REVIEW

CURRENT
OPINION Fluids and hyperosmolar agents in neurocritical
care: an update
Salia Farrokh a,b,, Sung-Min Cho b,, and Jose I. Suarez b

Purpose of review
To discuss recent updates in fluid management and use of hyperosmolar therapy in neurocritical care.
Recent findings
Maintaining euvolemia with crystalloids seems to be the recommended fluid resuscitation for neurocritical
care patients. Buffered crystalloids have been shown to reduce hyperchloremia in patients with
subarachnoid hemorrhage without causing hyponatremia or hypo-osmolality. In addition, in patients with
traumatic brain injury, buffered solutions reduce the incidence of hyperchloremic acidosis but are not
associated with intracranial pressure (ICP) alteration. Both mannitol and hypertonic saline are established
as effective hyperosmolar agents to control ICP. Both agents have been shown to control ICP, but their
effects on neurologic outcomes are unclear. A recent surge in preference for using hypertonic saline as a
hyperosmolar agent is based on few studies without strong evidence.
Summary
Fluid resuscitation with crystalloids seems to be reasonable in this setting although no recommendations can
be made regarding type of crystalloids. Based on current evidence, elevated ICP can be effectively
reduced by either hypertonic saline or mannitol.
Keywords
fluid, hyperosmolar therapy, intracranial pressure, neurocritical care, resuscitation

INTRODUCTION heterogeneity and small sample size of the studies

Crystalloids can be used for volume resuscitation in
neurocritical patients. Sodium chloride 0.9% has
been the most commonly used fluid in critically
ill patients [1]. Several studies have reported hyper-
chloremia-induced metabolic acidosis, acute kidney
injury (AKI), and death with sodium chloride 0.9%
& &&
administration [2,3 ,4 ]. The assumption has been
that buffered solutions such as plasma-lyte with
electrolyte compositions closer to that of plasma
may be safer alternatives [5]. Finally, human albu-
min has been used in neurocritical care patients
for volume expansion or neuroprotection with con-
flicting results.
Hyperosmolar therapy with mannitol and
hypertonic saline (HTS) is widely used to treat ele-
vated intracranial pressure (ICP) [6]. The main
causes of elevated ICP include intracranial mass
lesions and cerebral edema secondary to traumatic
brain injury (TBI), acute ischemic stroke (AIS), intra-
cranial hemorrhage (ICH), and subarachnoid hem-
orrhage (SAH). Although a few studies showed that
HTS is better than mannitol at reducing ICP, it is
difficult to draw meaningful conclusions owing to
[7,8].
FLUID MANAGEMENT AND GENERAL
RESUSCITATION IN CRITICAL CARE
Administration of crystalloids is a universal
approach to resuscitating critically ill patients, but
whether crystalloid composition affects overall out-
comes remains unclear [9]. A few observational
a
Department of Pharmacy, Division of Critical Care and Surgery, Johns
Hopkins Hospital and bDivision of Neurosciences Critical Care, Depart-
ments of Anesthesiology and Critical Care Medicine, Neurology, and
Neurosurgery Johns Hopkins School of Medicine, Baltimore Maryland.
USA
Correspondence to Jose I. Suarez, MD, Professor and Director, Neuro-
sciences Critical Care, Departments of Anesthesiology and Critical Care
Medicine, Neurology, and Neurosurgery, Johns Hopkins University
School of Medicine, 1800 Orleans St Sheikh Zayed Building, 3014C
Baltimore, MD 21287, USA. Tel: +1 410 955 7481;
e-mail: jsuarez5@jhmi.edu

Salia Farrokh and Sung-Min Cho contributed equally to this work.
Curr Opin Crit Care 2019, 25:105–109
DOI:10.1097/MCC.0000000000000585

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Neuroscience
KEY POINTS
 Crystalloids remain the fluid of choice for general
resuscitation of neurocritical care patients.
 Balanced crystalloids may reduce the risk of
hyperchloremia-induced acidosis, acute kidney injury,
and other complications in neurocritical care patients,
but no universal recommendations can be made
at present.
