SEPSIS ASSOCIATED

ENCEPHALOPHATY (SAE)
SOBARYATI

Neurology Department
Hasan Sadikin Hospital
Universitas Padjadjaran Bandung
 INTRODUCTION

• Sepsis is defined as a life threatening organ dysfunction

due to dysregulated host response to infection
• As a major cause of mortality and morbidity in hospital

• SAE is defined as brain dysfunction due to sepsis and

SIRS. Also called sepsis-associated delirium
• Brain dysfunction (SAE) has been neglected

• Clinically, acute impairment in the level of consciousness

and confusion (manifested by alteration in attention,
disorientation and concentration up to deep coma in
more severe cases)
 INTRODUCTION

• 9 -71% of patients with sepsis develop SAE

• Patients With known CNS pathology are at
greater risk for SAE
• Often described as a reversible syndrome
• New studies show prolonged cognitive
impairment and depressive symptoms in
sepsis survivors
• 63% mortality rate reported in SE patients
with reduced Glasgow Coma Scale to 3-8
points
 PATHOPHYSIOLOGY

• Brain Signaling during Sepsis

• Microscopic Brain Injury
• Endothelial and Blood Brain Barrier Dysfunction
• Cerebral Microcirculation
• Alterations in Neurotransmission
• Inflammatory Mediators and Complement System
• Oxydative Stress, Mitochondrial Dysfunction and
Apoptosis
• Calsium Homeostasis
 PATHOPHYSIOLOGY

1. Oxidative stress
• Occurs early (<6h)
2. Cytokines
• Pro-inflammatory cytokines (tumor necrosis factor (TNF),
Interleukin (IL)-1ß, IL-6) are significantly increased in SE
• Contribute to the development of longterm cognitive
dysfunction and behavioral symptoms
3. Complement cascade
• Excessive complement activation can also produce
reactive oxygen species, can facilitate proinflammatory
mediators and causes edema, cell necrosis or apoptosis
 PATHOPHYSIOLOGY
• Diminished cholinergic innervation - hippocampal, parietal and
prefrontal cortex-incapacities of memory functions

• Dysfunction of the neural circuits between medial temporal lobe,

posterior parietal cortex and dorsal prefrontal cortex by
disconnection from general activating projections from the
ascending reticular activating system (ARAS)- delirium and long-
term impairment in SE patients

• Cerebral endothelial dysfunction, microvasculature and blood-

brain-barrier (BBB) changes

• Impaired nutrition delivery and removal of metabolic waste

products as well as increased permeability

• Inappropriate blood supply to neurons may play an important role

for SE
 PATHOPHYSIOLOGY

• Aromatic amino acids (AAA)

• Normally restricted by BBB
• Increased in SE patients and correlate with
severity of encephalopathy
• May act as false neurotransmitter and/or disturb
neurotransmitter synthesis
• Increased serum levels of phenylalanine,
ammonia, and tryptophan with influence on
procalcitonin and IL-6 levels contributing to SE
development.
Pathophysiology

Review Article, Sepsis Associated Encephalopathy, Advances in Medicine Volume 2014

PATHOPHYSIOLOGY
 CLINICAL FEATURE

• Mild patients demonstrate a fluctuating confusional

state and inappropriate behavior.

• Inattention and writing errors (including spelling,

writing full sentences, orientation of writing on the
page)
•
• More severely affected show delirium, an agitated
confusional state or coma.
TIMELINE SEPSIS ASSOCIATED ENCEPHALOPATHY

Clinics (Sao Paulo). 2011 Oct; 66(10): 1825–1831

 CLINICAL FEATURE

• Most common motor sign is paratonic rigidity , a

resistance to passive movement of limbs that is
velocity-dependent

• Asterixis, multifocal myoclonus, seizures and tremor

are relatively infrequent

• Cranial nerve functions are almost invariably spared

•
• Lateralized features are almost never encountered
 CLINICAL FEATURE

• Clinical or laboratory evidence of peripheral nerve

dysfunction, namely critical illness polyneuropathy,
is found in 70% patients
•
• It is axonal type, later in onset and much slower to
recover than the encephalopathy
 Table : Medications associated with brain dysfunction in the ICU

Agent Mechanism of action

Benzodiazepines CNS sedation, neuronal inhibition by membrane
(long- and short-acting) hyperpolarization (GABA-agonist)

Opioids Anticholinergic toxicity, CNS sedation, fecal impaction

Antibiotics Inhibition of GABA-A receptors
Penicillins, cephalosporins, carbapenems, Quinolones
Antiarrhythmics Strong anticholinergic effects, sodium channel blockage,
Flecaïne, Amiodarone, Digoxin unknown
Beta-blockers Not yet described, association with delirium
Diuretics Dehydration and electrolyte disturbances
Anticholinergic toxicity, Increase of catecholamine activity,
Steroids GABA-agonist, altered serotonin activity
Beta-amyloïd protein generation, cytotoxicity of beta-
Inhaled anesthetics amyloïd potentiating, apoptosis-inducing
Ketamine NMDA-antagonism
Histamine-2 blocking agents Anticholinergic toxicity
Cimetidine
Nonsteroidal anti-inflammatory drugs Blood–brain-barrier permeability
Anticholinergics Anticholinergic toxicity
oxybutynin, bladder antispasmodics
Anticonvulsants CNS Sedation
phenobarbital, phenytoin
Antiparkinsonian agents Dopaminergic toxicity
L-Dopa, dopamine agonists, amantadine
Antidepressants Anticholinergic toxicity
(amitriptyline, imipramine, doxepin)

CNS central nervous system. Ann Intensive Care. 2013; 3: 15

 DIAGNOSIS

• No specific test available

• Electroencephalography (EEG)
• Most sensitive diagnostic tool
• Normal, diffuse slowing, excessive theta,
predominantly delta, triphasic waves, and
suppression or burst suppression
• Non-specific
Table : Electroencephalographic patterns in sepsis

Electroencephalographic Association with

findings adverse outcome

Normal EEG 0
Theta (mild generalized
slowing) +
Delta (severe slowing) +
Triphasic waves +
Periodic epileptiform
discharges +
Electrographic seizures ++
Generalized suppression or
burst-suppression
+++
Ann Intensive Care. 2013; 3: 15
• Short-latency and long-latency-SEP
• Measurement provide a valuable estimation of SE severity
•
• CSF examination
• Total protein may be elevated in severe SE cases, cell
counts and microbiological cultures remain normal
• Used to exclude direct infection in suspected
meningoencephalitis.

