate therapy, hypothermia therapy, invasive surgical
intervention were given during the experiment.
2.5. Assessment of efficacy and safety
ICP, MAP, CPP, pupil size and pupilary light reflexes were recorded
at regular intervals for 240 min (T0, T15, T30, T45, T60, T120, T180,
and T240 min) after initiation of infusion to compare the efficacy of the
two drugs. Vital signs such as heart rate (HR), respiratory rate were
recorded from T0 to T240 min and sodium; potassium, chlorine, creat­
inine, urea nitrogen and osmolality were recorded at T0 and T120 after
the infusion to compare the safety of the two drugs. The difference value
of ICP, MAP, CCP, HR were defined as the difference before and after the
hyperosmolar fluid infusion (eg. △ICPT45=ICPT0-ICPT45).
2.6. Statistical analysis
Data was processed using SPSS version 18.0 statistical software.
Quantitative data are presented as a mean ± SD. Comparison of nor­
mally distributed quantitative data was done by independent t-test.
Repeated-measures ANOVA were used for evaluating the effect of HS
and mannitol over various physiological and clinical parameters.
Tukey–Kramer multiple comparison for post-hoc analysis was used
when appropriate. P value less than 0.05 was considered significant.
3. Results
3.1. Patient characteristics
Seventy-four patients were admitted to our unit with hemispheric
stroke. Thirty-one family members of patients who refused to perform
invasive ICP monitoring were excluded, and eighteen patients were
excluded due to <2/3 of MCA territory affected and NIHSS < 15, and
eleven patients were excluded due to comorbidities, such as congestive
heart failure, renal failure, electrolyte disorders, et al. A total of 14 pa­
tients with LHI were enrolled, including 6 males and 8 females; aged
between 31 and 76 years (average 61.36 year). Clinical features are
listed in Table 1. Each patient had at least 1 episode of increased ICP
(range 1–6 episodes, average 3.5 episodes). A total of 49 episodes of
increased ICP were found, including 3 episodes of ICP = 15 mmHg and
46 episodes with ICP of >15 mmHg (25 episodes of 15–19 mmHg, 24
episodes of 20–45 mmHg, average 21.04 mmHg). Seven patients (13
episodes) had anisocoria or lack of pupillary reflex. In 49 episodes of
increased ICP, 24 were infused with HS, and all were judged effective;
25 were infused with mannitol out of which 4 episodes (16 %) were
judged ineffective. The time of medication ranged from 2− 66 hours
(average 15.5 h)
3.2. Comparison of ICP
Both HS and mannitol significantly reduced ICP to baseline
Y. Su et al. Clinical Neurology and Neurosurgery 200 (2021) 106359

Table 1 3.5. Comparison of side effect

Clinical features.
Variable All patients (N = 14) Vital signs prior to the treatments were similar between the two
groups. HR was higher in the HS group and reached statistical signifi­
Age, years, median (range) 62(31,76)
Male (%) 6(42.9) cance at T30, T45, T60 compared to the mannitol group (P < 0.05)
Left hemisphere (%) 7(50) (Fig. 3), while there was no difference in temperature, respiratory rate
NIHSS, median (IQR) 20(18,26) and oxygen saturation after treatment.
GCS, median (IQR) 8(6,11) There was no difference in serum potassium, sodium, chloride,
Intravenous thrombolysis (%) 3(21.4)
Maximum ICP, mmHg, median (IQR) 24(18,28)
creatinine, urea nitrogen, and plasma osmolality between the two
Minimum ICP, mmHg, median (IQR) 17(16,21) groups before treatment (P > 0.05). Changes in serum sodium levels and
Mechanical thrombectomy (%) 2(14.3) osmolality were not significant between the groups in spite of being
Tentorial herniation (%) 7(50.0) higher in the HS group. Compared with the mannitol group, only the
DC (%) 4(25.9)
serum chloride reached statistical significance at T120 (103.96 ± 3.77
Mortality (%) 2(14.3)
vs. 108.15 ± 3.67 mmol/L, P < 0.05).
