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Sepsis-associated

Review
Future Neurology
encephalopathy and its
differential diagnosis
Anthony Checinski1, Andrea Polito1, Diane Friedman1, Shidasp Siami2,
Djillali Annane1 & Tarek Sharshar†1
1
General Intensive Care Unit, Raymond Poincaré Teaching Hospital (AP-HP), University of Versailles Saint-
Quentin en Yvelines 104, Boulevard Raymond Poincaré, 92380 Garches, France
2
Department of Intensive Care Medicine, Hospital of Sud Essonne, Etampes, France
†
Author for correspondence: Tel.: +33 147 107 780 n Fax: +33 147 107 783 n tarek.sharshar@rpc.aphp.fr

Sepsis-associated encephalopathy (SAE) is defined as a diffuse cerebral

dysfunction resulting from the systemic inflammatory response to an infection
without direct infestation of the CNS. Although the pathophysiology of SAE is as
yet unknown, some mechanisms have been suggested that involve BBB disruption
as a consequence of proinflammatory mediators’ effects on endothelial cells. This
leads to an increased passage of neurotoxic and proinflammatory mediators into
the brain parenchyma, as well as an impairment of the movements of oxygen and
metabolites through the BBB. Both neurons and glial cells are affected, resulting
in neural functioning and neurotransmission impairment. The clinical translation
of this process is an alteration of consciousness and awareness. SAE is a frequent
condition in septic patients. Despite being considered reversible, SAE appears to
be associated with long-term cognitive impairment. Detection and diagnosis can
be challenging; it requires daily neurological assessment with the assistance of
clinical scores. Use of biomarkers and neurophysiological testing is discussed. The
aim of this article is to provide practical tools for detection of SAE, as well as an
updated overview of its pathophysiology and therapeutic perspectives.

Sepsis is often associated with an acute and
reversible deterioration of mental status, encom-
passing alterations of consciousness, awareness,
cognition and behavior. This so-called sepsis-
associated encephalopathy (SAE) or delirium
(SAD) [1] is considered to be a diffuse cerebral
dysfunction resulting from the systemic inflam-
matory response to an infection with no direct
CNS infestation [2] , although meningitis or a
brain abscess should be ruled out if there is any
doubt. All potential factors that may account for
brain dysfunction in a septic patient must be sys-
tematically considered, including drug toxicity
or metabolic disturbances. Most importantly,
encephalopathy often reveals an uncontrolled
sepsis [3] . Detection and treatment of causative
factors of SAD are crucial as it is associated not
only with increased mortality or morbidity, but
also with long-term psychocognitive disability.
Understanding of its complex pathophysio­logy
would help in the development of targeted
therapeutics. Despite its importance in terms of
prevalence and short- and long-term (i.e., cogni-
tive impairment) prognosis, the pathophysio­
logy of SAD remains unclear, although some of
its mechanisms have recently been unearthed.
The aim of this article is to provide a clear pic-
ture of its pathophysiology and provide some
insight into future therapeutics.
We attempted to identify all relevant studies
irrespective of language or publication status
(published, unpublished, in press or in prog-
ress). We searched the Cochrane database of
controlled trials and the Medline database using
the terms ‘sepsis-associated encephalopathy’,
‘sepsis-associated delirium’ and ‘septic shock’,
variably combined with ‘incidence’, ‘prevalence’,
‘conscience’, ‘awareness’, ‘confusion’, ‘neuro-
transmission’, ‘septic shock’, ‘endotoxin’, ‘LPS’,
‘CLP’, ‘microcirculation’, endothelial activa-
tion’, ‘blood–brain barrier’, ’microglial astro-
cytes’, ‘cytokines’, ‘NO’, ‘treatment’, ‘prognosis’,
morbidity’ and ‘mortality’. Studies were selected
on the basis of their relevance to SAE.
Mechanisms
Neurovascular complex
We believe that endothelial activation and its
induced BBB alterations are the major and pri-
mary mechanisms of SAD, as this would allow
the passage into the parenchyma of neurotoxic,
inflammatory or noninflammatory mediators.
Keywords
It is well documented that lipopolysaccharide
(LPS) and proinflammatory cytokines trigger n apoptosis n BBB n delirium
n neurotransmission n sepsis
the endothelial expression of CD40, E-selectin,
VCAM‑1 and ICAM‑1, and activate both endo- part of
thelial COX2 synthesis and the IkB-a/NF‑kB
pathway [4–6] . LPS also induces endothelial

