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Critical Care Management of Cerebral Edema in Brain Tumors

Article  in  Journal of Intensive Care Medicine · December 2015

DOI: 10.1177/0885066615619618

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State-of-the Art Review
Journal of Intensive Care Medicine
1-10
Critical Care Management of Cerebral ª The Author(s) 2015
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Edema in Brain Tumors DOI: 10.1177/0885066615619618
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Yoshua Esquenazi, MD1, Victor P. Lo, MD, MPH1, and Kiwon Lee, MD1

Abstract
Cerebral edema associated with brain tumors is extremely common and can occur in both primary and metastatic tumors. The
edema surrounding brain tumors results from leakage of plasma across the vessel wall into the parenchyma secondary to dis-
ruption of the blood–brain barrier. The clinical signs of brain tumor edema depend on the location of the tumor as well as the
extent of the edema, which often exceeds the mass effect induced by the tumor itself. Uncontrolled cerebral edema may result in
increased intracranial pressure and acute herniation syndromes that can result in permanent neurological dysfunction and
potentially fatal herniation. Treatment strategies for elevated intracranial pressure consist of general measures, medical inter-
ventions, and surgery. Alhough the definitive treatment for the edema may ultimately be surgical resection of the tumor, the
impact of the critical care management cannot be underestimated and thus patients must be vigilantly monitored in the intensive
care unit. In this review, we discuss the pathology, pathophysiology, and clinical features of patients presenting with cerebral
edema. Imaging findings and treatment modalities used in the intensive care unit are also discussed.

Keywords
cerebral edema, brain tumor, herniation, corticosteroids, blood–brain barrier

Illustrative Case
A 69-year-old right-handed male with a history of a left frontal
glioblastoma and a prior subtotal resection 6 months ago pre-
sented to the emergency department (ED) with a 4-day history
of headaches, nausea, emesis, and 1-day history of confusion
and somnolence. He was intubated in the ED upon arrival for
airway protection and admitted to the intensive care unit (ICU).
Computed tomograhy (CT) scan of the brain demonstrated evi-
dence of peritumoral edema along the prior resection cavity
with evidence of subfalcine herniation and midline shift but
no evidence of intracranial hemorrhage or hydrocephalus.
General measures of intracranial pressure (ICP) management
were employed, and he was initially loaded with 10 mg of
intravenous (IV) dexamethasone and continued on a regimen
of 4 mg IV every 6 hours. One gram of IV levetiracetam
was also given. Within 8 hours of admission, he was follow-
ing commands. Once his neurological conditioned improved,
an magnetic resonance imaging (MRI) of the brain was
obtained to rule out intracranial infection as well as to
evaluate the extent of the tumor. This revealed evidence of
significant perilesional edema in the setting of tumor recur-
rence (Figure 1). He was subsequently taken to surgery for
reresection of the tumor.
Cerebral edema is characterized as a net increase in
water content of the brain parenchyma and is a significant
cause of morbidity and mortality in patients with a variety
of pathologies of the central nervous system (CNS) such as
brain tumors, infections, stroke, or traumatic brain injury.1,2
Aggressive brain tumors such as malignant gliomas and meta-
static tumors and many benign tumors produce brain edema.1
In patients with brain tumors, in addition to the volume of the
blood, brain and cerebrospinal fluid (CSF) within a rigid skull,
the tumor volume becomes a part of the total intracranial vol-
ume and may result in increased ICP. This change will subse-
quently reduce cerebral perfusion pressure (CPP) and cerebral
blood flow (CBF) leading to brain ischemia, herniation, and
potential death. Although steroids have facilitated the manage-
ment of edema in patients with newly diagnosed tumors, the
long-term therapy of tumor-associated edema continues to be
challenging. The goal of the intensive care management of
patients with brain tumors is to anticipate and recognize poten-
tially harmful problems both preoperatively and postopera-
tively. Treatment strategies include both medical and surgical
interventions to stabilize patients and facilitate recovery.
In this review, we discuss the clinical features, pathophysiology,
1
Vivian L. Smith Department of Neurosurgery, University of Texas Health
Science Center at Houston, Houston, TX, USA
Received July 30, 2015, and in revised form October 5, 2015. Accepted for
publication November 6, 2015.
Corresponding Author:
Kiwon Lee, Vivian L. Smith Department of Neurosurgery, The University of
Texas Health Science Center at Houston, Medical School, 6431 Fannin St. MSB
7.152, Houston, TX 77030, USA.
Email: Kiwon.Lee@uth.tmc.edu

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2 Journal of Intensive Care Medicine

Figure 1. (A) Axial T2-fluid attenuation inversion recovery (FLAIR) magnetic resonance imaging (MRI) of the brain demonstrating significant
vasogenic edema along the left frontal lobe with evidence of mass effect and subfalcine herniation. The prior resection cavity is demonstrated.
(B) Solid component (recurrent tumor) along the medial border of the prior resection is demonstrated following administration of intravenous
(IV) contrast (gadopentetate dimeglumine [Gd-DTPA]) on axial T1 MRI.