• Serum markers
• S100B and neuron-specific enolase (NSE) are elevated in
adults and children
• Do not correlate with severity of SE
 IMAGING

• 1) CT scans
• mostly normal
• White matter hypodensities are reported

• 2) MR imaging
• Various degrees of leukencephalopathy as well as multiple
ischemic strokes
• Patients without MR abnormalities survived without
sequelae, while those who died showed clear MRI lesions
• Mainly within the white matter
• Corresponded to vasogenic edema, probably reflecting
blood–brain barrier breakdown.
• Infarction of basal ganglia secondary to fibrinoid necrosis
and thrombosis of small vessels neuropathologically
• a posterior reversible encephalopathy syndrome (PRES)
• MR angiography in this study revealed vasospasm and
• vessel “pruning”,
Table : Brain MRI patterns in sepsis

Brain MRI findings

Acute changes
• Cytotoxic edema (hippocampus, cortex) ischemic
lesions
• Vasogenic edema
• Posterior reversible encephalopathy syndrome
(PRES)

Chronic changes observed in survivors

• White matter disruption
• Brain atrophy (frontal cortex, hippocampus)
Ann Intensive Care. 2013; 3: 15
NEUROPATHOLOGICAL FINDINGS

• Cerebral hemorrhage, ischemic infarcts and central

pontine Myelinolysis(17%)

• Disseminated micro-abscesses (~67%)

• Ischemic and apoptotic neurons were found in

paraventricular and supraoptic nuclei as well as in
locus coeruleus.
 ALGORITHM FOR DIAGNOSIS OF SEPSIS ASSOCIATED ENCEPHALOPATHY

RASS: Richmond Agitation-Sedation Scale, FOUR: Full Outline of Unresponsiveness, GCS: Glasgow coma scale, SEP:
somatosensory evoked potentials, NSE: neuron specific enolase, CAM/CAM-ICU: Confusion Assessment Method
(Intensive Care Unit), and ATICE: Assessment to Intensive Care Environment. Adv Med. 2014
 TREATMENT

• No specific treatment options for SAE

• Early detection of delirium, may be the first manifestation of
sepsis

• Most importantly, adequate and immediate therapy of

the underlying sepsis syndrome and supportive
intensive care are required

• Managements of sepsis :
• Initial resuscitation
• Infection issues
• Hemodynamic support
• Adjunctive Therapy
• Supportive Therapy
 TREATMENT

• In the treatment of delirium, identify and discontinue

any medication with anticholinergic, histaminergic,
and other psychotropic drug.

• Identify other modifiable risk factor (bladder catheter,

physical restraint)

• Low dose neuroleptics ( avoid lorazepam, prefer

dexmetomidine)
 TREATMENT

• Administration of a mixture of amino acids with high

concentrations of branched-chain amino acids

• Activated protein C, that affect or counteract the

procoagulant state in sepsis may be directly or indirectly
beneficial to brain function in sepsis

• Ascorbate (ascorbic acid 20mg/kg) is antioxidant. Found

useful in animal model.

• Experimental treatment-Magnesium, glutamate release

inhibitor riluzole or an antioxidant treatment, selective
antagonists of pro-inflammatory cytokine receptors

• Coupled plasma filtration adsorption, an extracorporal

therapy, aimed at the nonspecific removal of cytokines and
mediators involved in systemic inflammation
 Potential strategies to reduce brain dysfunction in ICU
patients

Pharmacological measures Type of study

Reduce use of benzodiazepines and opioids Observational studies
Perform daily sedation stops RCT
Use dexmedetomidine (versus benzodiazepines or
propofol) as sedative RCT
Pain assessment: sedation – analgesia – delirium protocol Observational studies
Prevention of metabolic disturbances (severe hypoxemia,
fever, dysnatremia(s), prolonged hyperglycemia…)
Observational studies
Nonpharmacological measures
Sleep protocol RCT (non-critical care
Reorientation and cognitively stimulating activities setting)
Rehydration
Use of eyeglasses, magnifying lenses, and hearing aids
Avoid use of physical restraints Observational studies
Early mobilization RCT
Ann Intensive Care. 2013; 3:
 OUTCOME

• Although SAE may precede other symptoms of

sepsis, a diagnosis is usually missing until mixed
encephalopathy becomes overt

• Outcomes are variable and may be related to the

degree of encephalopathy and the occurrence of
prior neurological disorders
 REFERENCES

• Neurological Sequelae of Sepsis: I) Septic

Encephalopathy; The Open Critical Care Medicine
Journal, 2011, Volume 4
• Sepsis-associated encephalopathy; Neurol J
Southeast Asia 2003; 8 : 65 – 76
• Understanding brain dysfunction in sepsis; Sonneville
et al.; Annals of Intensive Care 2013, 3:15
• Sepsis-Associated Encephalopathy: Review of the
Neuropsychiatric Manifestations and Cognitive
Outcome; J Neuropsychiatry Clin Neurosci 23:3,
Summer 2011
CONCLUSSION