10.2217/FNL.10.62 © 2010 Future Medicine Ltd Future Neurol. (2010) 5(6), 901–909 ISSN 1479-6708 901
 Review Checinski, Polito, Friedman, Siami, Annane & Sharshar
expression of IL‑1 and TNF‑a receptors, pro-
duction of IL‑1b, TNF‑a and IL‑6, as well as the
activation of both endothelial and inducible nitric
oxide (NO) synthetase (NOS) [7,8] . In addition to
the direct release of proinflammatory cytokines
and NO into the brain parenchyma, endo­thelial
activation contributes to brain dysfunction by
compromising microcirculation, impairing oxy-
gen, nutrient and metabolite movements and
altering the BBB.
While microcirculatory dysfunction has been
induced experimentally, the effects of sepsis on
cerebral blood flow (CBF) and its autoregula-
tion during sepsis are controversial. Both human
and experimental sepsis studies demonstrated
increased, unchanged or reduced CBF [9] , as well
as altered or preserved autoregulation [9] . It has
been shown that delirium in septic patients is sec-
ondary to disturbed autoregulation rather than to
altered CBF or tissue oxygenation [10] . Conversely,
a neuropathological study of patients who had
died from septic shock showed that ischemia is
consistently present in brain areas that are sus-
ceptible to low CBF [11] . In addition to ischemia,
microcirculatory alteration can induce hemor-
rhage, sometimes through coagulopathy. In
approximately 9% of cases, the aforementioned
neuropathological study revealed hemorrhages
that were always associated with clotting disor-
ders [11] . However, septic shock patients with and
without hemorrhages did not statistically differ
for clotting tests, platelets counts and incidences
of disseminated intravascular coagulopathy [11] .
The other consequences of endothelial activa-
tion include impairment of oxygen, nutrient and
metabolite movements but, most importantly,
BBB breakdown, which facilitates the passage
of neurotoxic factors. Alteration of the BBB
has been evidenced in a model of sepsis using
various techniques, including electronic micros-
copy [12,13] and MRI [14] . It may result from com-
plement or TNF‑a activation, as their inhibition
reduces brain edema and inflammation  [15,16] .
Interestingly, glutamate plays an important role
in BBB permeability [17] . In septic patients, brain
MRI has demonstrated BBB alterations, revealed
by a vasogenic edema either localized around the
Wirchow–Robin spaces or diffused in the whole
white matter [19] . It can also predominate in pos-
terior lobes, being consistent with a posterior
reversible encephalopathy syndrome.
Intracellular dysfunctions
The passage of neurotoxic mediators, as well as
alterations of oxygenation and metabolic dis-
turbances (especially glucose), affect brain cell
902 Future Neurol. (2010) 5(6)
metabolism, thereby affecting their activity and
viability. Oxidative stress is an early phenomenon
observed in all types of brain cells and in vari-
ous brain areas, especially the hippocampus and
cortex [20,21] . It can be induced by NO (via for-
mation of peroxinitrite) [22] , a decrease in antioxi-
dant factors (heat shock protein or ascorbate) [23] ,
an imbalance between superoxide dismutase and
catalase activity [20] , mitochondrial dysfunc-
tion  [21] , hyperglycemia and hypoxemia. This
process can be deleterious. For instance, expres-
sion of inducible NOS (iNOS), dysfunction of
the respiratory chain and formation of super­
oxide anions within a medullar autonomic cen-
ter sequentially precede hypotension in a model
of endotoxinic shock [22] . However, it should be
noted that previous studies have not shown any
decrease in brain energy during sepsis [24] .
One major consequence of oxidative stress is
apoptosis, which has been reported in septic ani-
mals [25,26] and patients [27] . In septic rats, apopto-
sis was mitochondrially mediated and associated
with an increase in intracellular proapoptotic
(BAX) factors and a decrease in antiapoptotic
(bcl‑2) factors [25,26] . In septic patients, intensity
of apoptosis correlated with expression of endo-
thelial iNOS [27] . In addition to NO, other pro-
apoptotic factors have been incriminated, such
as glutamate, TNF‑a and glucose. The excito-
neurotoxicity of glutamate has been extensively
investigated in various neurological dis­orders  [28] .
Interestingly, recycling and glutamate export
of ascorbate by astrocytes are inhibited in sep-
sis  [29,30] , and both plasma and CSF ascorbate
levels are decreased in patients with SAE [31] .
The proapoptotic role of TNF‑a, along with
other proinflammatory cytokines, is supported
by the case report of multifocal necrotizing
leuko­encephalopathy [32] , which is characterized
by apoptotic and marked inflammatory lesions
of the pons and excessive systemic inflamma-
tory responses. On the other hand, no correla-
tion was found between TNF‑a expression and
brain cell apoptosis [27] . Finally, hyper­glycemia
increases microglial vulnerability to LPS-
mediated toxicity [33] . However, we should not
always consider apoptosis a deleterious phenom-
enon. For instance, it has been demonstrated to
facilitate plasticity.
Microglial hypothesis
Recently, van Gool et  al. proposed that one
mechanism of delirium could be overactivation
of microglia secondary to impairment of their
cholinergic inhibition [34] . This hypothesis is con-