imaging findings, and interventions of patients presenting
with cerebral edema that are encountered in the neurosurgical
ICU.
Pathology and Pathophysiology
Edema associated with brain tumors is typically considered to
be vasogenic in nature with a primary disturbance at the level
of the microvasculature. The blood–brain barrier (BBB) is
composed of a complex network of endothelial cells, pericytes,
and astrocyte foot processes that form tight junctions. Under
normal physiological conditions, the BBB selectively excludes
exogenous hydrophilic molecules from passively entering the
CNS. In conditions associated with BBB disruption (such as
in primary or metastatic brain tumors), extravasation of plasma
fluid and proteins occurs, leading to vasogenic edema and
increased interstitial fluid pressure within the tumor.3 The
balanced interaction of cells comprising the BBB is disturbed
in the presence of a brain tumor, which leads to failure of this
important protective barrier. Histological studies of the BBB in
primary and metastatic brain tumors reveal abnormal tight
junctions, increased pinocytotic activity, and the presence of
fenestrations. Additionally, the basement membrane is thick-
ened and irregular with diminished interactions between peri-
cytes and astrocytes.4-6 Vascular endothelial growth factor
(VEGF) is a major proangiogenic peptide that is partly respon-
sible for the loss of integrity of the BBB in brain tumors.
Gliomas, meningiomas, and metastatic tumors all have upregu-
lation of VEGF,7-9 and hypoxia, and microenvironmental
factors (low pH) commonly found in tumors can lead to over-
expression of VEGF.10,11 The VEGF is secreted by tumor cells
as well as host stromal cells and binds to its receptors, VEGFR1
and VEGFR2, which are located primarily on the surface of
endothelial cells. The VEGF stimulates creation of interen-
dothelial gaps, fragmentations, and fenestrations in the brain
endothelium, which are associated with degeneration of the
basement membrane.12 These structural changes lead to fluid
leakage from the intravascular compartment into the brain par-
enchyma, which results in vasogenic edema and increased
interstitial fluid pressure.13 As the malignant grade of a glioma
increases, VEGF expression increases, thus leading to more
edema compared to low-grade tumors.14 Other molecular
mechanisms considered to be involved in the development of
cerebral edema are currently still being investigated. Metabo-
lites of the arachidonic acid pathway such as leukotrienes and
prostaglandins have been proposed as a factor in cerebral
edema in gliomas. Leukotrienes have been found to disrupt the
blood–tumor–brain barrier.15 Prostaglandins have also been
found to play a role in oncogenesis and edema.16 Certain pros-
taglandins such as prostaglandin E2 (PGE2) and prostaglandin
F2a (PGF2a) have been discovered to increase microvascular
permeability and alteration in BBB integrity.17,18 Furthermore,
it is the cyclooxygenase 2 (COX-2)-dependent pathway pro-
duction of PGE3 that has been demonstrated to induce cerebral
edema via microglia.19-22 Nitric oxide has been found to be a
potential mediator of vasodilation and tumor blood flow in pri-
mary brain tumors. Increased nitric oxide synthase (NOS)
expression was found in glial neoplasms and metastasis.23
Currently, NOS enzymatic activity levels have not demon-
strated a correlation between quantity and expression; how-
ever, the presence of its activity may indicate tumor
differentiation and malignancy.23