Abbreviation: DCdecompressive craniectomy; GCSGlasgow Coma Scale; ICPin­ None of the 14 patients had drug-related acute heart failure, acute
tracranial pressure; IQRinterquartile range; NIHSSNational Institute of Health pulmonary edema, acute renal failure, moderate to severe electrolyte
Stroke Scale score.
(blood potassium, blood sodium, blood chlorine) disorder, moderate or
severe plasma osmolality change or permeability encephalopathy dur­
(repeated-measures ANOVA, main effect of measurement time ing the period of medication.
P < 0.000). The mean ICP before treatment was >20 mmHg, reaching
15 mmHg by T30 in the mannitol group and T45 in the HS group. ICP
reached the lowest at T120 in both the groups. While, HS continued to 3.6. Outcome
lower the ICP till T240, mannitol had begun to rebound by this time
(Fig. 1). Despite better results with HS at all ime points except for T180 Tentorial herniation was observed in 7 patients (50.0 %), 3 of whom
(Fig. 2B), the ICP reducing effect was not statistically significant from were reversed by intravenous hypertonic injection, the rest of patients
the mannitol group (repeated-measures ANOVA, P = 0.520). underwent DC surgery, and 3 patients survived the operation.

3.3. Comparison of MAP 4. Discussion

In the mannitol group, MAP started to decrease at T15 and reached
the lowest at T120 and begun to rise at T240. In the HS group, however,
MAP remained stable at all ime points except for T60 (Fig. 1). There was
a significant difference in MAP at T120 between the two groups
(P < 0.01) (Fig. 2A). There was no significant of the overall effect be­
tween the two groups (repeated-measures ANOVA, P = 0.498) (Fig. 1).
3.4. Comparison of CPP
The mean CPP before treatment was >70 mmHg in both the groups.
The mean CPP values started to increase at T15 in the both groups,
peaked at T30 in the mannitol group and T180 in the HS group (Fig. 1).
The rate of the increase was better in the HS group at each time point
except for T60 and the difference in CPP at T120 were significant be­
tween the groups (P < 0.01) (Fig. 2C). However, the overall effect of the
two groups had no significant difference (repeated-measures ANOVA,
P = 0.302).
In this study, we found that both HS and mannitol can effectively
reduce ICP. HS tended to reduce ICP more effectively and for a longer
duration mannitol in patients with LHI, although there was no statistical
difference between the two groups. Mannitol had a greater impact on
MAP while HS increased CPP more effectively. Although the two drugs
had minimal effect on most of the physiological parameters, HS accel­
erated HR and increased serum osmium, chlorine and plasma
osmolality.
This study found that patients with LHI accompanied by disturbance
of consciousness had a high incidence of intracranial hypertension in
early stages. Even after treatment with antihypertensive drugs, 50 % of
them still suffered from tentorial herniation, which was consistent with
the reported incidence of LHI herniation (32 %–78 %) [10,11]. For
monitoring episodes of increased ICP, ICP monitoring is more sensitive
and accurate than pupillary observations. Therefore, ICP monitoring in
patients with LHI accompanied by disturbance of consciousness is
necessary for accurate treatment of ICP hypertension and also for
reduction of the frequency of invasive DC. Previous studies noted that
initial conservative management reduced DC rates without an excess of
death or survival with severe disabilities [12,13]. In case the drug
cannot prevent the progression of ICP, better pre-operative preparation

Fig. 1. Comparative trends of mean arterial pressure, intracranial pressure and cerebral perfusion pressure between M group(A) and HS group(B). There were
significant changes in ICP compared to baseline (T0) in both groups(Post-hoc analysis (Tukey-Kramer) – *P < 0.05 and #P < 0.01). MAP: Mean Arterial Pressure, ICP:
Intracranial Pressure, CPP: Cerebral Perfusion Pressure, HS: Hypertonic Saline group, M: Mannitol group.