sistent with the major role of microglial cells in
future science group
 Sepsis-associated encephalopathy & its differential diagnosis
the host’s defense of the brain but also in neuro-
inflammatory and neurodegenerative processes.
It has been shown that microglial cells were either
activated or apoptotic in patients who had died
from septic shock [11,35] . However, the interactions
between neurons and glial cells that determine
brain cell survival are so complex that activated
microglial cells can become neuroprotective or
neurotoxic. Large amounts of glutamate are also
released by activated microglia; this cell activa-
tion is consistently observed during sepsis [36] .
Furthermore, it is unknown whether microglial
apoptosis is an adaptive, negligible or deleteri-
ous phenomenon. On the other hand, Petito and
Roberts suggested that apoptotic death of reactive
astrocytes might be a physiological mechanism
whereby the brain removes an excess number
of astrocytes that have proliferated after certain
types of brain injury [37] . This can also apply
for microglia. There are many factors that can
activate or alter microglia, including cytokines
and NO. A recent in  vitro study showed that
hyperglycemia increased microglial vulnerability
to LPS-mediated toxicity through formation of
oxidative free radicals [38] .
Alteration of neurotransmission
The final consequence of these processes is an
alteration of neurotransmission, which accounts
for an alteration of consciousness and awareness,
as hypothesized in critical illness-associated
delirium [39] . Experimental sepsis alters cholin-
ergic  [40] , brain b‑adrenergic, GABA and sero-
toninergic release or receptor expression [41,42] ,
predominately in the cortex and hippocampus
[43] . NO, cytokines and prostaglandins may be
involved [42,44] . Neurotransmitter synthesis is
also impaired by ammonium, tyrosine, trypto-
phan and phenylalanine, whose plasma levels
are increased secondary to liver dysfunction
and muscle proteolysis [45] . Their neurotoxic
effect might be potentiated by the decrease in
branched-chain amino acids [45] .
We are not able to state which mechanism
is the most important; we think that they are
intertwined. Our scenario is that endothelial
activation and BBB alteration induce brain
inflammation, which will affect brain cells by
inducing oxidative stress and will culminate
in altered neurotransmission. Metabolic dis-
turbances (e.g., hyperglycemia and neurotoxic
amino acids) or other neurotoxic factors may
also contribute to encephalopathy. Finally,
hemodynamic alterations, coagulopathy disor-
ders and hypoxemia may induce brain damage
or worsen this neuroinflammatory process.
future science group
Review
Diagnosis & prognosis
Sepsis encephalopathy is clinically character-
ized by an alteration of awareness/consciousness,
which ranges from an altered sleep/wake cycle to
deep coma and impairment of cognition, which
includes symptoms of delirium, such as disorien-
tation, hallucination, impaired attention or dis-
organized thinking. It is often accompanied by
changes in motor activity, ranging from agitation
to hypoactivity [2] . Agitation and somnolence can
alternate over the course of the day. Other, less
frequent motor symptoms include paratonic rigid-
ity, asterixis, tremor and multifocal myo­clonus.
Alterations of electroencephalographic activity are
usually present. Indeed, sepsis is associated with
seizures (usually nonconvulsive) or periodic dis-
charges [46] . According to its severity, it can induce
excessive q, predominant d, triphasic waves and
suppression or burst suppression [47] . It is also asso-
ciated with alterations in somatosensory-evoked
potential latency or amplitude  [48,49] . While
plasma levels of neuron-specific enolase and S‑100
b-protein are elevated in patients with SAE [50] ,
they have been reported not to be correlated with
clinical or EEG severity [51] . As mentioned earlier,
brain MRI can reveal cerebral infarcts, posterior
reversible encephalopathy syndrome or localized-
to-diffuse leukoencephalopathy [18,19] . However,
brain MRI may fail to detect some brain lesions
observed in neuropathological studies, such as
hemorrhages related to disseminated intravascu-
lar coagulopathy, microabscesses or multifocal
necrotizing leukoencephalopathy [11] .
Sepsis is undoubtedly a cause of agitation [52]
and delirium [53] . A Glasgow Coma Scale (GCS)
score of less than 12 is reported in a third of
septic patients. Presence of encephalopathy is
an independent prognosis factor of sepsis. Thus,
mortality rates increase by up to 63% when GCS
scores drops below 8 [54] or by up to 67% when
EEG shows burst suppressions [44] . Mortality
rates also increase with plasma levels of biomar-
kers, although they do not correlate with clinical
and neurophysiological severity [9] . There are no
outcome studies on long-term psychological and
cognitive sequelae of SAD, as such. Nonetheless,
in a study on acute respiratory distress syndrome
survivors, mostly of septic origin, Hopkins et al.
demonstrated that 30% of their patients exhib-
ited a cognitive decline 1 year after discharge,
and that 78% of the patients had at least one cog-
nitive functioning impairment [55] . As a result,
those patients experience a poor quality of life.
Furthermore, delirium, mostly of septic origin, is
associated with long-term cognitive decline and