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Esquenazi et al
Figure 2. (A) Axial T2-weighted imaging 24 hours following gross total resection (GTR) of the enhancing portion of the tumor. Postoperative
changes are appreciated along the resection cavity. (B) Persistent vasogenic edema is present following GTR.
In addition to the molecular mechanisms of cerebral edema,
the physiologic mechanism must also be considered. Bulk flow
is a pathophysiologic mechanism in which small pressure gra-
dients are sufficient to prevent or redirect the spread of edema.
Cerebral edema tends to propagate in regions of low resistance
(ie, white matter) instead of areas of high resistance (ie, gray
matter). The concept of bulk flow was initially confirmed by
mathematical models based on CT measurements; however,
modern diagnostic imaging with MRI and diffusion tensor
image also corroborated the findings.24-27 Cerebral edema not
only depends on rate of production but also on reabsorption
of extravasated fluid in the ventricular and subarachnoid cere-
bral spinal fluid.28,29 In addition to understanding the patho-
physiologic mechanism of cerebral edema, studying fluid
dynamics in tumor and brain interstitial space has the potential
to be utilized in drug delivery to malignant gliomas.30
Clinical Presentation
The initial neurological evaluation is of critical importance,
and both preoperative and postoperative assessments are essen-
tial to detect signs and symptoms of raised ICP and neurologi-
cal deterioration. Papilledema, headaches that are worse in the
morning, nausea and vomiting, abnormal eye movements,
pupillary changes, and impaired consciousness are the classic
signs of raised ICP. Vomiting is more common in children than
in adults and is more often associated with infratentorial lesions
that lead to obstructive hydrocephalus. Hemiparesis, cognitive
decline, aphasia, and other focal neurologic signs may be the
result of either tumor growth or brain edema. Seizures are a
common presenting manifestation of low-grade tumors31 but
can also occur in patients harboring high-grade tumors and lead
to acute elevations in ICP. The location of the tumor is also
an important consideration, since supratentorial tumors are
associated with a higher degree of seizure activity, with those
tumors located in or adjacent to the perirolandic cortex and
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3
temporal lobe being especially prone to epileptogenic activ-
ity.32 Infratentorial lesions may need urgent attention, given the
vulnerability of the brain stem. In these cases, a small amount
of edema may result in severe neurologic compromise with
rapid alteration in the level of consciousness, hydrocephalus,
and mass effect on the brain stem requiring emergent interven-
tion. Brain tumor edema can lead to elevations in ICP that can
lead to brain shifts and eventually herniation beneath the major
dural folds (falx cerebri and tentorium cerebelli), producing
brain and/or cranial nerve injury. These shifts may obstruct
the normal drainage pathways of the CSF, leading to hydro-
cephalus that further exacerbates the patient’s intracranial
hypertension.
Herniation Syndromes
Herniation syndromes are important to recognize because the
presenting clinical signs and symptoms can often be the precur-
sor of serious neurologic sequelae or death.33 The following are
the most common types of herniation syndromes encountered
in patients with brain tumors. Subfalcine herniation: With
supratentorial mass lesions, local mass effect can lead to cingu-
late gyrus herniation. This is commonly seen in patients with
supratentorial metastasis as well as low- or high-grade gliomas
and may cause ventricular shifts (Figures 2 and 3). The perical-
losal branches of the anterior cerebral artery run in close prox-
imity to the free edge of the falx. Hence, displacement of the
cingulate gyrus under the falx by a hemispheric mass may
compress the distal anterior cerebral arteries and can result in
ischemia or infarction. Uncal herniation: This is the most com-
mon type of herniation and has a classic presentation of
impaired consciousness, fixed and dilated ipsilateral pupil, and
contralateral hemiparesis. The uncus is located in the mesial
temporal lobe, and with mass effect in the middle fossa of the
skull, the uncus can herniate over the tentorial edge and com-
press the oculomotor nerve. In addition, the uncus can herniate
4 Journal of Intensive Care Medicine
Figure 3. Coronal postcontrast T1-magnetic resonance imaging
(MRI) of the brain revealing a large left frontal enhancing mass with
solid and cystic components with evidence of subfalcine herniation.
This was consistent with a high-grade glioma.
into the mid-brain (Figure 4) and down into the posterior fossa
causing impaired consciousness as well as contralateral hemi-
plegia (by compressing the corticospinal tract). In patients with
large temporal lobe tumors and prolonged periods of uncal
herniation, the posterior cerebral artery can be compressed
between the uncus and the mid-brain causing an occipital lobe
infarct in the territory of its distribution. Central herniation:
With generalized cerebral mass effect, the entire mid-brain
may herniate downward, causing central transtentorial hernia-
tion. Patients are usually obtunded with altered breathing
pattern, pinpoint pupils, and loss of upward gaze. Tonsillar her-
niation: With expansion of the posterior fossa contents such as
in cases of infratentorial tumors, the cerebellum may herniate
down past the foramen magnum compressing the caudal
medulla. This can lead to cardiorespiratory dysfunction, altered
breathing patterns, and impaired consciousness.
Imaging
In vasogenic edema, there is increase in extracellular space vol-
ume because of disturbance of vascular permeability, which
enables the indiscriminate escape of plasma fluid and protein.
Unlike cytotoxic edema, vasogenic edema implies reactive
changes rather than permanent cellular damage and therefore
is reversible. In brain tumors, peritumoral edema is largely
based on imaging definition of different components of tumor
in relation to the presence or absence of contrast enhancement
after the administration of IV contrast agent such as gadopen-
tetate dimeglumine (Gd-DTPA) for MRI.34 In general, the
nonenhancing area of abnormality surrounding the enhancing
tumor core is referred to as peritumoral edema. In metastatic
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brain tumors or noninfiltrative primary tumors such as menin-
giomas, the peritumoral edema is synonymous with vasogenic
edema, where there is increased extracellular water due to leak-
age of plasma fluid from altered tumor capillaries, but no tumor
cells are present. In gliomas, however, the peritumoral edema is
better referred to as infiltrative edema because it represents
both vasogenic edema and infiltrating tumor cells that are
behind the BBB and usually invading along the white matter
tracts.34,35
Brain tumor edema is typically identified using CT and con-
ventional MRI. On CT, brain tumors are identified by abnormal
density values and/or displacement and distortion of adjacent
structures. Tumor-induced vasogenic edema typically extends
along the white matter extracellular fluid spaces and appears
hypodense on CT (Figure 5). Contrast-enhanced CT can be
helpful in defining the contrast-enhancing tumor border. Brain
tumor edema cannot be distinguished from noncontrast-
enhanced tumor on CT (Figure 5). Tumor-related edema can
be subtle on contrast-enhanced, T1-weighted images but is
readily apparent on T2-weighted images because of the higher
sensitivity to changes in water content of the brain. Fluid-
attenuated inversion recovery (FLAIR) imaging is a type of
T2-weighted imaging sequence in which the signal from
CSF is suppressed in order to increase the conspicuity of
lesions adjacent to ventricles or sulci36 (Figure 6). Diffusion-
weighted MRI (DW-MRI) may supplement conventional MRI
in the differential diagnosis of brain tumor edema, as it allows
for the differentiation between cytotoxic edema as seen in
cerebral infarction and vasogenic brain tumor edema. Distin-
guishing between vasogenic edema and infiltrative tumor is
important when exploring the potential antiedema versus
antitumor effects of anti-VEGF agents. Sequences such as
diffusion-weighted imaging and apparent diffusion coefficient
maps have been disappointing in distinguishing tumor from
edema,37,38 and overall, no single imaging study is ideal, and
a combination of MRI sequences are required to better distin-
guish infiltrative tumor versus vasogenic edema.39
Treatment
Treatment measures for elevated ICP consists of general
measures, medical interventions, and surgical interventions. Gen-
eral measures should be applied to all patients with brain tumors
and evidence of increased ICP. Even when interventions for ele-
vated ICPs are used, it is important to ensure the general measures
have also been addressed. Whenever an acute ICP elevation or
herniation syndrome is suspected, the patient should be treated
immediately, and this should not be delayed for further imaging.
General Measures
Positioning
Patient position is an important measure in the management of
ICPs. Elevating the head of bed decreases the CSF hydrostatic
pressure and facilitates the venous blood drainage. In normal
humans, elevation in the head of bed decreases ICP.40 The
Esquenazi et al 5

Figure 4. (A) Axial postcontrast T1-magnetic resonance imaging (MRI) of the brain revealing a peripherally enhancing lesion in the left anterior
temporal lobe. (B) There is extensive surrounding T2 signal hyperintensity in the left temporal lobe and mesial structures with compression of
the temporal horn. Uncal herniation is demonstrated with compression of the left cerebral peduncle (arrow) and the posterior cerebral artery.