 Mannitol and HTS probably have similar effect on ICP
reduction and patient factors should be taken into
consideration when choosing the optimal agent.
studies in critically ill patients concluded that
increases in the serum chloride concentration were
independently associated with increased risk of AKI
and higher mortality [10,11]. Two randomized con-
trolled trials (RCTs), isotonic solution administra-
tion logistical testing and SPLIT [the 0.9% Saline vs
Plasma-Lyte 148 (PL-148) for ICU fluid Therapy],
showed no significant difference in the incidence
of mortality or AKI between patients treated with
saline and those treated with balanced crystalloid
&
solutions [2,3 ]. In contrast, a recent large clinical
trial [the Isotonic Solutions and Major Adverse
Renal Events Trial (SMART)] showed that balanced
crystalloid solutions resulted in a lower rate of all-
cause in-hospital mortality, renal -replacement ther-
&&
apy, and major adverse kidney event [4 ]. There are
no available studies investigating the long-term
effect of these solutions on clinical outcomes. Given
the paucity of data, a large, multicenter, blinded,
RCT (the Plasma-Lyte 148 v Saline) is ongoing to
assess whether the use of Plasma-Lyte alters the 90-
day all-cause mortality when compared with
&
sodium chloride 0.9% [12 ].
Extrapolating the results of these trials to
patients with neurologic injury may not be the best
approach because such patients are often underrep-
resented. Only 17.3% of ICU admissions in the
SMART trial, for example, had TBI, representing
8.8% in the balanced crystalloid group and 8.5%
&&
in the sodium chloride 0.9% group [4 ]. In fact, in
this single-center study, clinicians were given the
option of using sodium chloride 0.9% in patients
with TBI owing to concerns that the relative hypo-
tonicity of balanced crystalloids could increase ICP.
The 2018 joint European Society of Critical Care
Medicine (ESICM) and Neurocritical Care Society
(NCS) consensus on the administration of fluid
therapy in neurocritical care patients does not pro-
vide any specific recommendations regarding the
use of buffered crystalloids [13]. In the latter guide-
lines, strong recommendations are given for the use
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of crystalloids as preferred maintenance fluids and
against the use of colloids, including albumin, glu-
cose containing hypotonic solutions, and other
hypotonic solutions in neurocritical care patients
[13]. Despite this general recommendation, two
subgroups of neurocritical care patients – those with
TBI and SAH – deserve a more specialized approach.
Subarachnoid hemorrhage
Delayed cerebral ischemia (DCI) after aneurysmal
SAH (aSAH) is the main driver of poor outcomes.
Because hypovolemia has been associated with DCI,
one commonly recommended treatment strategy is
maintenance of euvolemia [14]. Meticulous moni-
toring of fluid balance is used to guide fluid man-
agement in practice. However, new evidence
suggests that fluid balance may be a poor indicator
&
of volume status [15 ]. In addition, euvolemia as a
fluid management goal is subject to interpretation,
as evidenced by the high variability in maintenance
fluid management strategies used for aSAH across
the United States. The ESICM and NCS consensus
statement provided strong recommendations that
physicians assess the efficacy of fluid resuscitation in
SAH patients with DCI using a multimodal approach
that includes arterial blood pressure and reversal of
neurologic deficit as the main endpoints [13]. Nev-
ertheless, if DCI is suspected, sodium chloride 0.9%
(15 ml/kg) may be infused over 1 h as a first step.
This strategy has been shown to improve cerebral
blood flow in regions with low baseline flow in
patients with vasospasm [16]. Given the concern
for hyperchloremia-induced metabolic acidosis
and AKI, clinicians may choose to initiate buffered
crystalloids in those without risks for cerebral
edema. In a single-center, RCT that compared buff-
ered crystalloids to sodium chloride 0.9% in 36 SAH
patients, buffered crystalloids reduced the rate of
hyperchloremia but did not cause more frequent
hyponatremia or hypo-osmolality [17]. These results
should be confirmed in larger studies before this
strategy is used universally in SAH patients.