3
Y. Su et al.
Fig. 2. Comparison the difference value of MAP(A), ICP(B), CPP(C) between
two groups after treatment. There were significant intergroup differences in
MAP and CPP (Student’s t-test- #P < 0 .01). MAP: Mean Arterial Pressure, ICP:
Intracranial Pressure, CPP: Cerebral Perfusion Pressure, HS: Hypertonic Saline
group, M: Mannitol group.
can be done before DC, to reduce the incidence of tentorial herniation
and mortality.
In this study, the decision to initiate osmotic therapy was made based
on neurological deterioration or ICP elevation above 15 mmHg, instead
of ≥20 mmHg. Parenchymal ICP monitoring may not reflect the exact
value of ICP due to pressure gradients within the central nervous system.
Poca et al. found that the incidence of tentorial herniation in LHI pa­
tients was 28.6 % with ICP of ≥20 mmHg and it increased by 8.3 % if
ICP ≥ 15 mmHg [14]. Sauvigny et al. found that ICP values in the
favorable and unfavorable outcome groups differed significantly in pa­
tients with LHI and TBI after DC, while the mean ICP lay below the limit
of 20 mm Hg in both the groups [15]. So, setting ICP of 15 mmHg as an
intervention threshold can be prognostic predictor which can help
4
Clinical Neurology and Neurosurgery 200 (2021) 106359
control the episodes early and improve the effectiveness of the therapy.
This study showed that both mannitol and HS effectively reduced ICP
to baseline. HS had a stronger and longer lasting ICP-lowering effect.
Therefore, HS can be an optimal and effective agent for lowering ICP,
especially if the clinical curative effect is not satisfactory with mannitol.
Osmotic agents work by creating osmotic gradient across the BBB by
exerting a shift of water from brain tissue into vascular space, reducing
brain edema, and therefore ICP [16]. The osmotic reflection coefficient
of sodium is higher than mannitol, making HS less likely to cross the BBB
and more potent in drawing fluid from the brain [17,18]. Furthermore,
there are reports suggesting that HS has other effects that may serve to
reduce ICP. It promotes laminar blood flow by hemodilution; shrinks
erythrocytes making them more deformable and enhancing their pas­
sage through capillaries [19]. These effects result in a biphasic reduction
in ICP after administration of HS: first by improving rheological prop­
erties, and then by osmotic activity through aquaporin receptors across
the BBB [20]. Besides, persistent reduction of ICP by HS has been related
to immune modulatory effects including reduction of microvascular
permeability [21]. A meta-analysis, published in 2011, of 5 RCT studies
on 112 patients with only 8 cases of ischemic stroke, showed that HS was
more effective in ICP control (RR: 1.16, 95 % CI: 1.00–1.33) than
mannitol [22]. Contrarily, a recently published meta-analysis of 12 RCT
studies including 438 patients with TBI revealed that HS was not su­
perior to mannitol in ICP control [23]. Because of several significant
methodological limitations such as small patient cohorts, complexicity
of included diseases and the use of varying and non-equiosmolar con­
centrations makes it difficult to interpret the findings of the previous
studies. Therefore, studies on osmotic drugs that can reduce ICP in pa­
tients with ischemic stroke need to be strengthened.
Mannitol decreased MAP while effectively reducing ICP. However,
MAP remained relatively stable in the HS group, making it a better
option for hypotensive patients. Mannitol, an osmotic diuretic macro­
molecule, cannot cross the BBB, draws water into the vascular
compartment and reduces the circulating blood volume, and thus MAP.
HS, on the other hand, with lower urine output and superior volume
expansion effect can maintain a better volume status in patients [24,25].
HS can increase cardiac output to ensure relative stability of blood
pressure by enhancing Na+-Ca2+ exchange, and extracellular calcium
content, enhancing myocardial contraction with intracellular dehydra­
tion and increasing of intracellular sodium [26].