For patients with some degree of suspected impairment of intra-

cranial compliance, but without clear indication for invasive ICP
monitoring, the head of bed can be positioned at 30 empirically.
In addition to elevating the bed, it is also important to take note
of patient head positioning, that is, the head facing straightfor-
ward, in order to decrease internal jugular vein compression that
may result from neck flexion. Efforts should also be made to
adjust or remove constricting garments or devices that encircle
the neck (eg, endotracheal tube collar).

Oxygenation and Ventilation

Figure 5. Noncontrast computed tomography (CT) scan of the brain
demonstrating significant vasogenic edema along the white matter of
the temporal lobe and insula. The edema appears hypodense and
cannot be reliably distinguished from the tumor on noncontrast
enhanced CT.
relationship of head position and ICPs has led most practitioners
to generalize its use, recommending the head of bed be elevated
to 30 in patients with decreased intracranial compliance.41-43
On the basis of cerebral physiologic principles, hypoxia and
hypercapnia are potent vasodilators and should be avoided in
patients with cerebral edema. It is recommended that PaCO2
be maintained at level to support adequate CBF. In patients
without acute ICP issues or herniation syndromes, a target
range of normocapnia (approximately 35-40 mm Hg) is gener-
ally accepted. Patients with declining neurologic status or seri-
ous intracranial disease may require intubation. In patients with
a Glasgow Coma Scale (GCS) of less than 8 or requiring sedation/
general anesthesia for ICP control, intubation is required. In intu-
bated patients, optimal ventilatory management can potentially
improve neurologic recovery and patient outcomes.44
Hemodynamics
The general measure of hemodynamic support is the mainte-
nance of euvolemia. Maintenance of fluid balance should be
accomplished with isotonic fluids, preferably 0.9% normal sal-
ine. Hypotonic saline should be avoided, as the free water frac-
tion will pass from the intravascular space into the brain, thus

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6 Journal of Intensive Care Medicine

Figure 6. (A) Noncontrast T1-weighted magnetic resonance imaging (MRI) of the brain demonstrating a large cystic hypointense lesion along
the left temporal lobe. (B) Ring enhancing with a necrotic center is demonstrated following administration of intravenous (IV) contrast
(gadopentetate dimeglumine [Gd-DTPA]). Peritumoral edema can be appreciated as the nonenhancing area of abnormality surrounding the
enhancing tumor core that is subtle. (C) T2-weighted imaging demonstrating the tumor-related edema, which is readily apparent. (D) T2-fluid
attenuation inversion recovery (FLAIR) demonstrating suppression of the cerebrospinal fluid (CSF) signal.

exacerbating cerebral edema. Fluid balance should be rigor-
ously monitored with fluid balance, body weight, and serum
electrolytes. Systemic hypotension must be avoided in patients
with elevated ICPs or cerebral edema. In a patient with regional
or global autoregulation failure, systemic hypotension will lead
to decreased CBF and potentially ischemia. The CPPs less than
50 mm Hg should be avoided in order to prevent cerebral ische-
mia. In addition, it may be better to initiate treatment with CPP
fall below 60 mm Hg to avoid a CPP <50 mm Hg. Vasopressors
should be used if needed to maintain adequate CPP. In cases of
hypertension, antihypertensives should be judiciously used.
Vasodilators use (nitroglycerine and nitroprusside) should be
avoided, as vasodilatory effects on cerebral vasculature may
exacerbate cerebral edema through cerebral hyperemia and
increased cerebral blood volume.45 It is important to maintain
normovolemia using normal saline as an initial choice of fluid
for patients with brain tumors and the sodium level to be vigi-
lantly monitored during the perioperative course.
Temperature
Several clinical and experimental studies have demonstrated
the negative effects of fever on outcome following brain
injury.46 The mechanism is thought to be the result of increased
oxygen demand; however, the precise mechanisms on cerebral
edema by fever are yet to be elucidated. Hypothermia has been
anecdotally demonstrated to be effective in lowering ICP, but
its effect on long-term outcome is not clear. In general, target
temperature should be normothermia, and antipyretic agents
should be used in order to not allow any fever.
Anticonvulsant
Seizures are a common and potentially devastating complica-
tion of both primary and metastatic brain tumors.47 Seizures
in patients with brain tumors may affect the airway, increase
the PaCO2, and exacerbate cerebral edema and ICP.
Postoperative electrolyte and metabolic alterations such as
hypoxia, hypernatremia or hyponatremia, and hyperglycemia
or acidosis may increase the risk of seizures. The effectiveness
of seizure prophylaxis in controlling postoperative seizures fol-
lowing craniotomy for tumor resection is unclear and further
trials are needed and needed to clarify their benefit in brain
tumor resection.48,49 It may be prudent to start prophylaxis for
patients with supratentorial brain tumors, however newer gen-
eration anticonvulsants such as levetiracetam are recom-
mended due to an improved safety profile over older
medications.50
Medical Interventions
Osmotherapy
Mannitol and hypertonic saline are used for rapid reduction of
ICP in patients with severe brain edema. Mannitol (25%) at a
dose of 0.5 to 1.5 g/kg is effective in reducing ICP with a peak
effect 15 to 35 minutes after infusion. However, persistent
hyperosmolarity is required to prevent the water gradient form
being reversed and for water to reenter the brain. The duration
of hyperosmolarity after a single bolus of mannitol is generally
several hours, but the reduction in ICP is briefer as the sugar
leaches into the brain and slowly equilibrates the water gradi-
ent.51 The osmotic diuresis following mannitol administration
can be quite significant,52 therefore fluid and electrolyte bal-
ance should be closely monitored and routinely assessed every
6 to 8 hours. Mannitol can be administered through a peripheral
or central IV catheter over 10 to 20 minutes. Complications
from mannitol include hypokalemia and alkalosis from the
diuresis, and a hyperglycemic hyperosmolar state in patients
with diabetes mellitus and the elderly individuals. Extremely
high osmotic levels after mannitol may produce renal damage,
which is usually self-limited within a few days after stopping
the mannitol. The upper limit of serum osmolarity that may
be safely attained with mannitol has been stated to be 320