brain atrophy [56,57] .
www.futuremedicine.com 903
 Review Checinski, Polito, Friedman, Siami, Annane & Sharshar
Diagnostic approach
Incidence and severity of SAE should prompt
physicians to detect a brain dysfunction, diag-
nose its causes and finally, whenever possible,
propose a treatment.
Detection
Detection is based on daily neurological assess-
ment of mental status [2,9] . We have at our dis-
posal validated scores for detecting delirium
and for monitoring awareness. The Confusion
Assessment Method for the Intensive Care Unit
(CAM‑ICU) [58] or the Intensive Care Unit
Delirium Screening Checklist (ICU‑DSC) [59]
can be proposed for delirium. Awareness can be
assessed with the help of sedation scores, such
as the Richmond Agitation and Sedation Scale
(RASS) or the Adaptation to the Intensive Care
Environment (ATICE) [60] . Detection of delirium
should be completed by an exhaustive neurologi-
cal examination assessing neck stiffness, motor
responses, muscular strength, plantar and deep
tendon reflexes and cranial nerves. In cases of
focal neurological signs, brain imaging will be
indicated. In cases of seizure (including palpebral
myoclonus) or neck stiffness, EEG and a lumbar
puncture will be required before or after neuro-
imaging. Although neurological examination is
limited by sedation, we think that neurological
examination should be performed daily in sedated
patients. Occurrences of sudden changes in men-
tal status that are unexplained by the modifica-
tion of sedative infusion rate, a fortiori occurrence
of focal neurological sign, seizure or neck stiffness
should lead the physician to consider complemen-
tary investigations. Beside clinical examination,
neurophysiological testing and assessment of bio-
markers have been proposed for detecting brain
dysfunction in sedated septic patients. In con-
trast to EEG, somatosensory-evoked potentials
are not affected by sedative drugs [48] , but they
are too cumbersome to be routinely performed
at the bedside. The usefulness of the bispectral
index is controversial in critically ill patients [61] .
Measurements of biomarkers (i.e., neuron-specific
enolase and S‑100 b-protein) are simple to take,
but their specificity and sensitivity for detecting
SAE or lesions have not yet been demonstrated
fully enough to recommend their routine mea-
surement [51] . Neither can neuroimaging nor CSF
analysis yet be considered as monitoring tools.
Complementary investigations
Cerebrospinal fluid analysis should always be
performed whenever meningitis is suspected,
and brain imaging should be carried out if there
904 Future Neurol. (2010) 5(6)
are focal neurological signs or seizures (Figure 1) .
Seizure (including palpebral myoclonus) indicates
EEG but also an unexplained altered neuro­logical
state, as it can be secondary to nonconvulsive epi-
lepsy, which is treatable. Brain imaging needs to
be addressed if no cause for encephalopathy has
been identified. Of course, the risks and benefits
of brain imaging should be considered before
transporting the patient. Although more time
consuming, we prefer MRI to CT scans as it is
more informative. MRI better detects recent isch-
emic stroke, white matter lesions or BBB rupture,
and is more useful for exploring cerebral arter-
ies. In addition to the importance of etiological
diagnosis for the physician and the relatives of
the patient, assessment of the nature and extent
of brain damage may also influence the treatment
of patients. For example, evidence of brain hemor-
rhage should lead to discontinuation of any drug
with an anticoagulant activity.
Standard laboratory tests for detecting meta-
bolic disturbances, liver dysfunction and renal
insufficiency must also be carried out. The
patient’s drug chart must be screened to identify
neurotoxic treatments that could be discontinued
or tapered according to their plasma levels or their
liver and/or renal function. It must be emphasized
that encephalopathy is often multifactorial; there-
fore, the physician should not stop his enquiry
once he has identified one factor. Indeed, critically
ill patients are susceptible to developing delirium
that can result from various causes, which can be
entwined, masked or worsened by a septic pro-
cess. This is classically the case for patients with
hepatic or uremic encephalopathy. The physician
must be prudent before ascribing encephalopathy
to drug or alcohol withdrawal in septic patients.
For instance, the latter occurs in only 5% of
hospitalized alcohol-dependent patients, usually
within 48–72 h of the patient’s last drink, and is
characterized by major psychomotor agitation,
zoopsies and autonomic signs (hyperpyrexia,
tachycardia, hypertension and diaphoresis). We
recommend prevention of thiamine deficiency
in alcoholic or malnourished patients, which
induces Wernicke’s encephalopathy.
Finally, reappearance or persistence of encepha-
lopathy may indicate that sepsis is not controlled
and is a classical feature of deep abscess.
Treatment & therapeutic perspective
In the absence of specific treatment, treatment
of SAE essentially includes supportive measures
such as control of sepsis, management of organ
failure and metabolic disturbances and avoidance
of neurotoxic drugs.
future science group
 Sepsis-associated encephalopathy & its differential diagnosis Review

