REVIEW

URRENT
C
OPINION

Glucose control in acute brain injury: does

it matter?
Daniel A. Godoy a,b, Reza Behrouz c, and Mario Di Napoli d,e

Purpose of review
Alterations of blood glucose levels are secondary insults with detrimental consequences for the injured
brain. Here, we review various aspects of brain glucose metabolism and analyze the evidence on glycemic
control during acute brain injury.
Recent findings
An essential component in the overall management of acute brain injury, especially during the acute
phase, is maintaining adequate and appropriate control of serum glucose. This is one of the few
physiological parameters that is modifiable. Hypoglycemia should be rigorously avoided. However,
intensive insulin therapy is associated with unacceptable rates of hypoglycemia and metabolic crisis, and
does not necessarily provide benefit. Hyperglycemia is harmful to the injured brain as it compromises
microcirculatory blood flow, increases blood-brain barrier permeability, and promotes inflammation. In
addition, it triggers osmotic diuresis, hypovolemia, and immunosuppression.
Summary
Glucose is the primary energy substrate for the brain. During injury, the brain increases its needs and is
vulnerable to glucose deficit. In these situations, alternative fuel can be lactate, which has potential
implications for future research. In this review, various pathophysiological aspects of glucose metabolism
during acute brain injury, as well as the risks, causes, and consequences of glucose deficiency or excess,
will be discussed.
Keywords
brain injury, glucose, intensive insulin therapy, lactate, metabolic crisis

INTRODUCTION
Regardless of the etiology, acute brain injury (ABI)
occurs in two contiguous but distinct steps [1,2]. The
insult itself results in primary injury. Primary injury
is characterized by immediate, irreversible lesions at
macro- and microscopic levels, ultimately culminating in cell death [1,2]. Secondary injury consists of
a series of cerebral and/or systemic derangements
that perpetuate or worsen the primary insult [1,2].
In contrast to primary injury, secondary insults
are potentially reversible and preventable with
modulation of physiological parameters including
blood pressure, blood gas, temperature, and serum
glucose [1,2]. A critical principle in the overall management of ABI, especially during the acute phase, is
to avoid secondary insults. In that regard, maintaining adequate and appropriate control of serum
glucose is essential. Here, we present an overview
of the implications and advances in understanding
the central role of glucose metabolism in ABI, as well
as strategies for management.
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BASIC PHYSIOLOGY OF GLUCOSE

METABOLISM IN THE BRAIN
Glucose is the primary nutritional substrate for the
brain. Glucose metabolism maintains normal brain
physiology by providing fuel for generation of
adenosine triphosphate as well as the precursors
for biosynthesis of neurotransmitters. Daily glucose
a

Neurointensive Care Unit, Sanatorio Pasteur, bIntensive Care Unit,

Hospital Interzonal de Agudos San Juan Bautista, Catamarca, Argentina, cDepartment of Neurology, School of Medicine, University of Texas
Health Science Center, San Antonio, Texas, USA, dNeurological Service,
San Camillo de Lellis General Hospital, Rieti and eNeurological Section,
SMDN, Centre for Cardiovascular Medicine and Cerebrovascular Disease Prevention, Sulmona, LAquila, Italy
Correspondence to Daniel A. Godoy, Unidad de Cuidados Neurointensivos, Sanatorio Pasteur, Unidad de Terapia Intensiva, Hospital Interzonal
de Agudos San Juan Bautista, Catamarca, Argentina. Tel: +00 54 3834
432000/6; fax: +00 54 3834 432006;
e-mail: dagodoytorres@yahoo.com.ar
Curr Opin Crit Care 2016, 22:120127
DOI:10.1097/MCC.0000000000000292
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Glucose control in acute brain injury: does it matter? Godoy et al.