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Esquenazi et al
mOsm/L, although levels higher than this may be tolerated.51
As a consequence of the disruption of the BBB in patients with
brain tumors, mannitol may leak from the intravascular com-
partment into the brain parenchyma and thus can exacerbate
vasogenic edema if used over a sustained time.53,54
Hypertonic Saline
A state of hyperosmolarity is achieved by saline in concentra-
tions of 3% to 23% by adding solute to the circulation directly
rather than by diuresis. Therefore, the vascular compartment is
expanded with saline, instead of contracted, as it is with the use
of mannitol. Both a continuous infusion of a solution (2%-3%)
or a bolus of high concentration of hypertonic saline (23.4%)
can be used to sustain the level of hypernatremia. A central
venous catheter is needed for administration of 3% sodium
chloride if it is used for more than a day or two or if higher con-
centrations are administered. Complications from hypertonic
saline include sodium and fluid overload and can cause conges-
tive heart failure in patients with poor cardiac output.51,55 It is
important to remember that once a serum hypertonicity has
been reached, one should not abruptly stop the continuous infu-
sion of hypertonic saline in order to avoid rebound ICP crisis.
Weaning should always be done gradually over 12 to 24 h or
even longer.
Sodium alterations (hyponatremia or hypernatremia)
are the most common and clinically important electrolyte
abnormalities in patients with brain tumors and should be
closely monitored in the perioperative period. Evidence
from randomized prospective trials of the role of osmother-
apy in patients with brain tumors is lacking, and therefore
the use of these medications is not routinely recommended
in these patients.
Steroids
Corticosteroid use in the management of patients having brain
tumor with surrounding edema has been widely used for sev-
eral decades.56-58 Its effect on peritumoral edema has been well
documented.59-61 Despite the long-standing clinical use and
impact of steroid use in neuro-oncology, the exact mechanisms
by which their effects are exerted remain unclear. It has been
suggested that the effects on edema are due to the reduction
in permeability of tumor capillaries.1,14,62 Dexamethasone,
first synthesized in 1958, offered a unique benefit in that it had
a low index of sodium and water retention compared to other
corticosteroids available at that time.63 Dexamethasone has
remained the most favorable steroid for peritumoral edema,
in part due to its long half-life, low mineralocorticoid activity,
and relatively low tendency to induce psychosis.58 In addition,
dexamethasone use has the added benefit of controlling tumor-
associated pain, limiting nausea and vomiting, and improving
appetite in patients with cancer.64 Administration of dexa-
methasone 1 to 2 days prior to an elective surgical procedure
has the potential to reduce edema and remarkably improve the
clinical condition prior to surgery.63 In patients presenting with
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7
acute neurologic symptoms secondary to a brain tumor, a large
dose of dexamethasone (10-20 mg) is given intravenously.
Maintenance dosing of dexamethasone typically consists of
oral or IV administration at a daily dose of 4 to 24 mg in
divided doses.58,65,66 A commonly used regimen, including at
our institution, is 4 mg every 6 hours. Neurologic improvement
should be expected within 48 hours. Using the lowest possible
effective dose should also be considered in order to avoid sys-
temic side effects of steroid use. A prophylaxis against gastro-
intestinal complications such as stress ulcer should be done and
systemic hyperglycemia need to be watched and avoided.
Future Therapies
With continued research into the mechanisms of cerebral
edema due to tumors, novel medical interventions are cur-
rently being investigated to disrupt the pathway of edema for-
mation. Given the role of VEGF in cerebral edema, inhibition
of VEGF has been explored as a possible treatment option.
Selective inhibition of VEGF with SU5416 (semaxanib) has
been found to prolong survival in rodent models with intracer-
ebral gliosarcoma and Glioblastoma (GBM).67 Pan-inhibition
of VEGF with AZD2171 has been demonstrated to be effec-
tive in normalizing vasculature and decreasing edema in
patients with GBM.68 With the COX-2-dependent pathway
production of prostaglandins inducing cerebral edema, efforts
have been taken to explore selective COX inhibitors. The
COX-2 inhibitors have been found to induce apoptosis and
prevent angiogenesis.69,70 A selective COX-2 inhibitor SC-
236 has been shown to increase survival when administered
to rats with intracerebral gliosarcoma.71 The increase in sur-