The increase of CPP in HS group was more notable than the mannitol
group because HS had a stronger ICP lowering effect with minimal effect
on MAP. Therefore, HS would be an ideal choice for treatment in pa­
tients suffering from high ICP and low CPP. Al-Rawi et al. found that HS
significantly increased CPP by >20 % and lasted for more than 60 min in
patients with spontaneous subarachnoid hemorrhage [27]. In a recent
study performed in patients with TBI, Cottenceau et al. found that both
HS and mannitol elevated CPP and cerebral blood flow but this effect
was more obvious in the HS group [28].
In this study, we found that vital signs, serum electrolyte and renal
function were wihin the normal range within hours after infusion of HS
and mannitol. But notably, HS was associated with faster HR and higher
chloride levels. Higher serum sodium levels and osmolality seen with HS
were not significant compared with mannitol. Similar findings were
reported in various other studies. In a recent meta-analysis involving 12
randomized controlled trials (RCTs) with 438 patients, Gu et al. found
that both serum sodium and osmolality were increased after adminis­
tration of HS but not mannitol [23]. Studies also reported that HS was
associated with increasing risk of hypokalemia, renal damage, phlebitis,
venous thrombosis, which were not observed in this study. Serum so­
dium level greater than 160 mmol/L might contribute to higher mor­
tality, primarily from congestive heart failure and pulmonary edema due
to the rapid expansion of blood volume [29]. Therefore, it is imperative
that adverse reactions be closely monitored when treating with osmotic
agents.
This study has several limitations. Firstly, because each patient was
Y. Su et al.
Fig. 3. Comparison the absolute (A) and difference value(B) of HR between two groups. There was significant intergroup difference in difference value of HR at T30,
T45, T60. (Student’s t-test- *P < 0.05). HR: Heart Rate (beats/minute), HS: Hypertonic Saline group, M: Mannitol group.
given the drugs alternately, we cannot draw any conclusions on long-
term adverse effects and clinical outcomes. Secondly, the sample size
of this study was fairly small and therefore, it might affect the ability to
discern a difference between HS and mannitol. Also, slow patient
enrollment into the hemispherical stroke trials especially accompanies
invasive monitoring, is a real-world obstacle. Therefore, multicenter
randomized, controlled clinical trials with larger samples are needed to
validate the present findings.
In conclusion, we found that equi-osmolar doses of 20 % mannitol
and 10 % HS were equally effective in reducing ICP and either can serve
as the first-line agent in LHI patients. Although HS tended to be more
effective in increasing CPP and maintaining MAP stability, it was also
adversely associated with faster HR and higher serum chloride, sodium
levels and osmolality. Mannitol can be recommended to treat patients
with pretreatment brain hypoperfusion, while HS is more suitable in
patients with pretreatment hypovolemia or hyponatremia. We hoped
that this study would provide the basis for further research and guidance
to clinicians for making better and safer choices when using osmotic
agents.
Sources of funding
None.
CRediT authorship contribution statement
Yingying Su: Conceptualization, Writing - review & editing. Yifei
Liu: Data curation. Zhongyun Chen: Writing - original draft, Formal
analysis. Lili Cui: Data curation, Visualization.
Declaration of Competing Interest
None.
Acknowledgments
We thank all of the patients and families who participated in this
trial.
References
[1] K.E. Wartenberg, Malignant middle cerebral artery infarction, Curr. Opin. Crit.
Care 18 (2) (2012) 152–163.
[2] E.F. Wijdicks, K.N. Sheth, B.S. Carter, D.M. Greer, S.E. Kasner, W.T. Kimberly,
S. Schwab, E.E. Smith, R.J. Tamargo, M. Wintermark, Recommendations for the
management of cerebral and cerebellar infarction with swelling: a statement for
healthcare professionals from the American Heart Association/American Stroke
Association, Stroke 45 (4) (2014) 1222–1238.