 The injured brain increases metabolic demand and is

very susceptible to an imbalance between demand and
supply of glucose.
 Hypoglycemia and hyperglycemia are detrimental to
the injured brain, so both scenarios should be avoided.
 Blood glucose levels should be monitored routinely
and frequently.
 It is reasonable to maintain blood glucose levels
between 110 and 180 mg/dl.
 Intensive insulin therapy does not provide any benefit in
ABI and is potentially detrimental.
 To achieve optimal glucose control, we suggest the
development of an institutional insulin protocol and
adequate nutritional support.

consumption by the brain is approximately 120 g,

which corresponds to 2025% of glucose utilization
by the whole body at rest [35]. Under normal
conditions, the brain uses glucose at a rate of
5 mg/min/100 g of parenchyma [35]. Consumption by the brain is not homogeneous and depends
largely on the metabolic activity of individual
regions [35]. For example, the gray matter consumes about 515 mg/min/100 g of tissue, whereas
the white matter utilizes 1.52 mg/min/100 g [5].
The brain lacks glucose stores; only a negligible
amount of glycogen is stored in astrocytes but
exhausted as rapidly as 2 min after glucose supply
is interrupted [35]. When this occurs, glycogen in
astrocytes is converted to lactate, released into the
extracellular space, and is eventually taken up by
neurons to maintain oxidative metabolism [4,6,7].
The lactate generated via this pathway can be
shuttled into neurons, where it can be used as
alternative fuel to respond to energy demands. This
compensatory pathway is called the astrocyte-neuron
lactate shuttle [3,6,7].
With small reserves, the brain needs a continuous supply of glucose through adequate cerebral
blood flow. Glucose gains entry into the brain by
facilitated diffusion across the blood-brain barrier.
In the adult brain, there is selective permeability for
glucose [8]. The glucose transporter (GLUT)-1 mediates transport of glucose across the endothelial
membrane into the extracellular fluid, and GLUT3 facilitates entry into the neuron [8]. Intracellular
glucose is then phosphorylated into glucose-6-phosphate, to which the cell membrane is impermeable.
The trapped glucose-6-phosphate is then converted
to pyruvate that enters the tricarboxylic acid cycle

for generation of high-energy electrons. This is followed by electron transport chain and oxidative
phosphorylation to produce adenosine triphosphate. Neurons and astrocytes have receptors for
insulin, but the brain itself does not produce insulin
and cannot modulate glucose uptake by astrocytes
and neurons [6]. Insulin may selectively participate
in the regulation of glucose metabolism in the
cerebral cortex [7].

GLUCOSE METABOLISM IN THE INJURED

BRAIN
Hyperglycolysis
Metabolic demands increase markedly in the
injured brain, which is extremely vulnerable to
deficits in energy substrates (oxygen and glucose)
(Fig. 1) [6,9]. Various studies looking at postinjury
metabolism have shown an increase in glucose utilization, especially in the first 48 h [9,10]. This
phenomenon, called hyperglycolysis, may be focal
or diffuse, and is defined as an increase in glucose
utilization by more than two standard deviations
from the baseline, obtained by fluorodeoxyglucose
positron emission tomography (PET) [9,10]. Hyperglycolysis implies a reduction in oxidative metabolism and a relative increase in anaerobic glycolysis.
It is a well-described state after severe traumatic
brain injury (TBI), aneurysmal subarachnoid hemorrhage and spontaneous intracerebral hemorrhage
[912]. Hyperglycolysis is an adaptive response
aimed to maintain or restore ionic balance and

A
B

Risk secondary brain injury

KEY POINTS

Metabolic demand increase

Cerebral glucose uptake adaptation

Neuroglycopenia
Glucose transporter adaptation

Metabolic crisis
Excitotoxicity

Tight target

4.56.0

Optimal suggested target

6.08.0

8.510.0

Conventional target

10.011.0

>11.0

Blood glucose level (mmol/l)

FIGURE 1. Suggested optimal target of blood glucose levels

in acute brain injury. To convert to mg/dl, multiply by 18.
(a) Basal state; (b) during injury, the demand of glucose
increases, so the curve shifts to the right. Pathophysiological
processes that affect glucose metabolism are depicted in
arrows. Adapted from Godoy et al. [5].