vival SC-236 was comparable to treatment with dexametha-
sone.71 However, initial reports of selective COX-2
inhibitor (rofecoxib) and PPAR-g in combination with che-
motherapy is only moderately active in patients with recurrent
high-grade gliomas.72
Surgery
Cerebral edema and increased ICP secondary to a space-
occupying lesion will never be satisfactorily normalized with
medical intervention only. Intracranial masses producing cere-
bral edema and elevated ICPs must be resected while preser-
ving neurologic function. Intraventricular catheterization is
the most widely used method for recording ICP. It can be
placed in acute situations in the ED or ICU for the temporary
management of hydrocephalus that often occurs as a result of
an obstructing brain mass. In addition, it allows treatment of
increased pressure through CSF drainage. Decision making
regarding brain tumor surgery is complex, factoring timing of
surgery, patient age, tumor location as well as expected
response of the tumor type to radiation therapy and chemother-
apy. Details of the decision-making factors of surgical resec-
tion are beyond the scope of this review.
8 Journal of Intensive Care Medicine
Conclusion
Cerebral edema caused by brain tumors may lead to devastating
neurologic consequences. It is important for all practitioners
treating patients with brain tumors to have an understanding of
the pathophysiology of the edema, imaging findings as well as
recognize its clinical presentation and sequelae. Although the
definitive treatment for cerebral edema may ultimately be surgi-
cal resection of the tumor, the impact of the critical care manage-
ment cannot be underestimated, and continuous neurological
monitoring is advised.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
References
1. Papadopoulos MC, Saadoun S, Binder DK, Manley GT, Krishna
S, Verkman AS. Molecular mechanisms of brain tumor edema.
Neuroscience. 2004;129(4):1011-1020.
2. Raslan A, Bhardwaj A, Medical management of cerebral edema.
Neurosurg Focus. 2007;22(5):e12.
3. Bruce JN, Criscuolo GR, Merrill MJ, Moquin RR, Blacklock JB,
Oldfield EH. Vascular permeability induced by protein product of
malignant brain tumors: Inhibition by dexamethasone. J Neuro-
surg. 1987;67(6):880-884.
4. Connolly DT. Vascular permeability factor: A unique regulator of
blood vessel function. J Cell Biochem. 1991;47(3):219-223.
5. Criscuolo GR. The genesis of peritumoral vasogenic brain edema
and tumor cysts: A hypothetical role for tumor-derived vascular
permeability factor. Yale J Biol Med. 1993;66(4):277-314.
6. Criscuolo GR, Lelkes PI, Rotrosen D, Oldfield EH. Cytosolic cal-
cium changes in endothelial cells induced by a protein product of
human gliomas containing vascular permeability factor activity.
J Neurosurg. 1989;71(6):884-891.
7. Bastin ME, Carpenter TK, Armitage PA, Sinha S, Wardlaw JM,
Whittle IR. Effects of dexamethasone on cerebral perfusion and
water diffusion in patients with high-grade glioma. AJNR Am J
Neuroradiol. 2006;27(2):402-408.
8. Furuse M, Hirase T, Itoh M, et al. Occludin: a novel integral
membrane protein localizing at tight junctions. J Cell Biol.
1993;123(6 pt 2):1777-1788.
9. Gaetani P, Butti G, Chiabrando C, et al. A study on the biological
behavior of human brain tumors. part I. arachidonic acid metabo-
lism and DNA content. J Neurooncol. 1991;10(3):233-240.
10. Go KG, Wilmink JT, Molenaar WM. Peritumoral brain
edema associated with meningiomas. Neurosurgery. 1988;23(2):
175-179.
11. Goldman CK, Bharara S, Palmer CA, et al. Brain edema in menin-
giomas is associated with increased vascular endothelial growth
factor expression. Neurosurgery. 1997;40(6):1269-1277.
Downloaded from jic.sagepub.com at HAM TMC on February 24, 2016
12. Gorman AM, Hirt UA, Orrenius S, Ceccatelli S. Dexamethasone
pre-treatment interferes with apoptotic death in glioma cells. Neu-
roscience. 2000;96(2):417-425.
13. Gerstner ER, Duda DG, di Tomaso E, et al. VEGF inhibitors in
the treatment of cerebral edema in patients with brain cancer. Nat
Rev Clin Oncol. 2009;6(4):229-236.
14. Heiss JD, Papavassiliou E, Merrill MJ, et al. Mechanism of
dexamethasone suppression of brain tumor-associated vascular
permeability in rats. involvement of the glucocorticoid receptor
and vascular permeability factor. J Clin Invest. 1996;98(6):
1400-1408.
15. Chio CC, Baba T, Black KL. Selective blood-tumor barrier dis-
ruption by leukotrienes. J Neurosurg. 1992;77(3):407-410.
16. Taketo MM. Cyclooxygenase-2 inhibitors in tumorigenesis (part
II). J Natl Cancer Inst. 1998;90(21):1609-1620.
17. Jaworowicz DJ Jr, Korytko PJ, Singh Lakhman S, Boje KM.
Nitric oxide and prostaglandin E2 formation parallels blood-
brain barrier disruption in an experimental rat model of bacterial