[3] S. Schwab, T. Steiner, A. Aschoff, S. Schwarz, H.H. Steiner, O. Jansen, W. Hacke,
Early hemicraniectomy in patients with complete middle cerebral artery infarction,
Stroke 29 (9) (1998) 1888–1893.
[4] J. Hofmeijer, L.J. Kappelle, A. Algra, G.J. Amelink, J. van Gijn, H.B. van der Worp,
Surgical decompression for space-occupying cerebral infarction (the
Hemicraniectomy After Middle Cerebral Artery infarction with Life-threatening
5
Clinical Neurology and Neurosurgery 200 (2021) 106359
Edema Trial [HAMLET]): a multicentre, open, randomised trial, Lancet Neurol. 8
(4) (2009) 326–333.
[5] J. Zhao, Y.Y. Su, Y. Zhang, Y.Z. Zhang, R. Zhao, L. Wang, R. Gao, W. Chen, D. Gao,
Decompressive hemicraniectomy in malignant middle cerebral artery infarct: a
randomized controlled trial enrolling patients up to 80 years old, Neurocrit. Care
17 (2) (2012) 161–171.
[6] M.T. Torbey, J. Bosel, D.H. Rhoney, F. Rincon, D. Staykov, A.P. Amar, P.N. Varelas,
E. Juttler, D. Olson, H.B. Huttner, K. Zweckberger, K.N. Sheth, C. Dohmen, A.
M. Brambrink, S.A. Mayer, O.O. Zaidat, W. Hacke, S. Schwab, Evidence-based
guidelines for the management of large hemispheric infarction : a statement for
health care professionals from the Neurocritical Care Society and the German
Society for Neuro-intensive Care and Emergency Medicine, Neurocrit. Care 22 (1)
(2015) 146–164.
[7] M. Li, T. Chen, S.D. Chen, J. Cai, Y.H. Hu, Comparison of equimolar doses of
mannitol and hypertonic saline for the treatment of elevated intracranial pressure
after traumatic brain injury: a systematic review and meta-analysis, Medicine 94
(17) (2015) e736.
[8] T. Kheirbek, J.L. Pascual, Hypertonic saline for the treatment of intracranial
hypertension, Curr. Neurol. Neurosci. Rep. 14 (9) (2014) 482.
[9] S. Schwarz, S. Schwab, M. Bertram, A. Aschoff, W. Hacke, Effects of hypertonic
saline hydroxyethyl starch solution and mannitol in patients with increased
intracranial pressure after stroke, Stroke 29 (8) (1998) 1550–1555.
[10] W. Hacke, S. Schwab, M. Horn, M. Spranger, M. De Georgia, R. von Kummer,
’MAlignant’ middle cerebral artery territory infarction: clinical course and
prognostic signs, Arch. Neurol. 53 (4) (1996) 309–315.
[11] S. Datar, C. McLouth, P. Reynolds, Factors associated with the outcome of very
elderly patients with large hemispheric infarction treated with medical
management only, Neurocrit. Care 28 (3) (2018) 322–329.
[12] P.T. Akins, Y.V. Axelrod, S.T. Arshad, K.H. Guppy, Initial Conservative
Management of Severe Hemispheric Stroke Reduces Decompressive Craniectomy
Rates, Neurocrit. Care 25 (1) (2016) 3–9.
[13] J.I. Frank, L.P. Schumm, K. Wroblewski, D. Chyatte, A.J. Rosengart, C. Kordeck, R.
A. Thisted, Hemicraniectomy and durotomy upon deterioration from infarction-
related swelling trial: randomized pilot clinical trial, Stroke 45 (3) (2014) 781–787.
[14] M.A. Poca, B. Benejam, J. Sahuquillo, M. Riveiro, L. Frascheri, M.A. Merino,
P. Delgado, J. Alvarez-Sabin, Monitoring intracranial pressure in patients with
malignant middle cerebral artery infarction: is it useful? J. Neurosurg. 112 (3)
(2010) 648–657.