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Neuroscience

membrane function during injury [6,9,10]. As a

consequence of hyperglycolysis, extracellular lactate, pyruvate and the relationship between the
two (L/P ratio) increases [9,10]. Increased lactate
in the absence of hypoxia indicates increased metabolism and not necessarily a shift toward anaerobic
metabolism [6,9,10]. For this reason, in the absence
of tissue hypoxia, elevated extracellular lactate is
associated with good outcomes in subarachnoid
hemorrhage or severe TBI [6,9,10]. However, in
some circumstances, lactate production predominates over its uptake after ABI, and mitochondrial
dysfunction may inhibit lactate oxidation [13 ].
Elevation of extracellular lactate concentration
leads to cerebral tissue acidosis, which is associated
with unfavorable clinical outcomes [14].
&

Metabolic crisis
In the brain, any imbalance in the supply and
demand for substrates can trigger metabolic crisis
[6,15,16]. Factors that stimulate secondary insult
(low blood pressure, seizures, intracranial hypertension, and fever) can also perpetuate this pathological state [6,15,16]. Metabolic crisis occurs in
approximately 25% of severe TBI patients. It is
characterized by an increased L/P ratio (>40) visa`-vis low-to-normal oxygen extraction on PET and
without cerebral ischemia [15]. Metabolic crisis
represents a severe reduction in oxidative metabolism with concomitant alteration in glucose consumption [6,15]. There are two types of metabolic
crises. Type I is characterized by increased L/P
ratio and tissue hypoxia, triggered by a profound
reduction in the supply of energy substrates [6,15].
In type II, increased L/P ratio occurs despite the
normal supply of energy substrates and the absence
of any compromise in tissue oxygenation [6,15]. The
exact nature of these crises is unknown, but they
may represent mitochondrial dysfunction or excessive increase in metabolic demands [6,14]. Metabolic crisis is present even in patients stabilized
after successful resuscitation and adequate control
of intracranial pressure and brain tissue oxygen
tension (PtiO2) [16]. One recognized trigger for
metabolic crisis is intensive insulin therapy (IIT),
a strategy aimed at maintaining blood glucose levels
strictly in the range of 80 to 110 mg/dl [17]. This
point will be discussed later.
Definitive diagnosis of metabolic crisis requires
advanced multimodal monitoring (microdialysis
and PET), which are not routinely available in the
majority of intensive care units. It is, therefore,
important to assume its presence, as metabolic
crisis has a substantial impact on final outcomes
[6,15,16,1821].
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HYPOGLYCEMIA AND
NEUROGLYCOPENIA
Hypoglycemia is defined as a blood glucose level less
than 70 mg/dl [22]. The brain cannot tolerate this
deficiency for prolonged periods of time because its
capacity for compensation is very limited [5,7]. The
exact incidence of hypoglycemia in patients with
ABI is unknown. The extent of brain injury is a direct
function of how profound and/or prolonged the
deficiency is [5,7,23]. Direct effects of hypoglycemia
include disturbances in cerebral blood flow,
autoregulation, and vasoreactivity [5,7]. Hypoglycemia triggers mitochondrial dysfunction due to
generation of oxygen free radicals, alteration of
transmembrane ion gradients, glutamate-mediated
excitotoxicity, and activation of apoptotic pathways
[5,6,23]. Regions that are particularly vulnerable to
the adverse effects of hypoglycemia are the basal
ganglia, hippocampus, and periventricular white
matter [23]. In critically ill patients, moderate hypoglycemia (4170 mg/dl) increases mortality by 40%,
and severe hypoglycemia (40 mg/dl) doubles this
risk [24].
Clinical and experimental data support the conclusion that injured brain is dependent upon the
rate and the manner of glucose utilization, rather
than the absolute serum levels [23]. In ABI, serum
glucose values considered in normal range
(80100 mg/dl) may be associated with insufficient
levels of glucose in the brain to meet its demands, a
state called neuroglycopenia, which is the origin of
metabolic crisis type II [15,18].

HYPERGLYCEMIA AND THE INJURED

BRAIN
Hyperglycemia is highly prevalent in patients with
ABI, even in nondiabetics [5]. The exact incidence of
hyperglycemia in ABI is not known because of lack
of a universal definition and validation, but an
average estimate of 40% has been proposed [5,8].
Stress-associated hyperglycemia is defined as fasting
blood glucose more than 140 mg/dl [22]. Whether
hyperglycemia is the cause of tissue damage or an
epiphenomenon related to the severity of injury is
unclear. Nonetheless, it clearly has an adverse
impact on various forms of ABI, including severe
TBI, subarachnoid hemorrhage, cerebral infarction,
spontaneous intracerebral hemorrhage, and spinal
cord injury [5,8]. Hyperglycemia occurs more frequently on admission, though the temporal profile
is rather heterogeneous [5,25,26]. Causes of hyperglycemia are manifold. ABI induces a neurohormonal and autonomic response, releasing
massive amounts of cortisol, catecholamines, and
cytokines, which in turn increase hepatic glucose
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Glucose control in acute brain injury: does it matter? Godoy et al.

production and ultimately, insulin resistance [5].