meningitis. Brain Res Bull. 1998;46(6):541-546.
18. Mark KS, Trickler WJ, Miller DW. Tumor necrosis factor-alpha
induces cyclooxygenase-2 expression and prostaglandin release
in brain microvessel endothelial cells. J Pharmacol Exp Ther.
2001;297(3):1051-1058.
19. Badie B, Schartner JM. Flow cytometric characterization of
tumor-associated macrophages in experimental gliomas. Neuro-
surgery. 2000;46(4):957-961; discussion 961-962.
20. Badie B, Schartner JM, Hagar AR, et al. Microglia
cyclooxygenase-2 activity in experimental gliomas: Possible
role in cerebral edema formation. Clin Cancer Res. 2003;
9(2):872-877.
21. Roggendorf W, Strupp S, Paulus W. Distribution and characteri-
zation of microglia/macrophages in human brain tumors. Acta
Neuropathol. 1996;92(3):288-293.
22. Streit WJ. Cellular immune response in brain tumors. Neuro-
pathol Appl Neurobiol. 1994;20(2):205-206.
23. Broholm H, Rubin I, Kruse A, et al. Nitric oxide synthase expres-
sion and enzymatic activity in human brain tumors. Clin Neuro-
pathol. 2003;22(6):273-281.
24. Aaslid R, Groger U, Patlak CS, Fenstermacher JD, Huber P, Reu-
len HJ. Fluid flow rates in human peritumoural oedema. Acta
Neurochir Suppl (Wien). 1990;51:152-154.
25. Bastin ME, Sinha S, Whittle IR, Wardlaw JM. Measurements of
water diffusion and T1 values in peritumoural oedematous brain.
Neuroreport. 2002;13(10):1335-1340.
26. Morita K, Matsuzawa H, Fujii Y, Tanaka R, Kwee IL, Nakada T.
Diffusion tensor analysis of peritumoral edema using lambda
chart analysis indicative of the heterogeneity of the microstruc-
ture within edema. J Neurosurg. 2005;102(2):336-341.
27. Uematsu H, Maeda M, Itoh H. Peritumoral brain edema in
intracranial meningiomas evaluated by dynamic perfusion-
weighted MR imaging: a preliminary study. Eur Radiol.
2003;13(4):758-762.
28. Reulen HJ, Tsuyumu M, Tack A, Fenske AR, Prioleau GR. Clear-
ance of edema fluid into cerebrospinal fluid. A mechanism for
resolution of vasogenic brain edema. J Neurosurg. 1978;48(5):
754-764.
Esquenazi et al
29. Wrba E, Nehring V, Chang RC, Baethmann A, Reulen HJ, Uhl E.
Quantitative analysis of brain edema resolution into the cerebral
ventricles and subarachnoid space. Acta Neurochir Suppl. 1997;
70:288-290.
30. Hall WA, Sherr GT. Convection-enhanced delivery: targeted
toxin treatment of malignant glioma. Neurosurg Focus. 2006;
20(4):e10.
31. Chang EF, Potts MB, Keles GE, et al. Seizure characteristics and
control following resection in 332 patients with low-grade glio-
mas. J Neurosurg. 2008;108(2):227-235.
32. Tandon N, Esquenazi Y. Resection strategies in tumoral epilepsy:
is a lesionectomy enough? Epilepsia. 2013;54(suppl 9):72-78.
33. Laine FJ, Shedden AI, Dunn MM, Ghatak NR. Acquired intracra-
nial herniations: MR imaging findings. AJR Am J Roentgenol.
1995;165(4):967-973.
34. Cha S. Update on brain tumor imaging: from anatomy to physiol-
ogy. AJNR Am J Neuroradiol. 2006;27(3):475-487.
35. Pallud J, Varlet P, Devaux B, et al. Diffuse low-grade oligoden-
drogliomas extend beyond MRI-defined abnormalities. Neurol-
ogy. 2010;74(21):1724-1731.
36. Kates R, Atkinson D, Brant-Zawadzki M. Fluid-attenuated inver-
sion recovery (FLAIR): Clinical prospectus of current and future
applications. Top Magn Reson Imaging. 1996;8(6):389-396.
37. Pauleit D, Langen KJ, Floeth F, et al. Can the apparent diffusion
coefficient be used as a noninvasive parameter to distinguish
tumor tissue from peritumoral tissue in cerebral gliomas? J Magn
Reson Imaging. 2004;20(5):758-764.
38. van Westen D, Latt J, Englund E, Brockstedt S, Larsson EM.
Tumor extension in high-grade gliomas assessed with diffusion
magnetic resonance imaging: values and lesion-to-brain ratios
of apparent diffusion coefficient and fractional anisotropy. Acta
Radiol. 2006;47(3):311-319.
39. Sorensen AG. Magnetic resonance as a cancer imaging biomar-
ker. J Clin Oncol. 2006;24(20):3274-3281.
40. Magnaes B. Body position and cerebrospinal fluid pressure. part
1: clinical studies on the effect of rapid postural changes. J Neu-
rosurg. 1976;44(6):687-697.
41. Bingaman WE, Frank JI. Malignant cerebral edema and intracra-
nial hypertension. Neurol Clin. 1995;13(3):479-509.
42. Frank JI. Management of intracranial hypertension. Med Clin
North Am. 1993;77(1):61-76.
43. Lang EW, Chesnut RM. Intracranial pressure. monitoring and
management. Neurosurg Clin N Am. 1994;5(4):573-605.
44. Nyquist P, Stevens RD, Mirski MA. Neurologic injury and
mechanical ventilation. Neurocrit Care. 2008;9(3):400-408.
45. Tietjen CS, Hurn PD, Ulatowski JA, Kirsch JR. Treatment mod-
alities for hypertensive patients with intracranial pathology:
options and risks. Crit Care Med. 1996;24(2):311-322.
46. Hajat C, Hajat S, Sharma P. Effects of poststroke pyrexia on
stroke outcome: A meta-analysis of studies in patients. Stroke.