Use of human albumin for volume expansion
and neuroprotection in DCI has been evaluated. The
ALISAH trial treated 47 SAH patients with different
doses of 25% human albumin ranging from 0.626 to
2.5 g/kg. The authors concluded that 25% human
albumin in doses up to 1.25 g/kg/day for 7 days is
safe and may be neuroprotective. Doses higher than
1.25 g/kg were associated with significant cardiovas-
cular complications [18]. A previous retrospective
study of 140 patients with aSAH showed that
patients who received 25% human albumin were
more likely to have a good outcome at 3 months
[19]. Given the lack of confirmation in adequately
Volume 25  Number 2  April 2019

powered larger clinical trials regarding the neuro-
protective effect of 25% human albumin in aSAH
patients, crystalloid solutions remain the treatment
of choice until future evidence becomes available. It
is important to emphasize that studies investigating
25% human albumin in aSAH have concentrated in
its neuroprotective effects rather than in its effects
on the intravascular volume.
Traumatic brain injury
Fluid resuscitation in patients suffering from TBI is
a crucial component of neuro critical care. In fact,
increased mortality has been reported in TBI
patients who are found to be under-resuscitated
[20]. In an RCT of 42 patients with severe TBI,
administration of sodium chloride 0.9% was com-
pared with isotonic balanced solution within the
first 12 h after brain injury. Balanced solutions
reduced the incidence of hyperchloremic acidosis
but were not associated with important effects on
ICP reduction [21]. The administration of HTS for
initial fluid resuscitation has also been studied.
Cooper et al. [22] randomized 229 hypotensive
(systolic blood pressure <100 mmHg) patients with
severe TBI to receive a rapid intravenous infusion of
either HTS 7.5% (250 ml) or lactated Ringers
(250 ml) in the prehospital setting. Survival to hos-
pital discharge and neurologic function at 6
months, measured by the extended Glasgow Out-
come Score (GOSE), were similar in both groups.
Patients enrolled in this study, regardless of group
assignment, were adequately resuscitated upon
arrival to the hospital as noted by normal blood
pressures, which translated in a lower than
expected mortality adjusted by underlying disease
severity.
Use of albumin in TBI patients for general resus-
citation has been an area of interest for many years.
A posthoc, subgroup analysis of one of the earlier
studies, The Saline versus Albumin Fluid Evaluation
(SAFE) trial, had shown that albumin 4% was asso-
ciated with higher mortality at 24 months, mostly as
a result of increased ICP [23]. Questions remain
whether these findings were related to the relative
hypotonicity of the 4% albumin solution or leakage
of albumin through an injured blood brain barrier
causing fluid shifts that led to elevations in ICP. On
the contrary, Baker et al. [24] reported higher arterial
oxygen pressure and higher regional tissue oxygen
tension with albumin compared with sodium chlo-
ride 0.9% and HTS in a rat model of TBI. To date,
controversy remains regarding the use of albumin in
TBI patients. Until further research is conducted,
crystalloid remains the treatment of choice for ini-
tial fluid resuscitation of TBI patients.
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Fluids and hyperosmolar therapy Farrokh et al.
ELEVATED INTRACRANIAL PRESSURE
AND CEREBRAL EDEMA
Traumatic brain injury
Hyperosmolar therapy is the mainstay for manage-
ment of elevated ICP. Mannitol had been the first-
tier therapy for treating elevated ICP; however, HTS
has gained popularity in recent years. In 2016, the
Brain Trauma Foundation concluded that although
hyperosmolar therapy may significantly lower ICP,
evidence from comparative studies was insufficient
to make a formal recommendation on specific agent
selection for patients with severe TBI [25]. The effect
on clinical outcomes was considered inconclusive
[25]. In a multicenter prospective observational
study of adult patients with moderate to severe
TBI and ICP more than 20 mmHg, the early use of
continuous HTS was independently associated with
survival at day 90. The adjusted hazard ratio for
survival was 1.74 [95% confidence interval (CI)
1.36–2.23, P < 0.001] in a propensity-score-adjusted
analysis, and there was no difference in achieving
favorable neurologic outcomes [defined as a Glas-
gow Outcome Scale (GOS) of 4–5] at day 90 [26]. A
systematic review of eight studies, confirmed the
association between continuous HTS and 90-day
survival [26]. A meta-analysis of 12 RCTs showed
that HTS was better than mannitol for controlling
elevated ICP (relative risk: 1.06; 95% CI 1.00–1.13;
P ¼ 0.04); however, there was no significant differ-
ence in favorable neurologic functional outcome
& &
(GOS 4–5) [27 ]. Both review articles [26,27 ] dem-
onstrated that HTS and mannitol are effective at
lowering elevated ICPs; however, the included stud-
ies contained significant heterogeneity in dosage
(concentration, volume) and formulation of agents,
initiation and duration of treatment, comorbidities
of patients, and definition of successful ICP treat-
ment. The ongoing multicenter randomized COBI
(COntinuous hyperosmolar therapy in traumatic
Brain-Injured patients) trial will compare functional
outcome at 6 months between standard care alone
vs. continuous hyperosmolar therapy (20% NaCl)
plus standard care. This trial will hopefully provide
definitive evidence regarding the effect of hyper-
osmolar therapy on functional outcome [28].