All strategies that have been shown to pre-
vent delirium should be applied in septic
patients. This includes nonpharmacological
measures such as reassurance, ensuring the
patient’s comfort and occupational therapy.
Pharmacological measures should be goal
directed. They should include pain treatment
and ensure good sleep rhythmicity.
Neurotoxic drugs should be discontinued and
sedation reassessed on a regular basis [62] .
Among treatments currently used in septic
patients, intensive insulin therapy, activated
protein C and steroids may have some effects
on endothelial activation, BBB breakdown,
neuroinflammation, oxidative stress and apop-
tosis, which are the main pathophysiological
mechanisms of SAE. However, there is no
clinical evidence that these treatments reduce
the incidence or severity of SAE [63–66] .
The experimentally tested mechanisms
essentially consist of iNOS and BBB. Although
iNOS inhibition reduces LPS-induced neu-
ronal apoptosis in septic rats [67] , it does not
improve consciousness and it can also aggra-
vate brain ischemia [68] and increase cardio-
vascular deaths [69] . Serum amyloid  P, mag-
nesium  [70,71] , riluzole [17,72] , calcium-channel
blockers and removal of circulating cyto-
kines  [73] reduce BBB permeability in septic
animals. Riluzole and silymarin also diminish
oxidative damage and brain injury in septic
rats [21,72] . While infusion of branched-chain
amino acids can reduce aromatic amino acids
in the brain by competing with their trans-
port, its effect on SAE have not been demon­
strated [74] . Modulation of brain signaling is
also appealing, notably modulation of cholin-
ergic control of microglia [34] . Interestingly,