2000;31(2):410-414.
47. Avila EK, Graber J. Seizures and epilepsy in cancer patients. Curr
Neurol Neurosci Rep. 2010;10(1):60-67.
48. Ansari SF, Bohnstedt BN, Perkins SM, Althouse SK, Miller JC.
Efficacy of postoperative seizure prophylaxis in intra-axial brain
tumor resections. J Neurooncol. 2014;118(1):117-122.
Downloaded from jic.sagepub.com at HAM TMC on February 24, 2016
9
49. Wu AS, Trinh VT, Suki D, et al. A prospective randomized trial of
perioperative seizure prophylaxis in patients with intraparenchy-
mal brain tumors. J Neurosurg. 2013;118(4):873-883.
50. Sayegh ET, Fakurnejad S, Oh T, Bloch O, Parsa AT. Anticonvul-
sant prophylaxis for brain tumor surgery: determining the current
best available evidence. J Neurosurg. 2014;121(5):1139-1147.
51. Ropper AH. Management of raised intracranial pressure and
hyperosmolar therapy. Pract Neurol. 2014;14(3):152-158.
52. Domaingue CM, Nye DH. Hypotensive effect of mannitol admi-
nistered rapidly. Anaesth Intensive Care. 1985;13(2):134-136.
53. Donato T, Shapira Y, Artru A, Powers K. Effect of mannitol on
cerebrospinal fluid dynamics and brain tissue edema. Anesth
Analg. 1994;78(1):58-66.
54. Nath F, Galbraith S. The effect of mannitol on cerebral white mat-
ter water content. J Neurosurg. 1986;65(1):41-43.
55. Fink ME. Osmotherapy for intracranial hypertension: mannitol
versus hypertonic saline. Continuum (Minneap Minn). 2012;
18(3):640-654.
56. Galicich JH, French LA, Melby JC. Use of dexamethasone in
treatment of cerebral edema associated with brain tumors. J Lan-
cet. 1961;81:46-53.
57. Ingraham FD, Matson DD, Mclaurin RL. Cortisone and ACTH as
an adjunct to the surgery of craniopharyngiomas. N Engl J Med.
1952;246(15):568-571.
58. Ryken TC, McDermott M, Robinson PD, et al. The role of ster-
oids in the management of brain metastases: A systematic review
and evidence-based clinical practice guideline. J Neurooncol.
2010;96(1):103-114.
59. Miller JD, Leech P. Effects of mannitol and steroid therapy on
intracranial volume-pressure relationships in patients. J Neuro-
surg. 1975;42(3):274-281.
60. Miller JD, Sakalas R, Ward JD, et al. Methylprednisolone treatment
in patients with brain tumors. Neurosurgery. 1977;1(2):114-117.
61. Yeung WT, Lee TY, Del Maestro RF, Kozak R, Bennett J, Brown
T. Effect of steroids on iopamidol blood-brain transfer constant
and plasma volume in brain tumors measured with X-ray com-
puted tomography. J Neurooncol. 1994;18(1):53-60.
62. Hedley-Whyte ET, Hsu DW. Effect of dexamethasone on blood-
brain barrier in the normal mouse. Ann Neurol. 1986;19(4):373-377.
63. Bell BA, Smith MA, Kean DM, et al. Brain water measured by
magnetic resonance imaging. correlation with direct estimation
and changes after mannitol and dexamethasone. Lancet. 1987;
1(8524):66-69.
64. Markman M, Sheidler V, Ettinger DS, Quaskey SA, Mellits ED.
Antiemetic efficacy of dexamethasone. randomized, double-
blind, crossover study with prochlorperazine in patients receiving
cancer chemotherapy. N Engl J Med. 1984;311(9):549-552.
65. Roth P, Wick W, Weller M. Steroids in neurooncology: actions,
indications, side-effects. Curr Opin Neurol. 2010;23(6):597-602.
66. Sturdza A, Millar BA, Bana N, et al. The use and toxicity of ster-
oids in the management of patients with brain metastases. Support
Care Cancer. 2008;16(9):1041-1048.
67. Takamoto T, Sasaki M, Kuno T, Tamaki N. Flk-1 specific kinase
inhibitor (SU5416) inhibited the growth of GS-9 L glioma in rat
brain and prolonged the survival. Kobe J Med Sci. 2001;47(4):
181-191.
10
68. Batchelor TT, Sorensen AG, di Tomaso E, et al. AZD2171, a pan-
VEGF receptor tyrosine kinase inhibitor, normalizes tumor vascu-
lature and alleviates edema in glioblastoma patients. Cancer Cell.
2007;11(1):83-95.
69. Jantke J, Ladehoff M, Kurzel F, Zapf S, Kim E, Giese A. Inhibi-
tion of the arachidonic acid metabolism blocks endothelial cell
migration and induces apoptosis. Acta Neurochir (Wien). 2004;
146(5):483-494.
70. Tuettenberg J, Grobholz R, Korn T, Wenz F, Erber R, Vajkoczy
P. Continuous low-dose chemotherapy plus inhibition of
Downloaded from jic.sagepub.com at HAM TMC on February 24, 2016
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Journal of Intensive Care Medicine
cyclooxygenase-2 as an antiangiogenic therapy of glioblastoma
multiforme. J Cancer Res Clin Oncol. 2005;131(1):31-40.
71. Portnow J, Suleman S, Grossman SA, Eller S, Carson K. A
cyclooxygenase-2 (COX-2) inhibitor compared with dexametha-
sone in a survival study of rats with intracerebral 9 L gliosarco-
mas. Neuro Oncol. 2002;4(1):22-25.
72. Hau P, Kunz-Schughart L, Bogdahn U, et al. Low-dose che-
motherapy in combination with COX-2 inhibitors and PPAR-
gamma agonists in recurrent high-grade gliomas - a phase II
study. Oncology. 2007;73(1-2):21-25.