Intracranial hemorrhage and acute ischemic
stroke
Cerebral edema, more specifically perihematomal
edema (PHE), is the key determinants of mortality
after ICH. Therefore, PHE has been a main focus of
therapeutic targets in ICH research [29,30]. First-tier
treatment for symptomatic PHE with elevated ICP
is hyperosmolar therapy. In a rat model of ICH,
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Neuroscience
osmotherapeutic agents administered at regular
intervals reduced inflammatory markers, suggesting
a potential benefit of neuroinflammation reduction
in addition to ICP control [31]. Despite the effec-
tiveness of hyperosmolar therapy in reducing ICP,
its effect on clinical outcome after ICH is not clear.
An analysis of the Intensive Blood Pressure Reduc-
tion in Acute Cerebral Hemorrhage Trial (INTER-
ACT-2) showed that mannitol was safe, but no
improvement in neurologic outcome was observed
at 90 days [32]. A post hoc analysis of the Ethnic/
Racial Variations of Intracerebral Hemorrhage
(ERICH) database showed that mannitol and HTS
were associated with unfavorable neurologic out-
come at 3 months [33]. However, this finding is
likely biased by using hyperosmolar therapy more
often in patients with worse edema. The sub studies
of INTERACT-2 and ERICH are limited because they
lack details such as PHE volumes and ICP data. Based
on current evidence, it is essential to consider the
adverse effects of each agent and the comorbidities
for an individual patient rather than making a sim-
ple comparison of mannitol and HTS. It is also
important to note the recent report of an association
between hyperchloremia and increased in-hospital
mortality in ICH with continuous infusion of 3%
&
HTS [34 ]. This association was also observed in a
cohort of 405 critically ill patients with AIS or ICH
with sodium chloride 0.9%, in whom new-onset
hyperchloremia was related to poorer outcome
&
[35 ]. Further studies might guide the choice
between the two hyperosmolar agents for treating
elevated ICP.
Evidence is sparse on the use of hyperosmolar
therapy that is specific to AIS. Generally, the current
management of cerebral edema and elevated ICP in
AIS is similar to that of ICH and TBI. The current
guideline of the American Stroke Association states
that data are insufficient to recommend mannitol or
HTS as a preemptive measure in patients with early
computed tomography swelling in the absence
of increased ICP, but osmotic therapy for patients
with clinical deterioration from cerebral edema is
reasonable [36]. Currently no data address the effect
of hyperosmolar therapy on functional outcomes
in AIS.
Subarachnoid hemorrhage
The common causes of elevated ICP in aSAH include
hydrocephalus, ICH with or without intraventricu-
lar hemorrhage, and global cerebral edema. Other
less common causes include cerebral edema from
DCI or subdural hematoma secondary to cortical
aneurysmal SAH. Cerebral edema in SAH is managed
with hyperosmolar therapy as described above for
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Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
other intracranial pathologies; however, the evi-
dence is limited. A systematic review of five obser-
vational studies with 175 patients showed that HTS,
ranging from 3 to 23.5%, was similar to mannitol for
reducing increased ICP in aSAH but evidence was
insufficient to recommend an optimal dose of HTS,
and it was unclear if it had any impact on outcomes
[37]. A cohort of 1267 SAH patients who were
treated with HTS, showed a strong association
between hyperchloremia and AKI as well as between
&
AKI and mortality [38 ].