Septic patient

Exclude CNS infestation

Consider discontinuation of sedation

Sedated Not sedated

Yes
Assess Brain imaging Focal neurological sign
• Motor response
• Brainstem response No

Abnormal Assess consciousness

Assess
Normal • Drugs
• Biochemistry Coma Conscious
• EEG

SAD cannot Assess awareness

be excluded Normal • ATICE
• CAM ICU

SAD likely
Abnormal Normal
Consider
• Discontinuation
of sedation
or
• SSEP MRI to assess brain lesions SAD unlikely

Figure 1. Diagnostic algorithm of sepsis-associated delirium.

ATICE: Adaptation to the Intensive Care Environment; CAM-ICU: Confusion Assessment Method for
Intensive Care Unit; SAD: Sepsis-associated delirium; SSEP: Somatosensory-evoked potential.

future science group www.futuremedicine.com 905

 Review Checinski, Polito, Friedman, Siami, Annane & Sharshar

pharmacological inhibition of the cholinergic
pathway has recently been shown to improve
sickness behavior [75] .
As proposed by Wilson et al., the antioxidant
effects of ascorbate may prevent iNOS induc-
tion during sepsis and preserve normal cell
function by protecting the glutamate uptake
rate. Therefore, it may be beneficial to patients
exposed to the neurological complications of
sepsis [76] .
Conclusion
The diagnosis of SAE is crucial as it is a fre-
quent and severe complication. It involves both
inflammatory and noninflammatory processes
that affect all brain cells and induce BBB altera-
tion, dysfunction of intracellular metabolism,
brain cell death and brain injuries. Its diagnosis
essentially relies on neurological examination,
which will then indicate specific neurological
tests. EEG is required in the presence of seizure,
neuroimaging is required in the presence of sei-
zure, focal neurological signs or suspicion of
cerebral infection, and both are required when
encephalopathy remains unexplained. CSF
analysis is indisputably required when men-
ingitis is suspected. SAE results from various
and combined factors that must systematically
be screened. Its treatment consists mainly of
controlling sepsis.
Future perspective
Among organ failures related to sepsis, enceph-
alopathy is less commonly assessed in clinical
practice and less extensively investigated in
clinical and basic research. The recent develop-
ment of neurological scores applicable to inten-
sive care unit patients, in addition to advances
in neuroradiology and neurophysiology, will
undoubtedly improve the neurological care
of critically ill patients. This will help in the
design of observational studies as well as clinical
trials. The short- and long-term prognoses of
SAE have to be addressed in large cohort stud-
ies. Intensive care unit physicians need to know
what neuromonitoring is appropriate (both
clinical and paraclinical) for septic patients, as
well as when neurophysiologic or neuroradio-
logic tests are needed. We believe that an early
assessment of SAE will improve the detection
and treatment of uncontrolled sepsis. It is likely
that such an approach will in itself reduce the
morbidity and mortality that is ascribable to this
brain dysfunction.