[15] T. Sauvigny, J. Gottsche, P. Czorlich, E. Vettorazzi, M. Westphal, J. Regelsberger,
Intracranial pressure in patients undergoing decompressive craniectomy: new
perspective on thresholds, J. Neurosurg. 128 (3) (2018) 819–827.
[16] A. Marmarou, A review of progress in understanding the pathophysiology and
treatment of brain edema, Neurosurg. Focus 22 (5) (2007) E1.
[17] M.H. Zornow, Hypertonic saline as a safe and efficacious treatment of intracranial
hypertension, J. Neurosurg. Anesthesiol. 8 (2) (1996) 175–177.
[18] J.D. Fenstermacher, J.A. Johnson, Filtration and reflection coefficients of the rabbit
blood-brain barrier, Am. J. Physiol. 211 (2) (1966) 341–346.
[19] N. Hijiya, K. Horiuchi, T. Asakura, Morphology of sickle cells produced in solutions
of varying osmolarities, J. Lab. Clin. Med. 117 (1) (1991) 60–66.
[20] J. Badaut, S. Ashwal, A. Obenaus, Aquaporins in cerebrovascular disease: a target
for treatment of brain edema? Cerebrovasc. Dis. 31 (6) (2011) 521–531.
[21] H. White, D. Cook, B. Venkatesh, The role of hypertonic saline in neurotrauma,
European journal of anaesthesiology, Supplement 42 (2008) 104–109.
[22] H. Kamel, B.B. Navi, K. Nakagawa, J.C. Hemphill 3rd, N.U. Ko, Hypertonic saline
versus mannitol for the treatment of elevated intracranial pressure: a meta-analysis
of randomized clinical trials, Crit. Care Med. 39 (3) (2011) 554–559.
[23] J. Gu, H. Huang, Y. Huang, H. Sun, H. Xu, Hypertonic saline or mannitol for
treating elevated intracranial pressure in traumatic brain injury: a meta-analysis of
randomized controlled trials, Neurosurg. Rev. (2018).
[24] J. Han, H.Q. Ren, Q.B. Zhao, Y.L. Wu, Z.Y. Qiao, Comparison of 3% and 7.5%
hypertonic saline in resuscitation after traumatic hypovolemic shock, Shock 43 (3)
(2015) 244–249.
[25] J. Fang, Y. Yang, W. Wang, Y. Liu, T. An, M. Zou, G. Cheng, Comparison of
equiosmolar hypertonic saline and mannitol for brain relaxation during
craniotomies: A meta-analysis of randomized controlled trials, Neurosurg. Rev. 41
(4) (2018) 945–956.
Y. Su et al.
[26] R. Frithiof, R. Ramchandra, S.G. Hood, C.N. May, Hypertonic sodium resuscitation
after hemorrhage improves hemodynamic function by stimulating cardiac, but not
renal, sympathetic nerve activity, Am. J.Heart Circul. Physiol. 300 (2) (2011)
H685–H692.
[27] P.G. Al-Rawi, M.Y. Tseng, H.K. Richards, J. Nortje, I. Timofeev, B.F. Matta, P.
J. Hutchinson, P.J. Kirkpatrick, Hypertonic saline in patients with poor-grade
subarachnoid hemorrhage improves cerebral blood flow, brain tissue oxygen, and
pH, Stroke 41 (1) (2010) 122–128.
Clinical Neurology and Neurosurgery 200 (2021) 106359
[28] V. Cottenceau, F. Masson, E. Mahamid, L. Petit, V. Shik, F. Sztark, M. Zaaroor, J.
F. Soustiel, Comparison of effects of equiosmolar doses of mannitol and hypertonic
saline on cerebral blood flow and metabolism in traumatic brain injury,
J. Neurotrauma 28 (10) (2011) 2003–2012.
[29] A.I. Qureshi, J.I. Suarez, Use of hypertonic saline solutions in treatment of cerebral
edema and intracranial hypertension, Crit. Care Med. 28 (9) (2000) 3301–3313.