Intracranial tumor
Hyperosmolar therapy is commonly used during the
perioperative period to improve brain elastance or
after surgery to manage cerebral edema and elevated
ICP. No guidelines exist for the management of
hyperosmolar therapy in patients with intracranial
tumor. Raghava et al. [39] assessed intraoperative
brain relaxation during craniotomy by randomizing
patients into two groups (3% HTS versus 20% man-
nitol), which demonstrated that both agents were
equally effective for brain relaxation; however, the
main criticism of the study, along with its small
sample size, is that the four point scale used
(1 ¼ perfectly relaxed, 2 ¼ satisfactorily relaxed,
3 ¼ firm brain, and 4 ¼ bulging brain) may be a
subjective measure without ICP data [39]. Another
RCT compared 5 ml/kg 20% mannitol versus 3%
HTS in patients with supratentorial brain tumors
where ICP values were recorded during and for
&
30 min after hyperosmolar infusion [40 ]. The
amount of ICP reduction from baseline to last ICP
measurement was greater in patients with HTS than
for those with mannitol. The authors concluded
that 3% HTS resulted in a higher ICP reduction
&
versus 20% mannitol [40 ]. Nevertheless, the find-
ings should be interpreted cautiously because of
small sample sizes in both studies.
CONCLUSION
Fluid resuscitation with crystalloids is recom-
mended for all neurocritical care patients. Until
further research is conducted, ICP can be managed
in different neurologic emergencies with mannitol
or HTS, as long as individual patient factors
are considered.
Acknowledgements
None.
Financial support and sponsorship
None.
Volume 25  Number 2  April 2019

Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest
1. Finfer S, Liu B, Taylor C, et al. Resuscitation fluid use in critically ill adults: an
international cross-sectional study in 391 intensive care units. Crit Care 2010;
14:R185.
2. Young P, Bailey M, Beasley R, et al., SPLIT Investigators; ANZICS CTG.
Effect of a buffered crystalloid solution vs saline on acute kidney injury among
patients in the intensive care unit: the SPLIT randomized clinical trial. JAMA
2015; 314:1701–1710.
3. Semler MW, Wanderer JP, Ehrenfeld JM, et al. Balanced crystalloids versus
& saline in the intensive care unit. The SALT randomized trial. Am J Respir Crit
Care Med 2017; 195:1362–1372.
Showed no significant difference in the incidence of mortality or AKI between
patients treated with saline and those treated with balanced crystalloid solutions.
4. Semler MW, Self WH, Wanderer JP, et al. Balanced crystalloids versus saline
&& in critically ill adults. N Engl J Med 2018; 378:829–839.
Showed that balanced crystalloid solutions resulted in a lower rate of all-cause in-
hospital mortality, renal-replacement therapy, and major adverse kidney event
(patients with brain injury were included).
5. Guidet B, Soni N, Della Rocca G, et al. A balanced view of balanced solutions.
Crit Care 2010; 14:325.
6. Freeman WD. Management of intracranial pressure. Continuum (Minneap
Minn) 2015; 21(5 Neurocritical Care):1299–1323.
7. Kamel H, Navi BB, Nakagawa K, et al. Hypertonic saline versus mannitol for
the treatment of elevated intracranial pressure: a meta-analysis of randomized
clinical trials. Crit Care Med 2011; 39:554–559.
8. Mortazavi MM, Romeo AK, Deep A, et al. Hypertonic saline for treating raised
intracranial pressure: literature review with meta-analysis. J Neurosurg 2012;
116:210–221.
9. Myburgh JA. Fluid resuscitation in acute medicine: what is the current
situation? J Intern Med 2015; 277:58–68.
10. Marttinen M, Wilkman E, Petäjä L, et al. Association of plasma chloride values
with acute kidney injury in the critically ill – a prospective observational study.
Acta Anaesthesiol Scand 2016; 60:790–799.
11. Shaw AD, Raghunathan K, Peyerl FW, et al. Association between intravenous
chloride load during resuscitation and in-hospital mortality among patients
with SIRS. Intensive Care Med 2014; 40:1897–1905.