Executive summary
Definition
n Sepsis-associated encephalopathy (SAE) is a diffuse cerebral dysfunction that is a consequence of the systemic inflammatory response
to an infection with no direct CNS infestation.
n As an independent mortality and morbidity factor, its importance is pinpointed by recent evidence of its relationship with long-term

cognitive impairment in sepsis survivors.

Mechanisms
n Endothelial activation by circulating proinflammatory mediators during sepsis results in cerebral microcirculatory dysfunction and
BBB breakdown.
n Cerebral blood flow autoregulation is impaired and metabolite transfers through the BBB are altered, while its permeability to

proinflammatory mediators and neurotoxic substances is increased.

n Changes in cerebral homeostasis and the effects of proinflammatory mediators on brain cells result in intracellular dysfunction.

n Microglia are also affected by these mechanisms and play an unknown role in brain dysfunction.

n Neurotransmission is altered as a consequence of these processes and accounts for the alterations of awareness and consciousness that

define SAE.
Diagnosis
n Daily clinical examination and the use of clinical scores are key to SAE detection and should be performed in nonsedated and sedated
patients alike.
n Complementary investigations are guided by clinical findings.

n Owing to the multifactorial etiology of delirium, enquiries should not be stopped after the discovery of one causative factor.

Treatment
n There are no specific treatments of septic encephalopathy.
n Treatment of SAE includes supportive measures, such as control of sepsis, management of organ failure and metabolic disturbances,
and delirium prevention measures, such as reassurance occupational therapy or neurotoxic drug discontinuation.
Future perspective
n SAE demands a multidisciplinary approach owing to its complex pathophysiology.
n It must become a secondary end point in clinical trials undertaken in sepsis, and the cerebral effects of the therapeutics that are
recommended must be better evaluated.

906 Future Neurol. (2010) 5(6) future science group

 Sepsis-associated encephalopathy & its differential diagnosis Review

It is important to gain a better understand-
ing of the cerebral effects of therapies frequently
instituted in the setting of sepsis, including
antibiotics, fluid resuscitation, vasopressors and
inotropes, lung protective ventilation, gluco­
corticoids, activated protein  C and intensive
glycemic control, as well as to evaluate the effects
of these interventions for preventing, treating or
worsening SAE. Delirium should be at least a
secondary end point of any clinical trial under-
taken in sepsis. Similarly, subgroup analyses
should be planned in clinical trials on delirium,
evaluating patients with or without sepsis. New
approaches should also be tested. For instance,
one major unanswered issue is whether target-
ing higher systemic blood pressures will result in
improved cerebral perfusion and oxygenation,
given that SAE is associated with both macro-
and microcirculatory failure. Their development
depends on advances in the understanding of
SAE mechanisms.
The complexity of brain physiology and that
of SAE pathophysiology makes collaborations
with researchers from multiple disciplines indis-
pensable. SAE is a topic that can foster collab-
orative efforts between physicians and scientists
with expertise in infectious diseases, neurology,
immunology, neurobiology, neurophysiology and
neuroradiology. Such collaborations are built on
the principle that the nervous system is a major
component of critical illness and neurology a
major dimension of intensive care medicine.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial
involvement with any organization or entity with a
financial interest in or financial conflict with the subject
matter or materials discussed in the manuscript. This
includes employment, consultancies, honoraria, stock
ownership or options, expert testimony, grants or patents
received or pending, or royalties. No writing assistance
was utilized in the production of this manuscript.

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908
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