The degree of hyperglycemia is related to the
severity of the primary insult, regardless of the
source [5]. However, it is unclear if this reaction is
region dependent (insular cortex, hypothalamus,
etc.). Other causes of hyperglycemia in ABI include
high-calorie diets, dextrose-containing intravenous
fluids, vasoactive amines (dopamine and norepinephrine), steroids, insulin resistance, or undiagnosed diabetes [5].
The deleterious effects of hyperglycemia include
increasing oxidative stress, activation of inflammatory cascades, tissue acidosis, endothelial dysfunction, and increased permeability of the blood-brain
barrier [27,28]. Stimulation of N-methyl-D-aspartate
receptors further compromises microcirculatory
perfusion and activates apoptotic pathways
[27,28]. At systemic level, hyperglycemia increases
blood osmolarity, stimulates diuresis leading to
hypovolemia, and may cause inflammation and
depressed immune function, which ultimately renders the individual susceptible to sepsis and organ
dysfunction [29].

independently predict mortality, perhaps because

of the severity of the insult or increased oxidative
stress [36]. The gold standard for periodic determination of serum glucose is standard laboratory
measurement; point-of-care glucometers were not
designed for critically ill patients [37]. Glucometers
lack accuracy and are subject to errors and wide
variability [8,37]. Some clinical conditions or medications can have a significant influence on glucose
levels measured by glucometers; anemia, jaundice,
acetaminophen, dopamine, and mannitol can lead
to overestimation, whereas edema, hypoperfusion,
norepinephrine, and PaO2 more than 100 mmHg
may lead to underestimation of the actual blood
sugar values [8,37]. Therefore, glucometers should
not be used as the sole method of serum glucose
monitoring. If a glucometer is used, it is important
to maintain proper calibration by frequent comparisons (at least twice a day) with samples analyzed in
the laboratory [37]. Continuous monitoring systems
with sensors implanted in the interstitial space or
blood using modern technology (spectroscopy,
optical fiber, and microdialysis) that yield results
in real time are in development [37].

INTENSIVE INSULIN THERAPY

During ABI, there is a linear relationship between
systemic and cerebral glucose, so, when oxidative
metabolism is compromised, a decrease of systemic
glucose (inclusive within the lower limit of the
range considered normal), can reduce cerebral glucose below a critical threshold (neuroglycopenia)
[1820,30].
The initial encouraging results for IIT were not
validated in subsequent studies [17]. Moreover, further investigations provided evidence against the
use of this therapeutic strategy [31,32]. Controlled
clinical studies of IIT in various models of ABI
showed no benefit in terms of survival or functional
outcomes [33,34]. Also, hypoglycemia rates were
unacceptably high [3134]. Furthermore, IIT is
strongly associated with the development of
metabolic crisis type II, electrocortical instability,
and poor outcomes [1820]. The plurality of the
evidence does not support IIT in neurocritically ill
patients.

OPTIMAL BLOOD GLUCOSE IN ACUTE

BRAIN INJURY

GLUCOSE MONITORING IN ACUTE BRAIN

INJURY

Maintaining optimum glycemic control in ABI is

multifaceted and must be achieved in a systematic
manner. Intravenous regular insulin is the drug of
choice for normalizing high serum glucose during
the acute phase of cerebral injury [5,8,3944]. Aside
from lowering blood sugar, insulin has many useful
properties such as neuroprotection, anti-inflammation, antiplatelet, pro-fibrinolysis, inhibition of

Glucose monitoring should be routine during ABI;

however, no standardized method exists and the
optimal frequency of sampling is unknown [35 ].
Glucose levels vary widely throughout the day,
depending on the circumstances (pain, fever,
surgery, stress, and drugs) [36]. Wide variations
&

The American Diabetes Association recommends

maintaining serum glucose levels between 140
and 180 mg/dl in hospitalized patients, but does
not specifically address the same in patients with
ABI [38]. Hypoglycemia should be corrected
immediately and avoided [3844]. The maximum
threshold for initiation of treatment for hyperglycemia remains controversial. Clinical practice
guidelines in various forms of ABI vary considerably
(Table 1) [3844]. Based on the available evidence,
we suggest a conservative approach, maintaining
a slightly sweet environment, taking precautions
to avoid neuroglycopenia and metabolic crisis
[5,8,20,3845]. Regarding the upper limit, maintaining levels below 180 mg/dl is reasonable
(Fig. 1) [5,8,20,3844].