12. Hammond NE, Bellomo R, Gallagher M, et al. The Plasma-Lyte 148 v Saline
& (PLUS) study protocol: a multicentre, randomised controlled trial of the effect
of intensive care fluid therapy on mortality. Crit Care Resusc 2017;
19:239–246.
Ongoing large multicenter blinded study to assess whether the use of Plasma-Lyte
alters the 90-day all-cause mortality when compared with sodium chloride 0.9%.
13. Oddo M, Poole D, Helbok R, et al. Fluid therapy in neurointensive care
patients: ESICM consensus and clinical practice recommendations. Intensive
Care Med 2018; 44:449–463.
14. Diringer MN, Bleck TP, Claude Hemphill J, et al. Critical care management of
patients following aneurysmal subarachnoid hemorrhage: recommendations
from the Neurocritical Care Society’s Multidisciplinary Consensus Confer-
ence. Neurocrit Care 2011; 15:211–240.
15. Vergouw LJM, Egal M, Bergmans B, et al. High early fluid input after
& aneurysmal subarachnoid hemorrhage: combined report of association with
delayed cerebral ischemia and feasibility of cardiac output-guided fluid
restriction. J Intensive Care Med 2017; 885066617732747.
Aggressive early fluid administration was associated with DCI. Invasive hemody-
namic monitoring was feasible to reduce fluid administration while maintaining
preload.
16. Jost SC, Diringer MN, Zazulia AR, et al. Effect of normal saline bolus on
cerebral blood flow in regions with low baseline flow in patients with
vasospasm following subarachnoid hemorrhage. J Neurosurg 2005;
103:25–30.
17. Lehmann L, Bendel S, Uehlinger DE, et al. Randomized, double-blind trial of
the effect of fluid composition on electrolyte, acid-base, and fluid homeostasis
in patients early after subarachnoid hemorrhage. Neurocrit Care 2013;
18:5–12.
18. Suarez JI, Martin RH, Calvillo E, et al. The Albumin in Subarachnoid Hemor-
rhage (ALISAH) multicenter pilot clinical trial: safety and neurologic out-
comes. Stroke 2012; 43:683–690.
1070-5295 Copyright ß 2019 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Fluids and hyperosmolar therapy Farrokh et al.
19. Suarez JI, Shannon L, Zaidat OO, et al. Effect of human albumin administration
on clinical outcome and hospital cost in patients with subarachnoid hemor-
rhage. J Neurosurg 2004; 100:585–590.
20. Clifton GL, Miller ER, Choi SC, Levin HS. Fluid thresholds and outcome from
severe brain injury. Crit Care Med 2002; 30:739–745.
21. Roquilly A, Loutrel O, Cinotti R, et al. Balanced versus chloride-rich solutions
for fluid resuscitation in brain-injured patients: a randomised double-blind pilot
study. Crit Care 2013; 17:R77.
22. Cooper DJ, Myles PS, McDermott FT, et al. Prehospital hypertonic saline
resuscitation of patients with hypotension and severe traumatic brain injury: a
randomized controlled trial. JAMA 2004; 291:1350–1357.
23. Myburgh J, Cooper DJ, Finfer S, et al. Saline or albumin for fluid resuscitation
in patients with traumatic brain injury. N Engl J Med 2007; 357:874–884.
24. Baker AJ, Park E, Hare GM, et al. Effects of resuscitation fluid on neurologic
physiology after cerebral trauma and hemorrhage. J Trauma 2008;
64:348–357.
25. Carney N, Totten AM, O’Reilly C, et al. Guidelines for the management of
severe traumatic brain injury, fourth edition. Neurosurgery 2017; 80:6–15.
26. Asehnoune K, Lasocki S, Seguin P, et al. Association between continuous
hyperosmolar therapy and survival in patients with traumatic brain injury – a
multicentre prospective cohort study and systematic review. Crit Care 2017;
21:328.
27. Gu J, Huang H, Huang Y, et al. Hypertonic saline or mannitol for treating elevated
& intracranial pressure in traumatic brain injury: a meta-analysis of randomized
controlled trials. Neurosurg Rev 2018; https://doi.org/10.1007/s10143-018-
0991-8.