ACHIEVING ACCEPTABLE GLYCEMIC

CONTROL

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Neuroscience
Table 1. Recommended glycemic values in neurocritically ill patients
Diagnosis

Organization

TBI

BTF

Year
2007 [5]

Recommended glycemia (mg/dl)

Type of evidence (classlevel)

NS

SCI

AANS

2013 [49]

NS

Hospitalized patients

ADA

2010 [46]

140180

IIaC

AHA

2013 [50]

Avoid <60

IC

AHA

2007 [6]

140180

IIaC

<180

GCPIV

Ischemic stroke

aSAH
ICH

ESO

2008 [6]

AHA

2012 [51]

To maintain glycemic control-NS

IIbB

ESO

2013 [52]

<180

GCP

AHA

2015 [53]

IC

ESO

2006 [54]

Glucose should be monitored.

HyperG and HypoG should be
avoided
<185

IIaC

2014 [55]

Any consideration

AANS, American Association of Neurological Surgeons; ADA, American Diabetes Association; AHA, American Heart Association; aSAH, aneurysmal
subarachnoid hemorrhage; BTF, brain trauma foundation; ESO, European Stroke Organization; GCP, good clinical practice; HyperG, hyperglycemia; HypoG,
hypoglycemia; ICH, intracerebral hemorrhage; NS, not specified; SCI, spinal cord injury; TBI, traumatic brain injury.

oxygen free radical formation, and regulation of the

vasodilatory effects of nitric oxide [27]. The earlier
glycemic control is initiated, the greater the benefit
[45]. At the same time, it is of utmost importance to
provide adequate calories to support the increased
metabolic demands during ABI and to avoid hypoglycemia [46]. Feeding via the enteral route should
be established as soon as possible, and an oversupply
of carbohydrates must be avoided [46]. Daily nutritional support optimally consists of 30 kcal/kg of
body weight or less, with lipids comprising 25%
of that [46]. A proposed algorithm by the authors
for controlling glucose levels in ABI is depicted in
Fig. 2.

GLUCOSE CONTROL IN THE FUTURE:

LACTATE AS ADJUVANT?
Energy dysfunction is an increasingly recognized
pathophysiologic phenomenon in ABI [3,6,1820]
Adequate glycemic control is an important therapeutic target to avoid or mitigate energetic crises
[6,1820,47 ]. As mentioned before, accumulation
of cerebral lactate is not always linked to tissue
hypoxia [6,1820]. Sometimes the increase in brain
lactate reflects accelerated metabolism secondary
to increased needs, with or without mitochondrial
dysfunction [1820,47 ]. Lactate may protect the
brain during periods of hypoglycemia, providing
some degree of neuroprotection [47 ]. In addition,
when combined with hypertonic saline, lactate provides at least the same beneficial effects on intracranial pressure and cerebral perfusion pressure as
&&

&&

&&

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&&

other osmotic agents [47 ]. These properties together

with an acceptable safety profile make lactate a promising agent for future therapy of ABI [47 ]. Extension
of the notion that the lactate is the preferred fuel
during injury has important clinical implications.
Therefore, this concept must be carefully evaluated
before incorporation into patient care protocols.
Microdialysis studies in TBI patients demonstrate
that improvement of brain energetics after hypertonic lactate infusion seems predominantly dependent on baseline cerebral metabolic state [48 ].
&&

&&

CONCLUSION
The injured brain has increased energy demands.
Hyperglycemia and hypoglycemia equally and
adversely impact outcome in ABI. The optimal
blood glucose levels during ABI are unknown. Maintaining values between 110 and 180 mg/dl appears
reasonable. It is important to emphasize the possibility of metabolic crisis even when serum glucose
levels are seemingly normal. Serial monitoring of
blood glucose levels should be routine and based on
institutional protocols. Regular insulin is the agent
of choice to correct and prevent hyperglycemia.
Adequate nutrition should accompany glycemic
control protocols. IIT is not recommended in
patients with ABI. Cerebral metabolic monitoring
provides valuable information, but cannot be universally applied in clinical practice yet. Some questions remain. How often and which is the most
accurate method for glycemic monitoring? What
are the optimal glycemic values? What is the true
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Glucose control in acute brain injury: does it matter? Godoy et al.

Acute cerebral injury

Glycemia
<100 mg/dl

Glycemia
> 100 < 180

Glucose level
monitoring

Serial glycemic
monitoring

Correct with
hypertonic dextrose
(100-glycemia) x 0.3
= ml IV bolus

Hyperglycemia
(> 180 mg/dl)

Diabetic

Nondiabetic
Early nutrition

Enteral route if
possible
Avoid excessive
carbohydrates
2520 calories/kg/day
25% of them lipids

Stop
Oral antidiabetic agents
long-acting insulin
Serial monitoring

IV regular insulin

Glycemia >350 mg/dl,

mechanical ventilation, sepsis, hyperosmolar state,
ketoacidosis, postoperative period

Yes
Blood glucose levels
(mg/dl)
160169
2 IU/h
170199
3 IU/h
200249
4 IU/h
250299
6 IU/h
300399
8 IU/h
400 o >
10 IU/h

No
Blood glucose levels
(mg/dl)
Reactive regimen**

Proactive regimen
insulin pump*

160200
201250
251300
301350

5U
10 U
15 U
20 U

Target (mg/dl)
>110 < 180

FIGURE 2. Algorithm proposed for control of blood glucose levels during acute brain injury. IU, international units; IV,
intravenous. To convert mmol/l to mg/dl multiply by 18. Proactive regimen: dilute 100 U of regular insulin in 100 ml of
normal saline (1 U 1 ml). Administer by pump infusion. Scheme for insulin infusion. Reactive regimen: scheme for
correction of glycemia values according to monitorized values. Modified from Godoy et al. [8].

role of lactate? Future investigations will hopefully

shed light on these issues.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.

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&&
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&&
hypertonic lactate therapy in patients with traumatic brain injury is dependent
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A very interesting series of cases of patients with severe head trauma with
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patients with basal alteration thereof.
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focused update of the 2013 guidelines for the early management of patients
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healthcare professionals from the American Heart Association/American
Stroke Association. Stroke 2015; 46:30203035.

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Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.

Glucose control in acute brain injury: does it matter? Godoy et al.

51. Connolly ES Jr, Rabinstein AA, Carhuapoma JR, et al.; American Heart
Association Stroke Council; Council on Cardiovascular Radiology and
Intervention; Council on Cardiovascular Nursing; Council on Cardiovascular Surgery and Anesthesia; Council on Clinical Cardiology. Guidelines for the management of aneurysmal subarachnoid hemorrhage:
a guideline for healthcare professionals from the American Heart
Association/American Stroke Association. Stroke 2012; 43:1711
1737.
52. Steiner T, Juvela S, Unterberg A, et al.; European Stroke Organization.
European Stroke Organization guidelines for the management of intracranial
aneurysms and subarachnoid haemorrhage. Cerebrovasc Dis 2013; 35:93
112.

53. Hemphill JC 3rd, Greenberg SM, Anderson CS, et al.; American Heart
Association Stroke Council; Council on Cardiovascular and Stroke Nursing;
Council on Clinical Cardiology. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from
the American Heart Association/American Stroke Association. Stroke 2015;
46:20322060.
54. Steiner T, Kaste M, Forsting M, et al. Recommendations for the management
of intracranial haemorrhage part I: spontaneous intracerebral haemorrhage.
The European Stroke Initiative Writing Committee and the Writing Committee
for the EUSI Executive Committee. Cerebrovasc Dis 2006; 22:294316.
55. Steiner T, Al-Shahi Salman R, Beer R, et al.; European Stroke Organisation.
European Stroke Organisation (ESO) guidelines for the management of
spontaneous intracerebral hemorrhage. Int J Stroke 2014; 9:840855.

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