The results of this meta-analysis did not provide a specific recommendation to
select hypertonic saline or mannitol as a first-line for the patients with elevated ICP
caused by TBI.
28. Roquilly A, Lasocki S, Moyer JD, et al. COBI (COntinuous hyperosmolar
therapy for traumatic Brain-Injured patients) trial protocol: a multicentre
randomised open-label trial with blinded adjudication of primary outcome.
BMJ Open 2017; 7:e018035.
29. Wu TY, Sharma G, Strbian D, et al. Natural history of perihematomal edema and
impact on outcome after intracerebral hemorrhage. Stroke 2017; 48:873–879.
30. Murthy SB, Urday S, Beslow LA, et al. Rate of perihaematomal oedema
expansion is associated with poor clinical outcomes in intracerebral haemor-
rhage. J Neurol Neurosurg Psychiatry 2016; 87:1169–1173.
31. Schreibman DL, Hong CM, Keledjian K, et al. Mannitol and Hypertonic Saline
Reduce Swelling and Modulate Inflammatory Markers in a Rat Model of
Intracerebral Hemorrhage. Neurocrit Care 2018; 29:253–263.
32. Wang X, Arima H, Yang J, et al. Mannitol and outcome in intracerebral hemorrhage:
propensity score and multivariable intensive blood pressure reduction in acute
cerebral hemorrhage trial 2 results. Stroke 2015; 46:2762–2767.
33. Shah M, Birnbaum L, Rasmussen J, et al. Effect of hyperosmolar therapy on
outcome following spontaneous intracerebral hemorrhage: Ethnic/Racial
Variations of Intracerebral Hemorrhage (ERICH) Study. J Stroke Cerebrovasc
Dis 2018; 27:1061–1067.
34. Riha HM, Erdman MJ, Vandigo JE, et al. Impact of moderate hyperchloremia
& on clinical outcomes in intracerebral hemorrhage patients treated with con-
tinuous infusion hypertonic saline: a pilot study. Crit Care Med 2017;
45:e947–e953.
Showed higher rates of in-hospital mortality in ICH patients who developed
moderate hyperchloremia while on continuous infusion 3% hypertonic saline.
35. Huang K, Hu Y, Wu Y, et al. Hyperchloremia is associated with poorer
& outcome in critically ill stroke patients. Front Neurol 2018; 9:485.
Although no independent association was found, new-onset hyperchloremia was
related to poorer outcome in critically ill AIS and ICH patients.
36. Wijdicks EF, Sheth KN, Carter BS, et al. Recommendations for the manage-
ment of cerebral and cerebellar infarction with swelling: a statement for
healthcare professionals from the American Heart Association/American
Stroke Association. Stroke 2014; 45:1222–1238.
37. Pasarikovski CR, Alotaibi NM, Al-Mufti F, Macdonald RL. Hypertonic saline for
increased intracranial pressure after aneurysmal subarachnoid hemorrhage: a
systematic review. World Neurosurg 2017; 105:1–6.
38. Sadan O, Singbartl K, Kandiah PA, et al. Hyperchloremia is associated with
& acute kidney injury in patients with subarachnoid hemorrhage. Crit Care Med
2017; 45:1382–1388.
This retrospective analysis showed a strong association between hyperchloremia and
acute kidney injury as well as acute kidney injury and mortality in patients with SAH.
39. Raghava A, Bidkar PU, Prakash MV, Hemavathy B. Comparison of equios-
molar concentrations of hypertonic saline and mannitol for intraoperative lax
brain in patients undergoing craniotomy. Surg Neurol Int 2015; 6:73.
40. Ali A, Tetik A, Sabanci PA, et al. Comparison of 3% hypertonic saline and 20%
& mannitol for reducing intracranial pressure in patients undergoing supraten-
torial brain tumor surgery: a randomized, double-blind clinical trial. J Neuro-
surg Anesthesiol 2018; 30:171–178.
In this prospective, randomized, double-blind study of 39 supratentorial tumor
surgery patients, 3% hypertonic saline provided more effective ICP reduction than
20% mannitol during surgery.
www.co-criticalcare.com 109