brain dysfunction during sepsis - cnerea.fr · concept of sickness behavior • behavior is a...

BRAIN DYSFUNCTION

DURING SEPSIS

[email protected]

University of Versailles

Raymond Poincaré Teaching Hospital

Garches - France

SEPTIC PATIENTS CAN DIE SEPTIC PATIENTS CAN DIE

FROM BRAIN FAILUREFROM BRAIN FAILURE

A 67 years old COPD womanwho developed a septic shockcomplicated suddenly by acomplicated suddenly by acoma (+ divergent eyes)

Sharshar et al – ICM - 2007

DIFFUSE VASOGENIC EDEMA

(BBB alteration)

SEPTIC PATIENTS CAN DIE SEPTIC PATIENTS CAN DIE

FROM BRAIN FAILUREFROM BRAIN FAILURE

A 72 years old woman withhistory of cirrhosis whodeveloped septic shockcomplicated by seizure and

FLAIRFLAIR

complicated by seizure andcoma without concomitanthypoxemia and hypotension

ADCADC

DIFFUSIONDIFFUSIONDIFFUSE CYTOTOXIC EDEMA

(microcirculatory alteration)

DEFINITIONDEFINITION

Levy et al - Crit Care Med - 2003

SEPSIS

1. Sepsis is an independant risk factors for agitation

(Jaber et al – ICM - 2003)

2. Sepsis is a major cause of delirium (Ely et al –2. Sepsis is a major cause of delirium (Ely et al –

JAMA - 2004) ~ 50%

3. Encephalopathy is occuring in 32 to 60% of septic

patients (Eidelman et al -JAMA -1996)

SEVERITYSEVERITY

GLASGOW COMA SCALE n APACHE II MORTALITY

15 19 17.2 (6.3) 16%15 19 17.2 (6.3) 16%

13-14 15 20.1 (5.4) 20%

9-12 8 23.1 (5.7) 50%

3-8 8 34.4 (7.0) 63%

Eidelman et al - JAMA - 1996

ELECTROENCEPHALOGRAMELECTROENCEPHALOGRAM

1. Excessive theta

2. Predominant delta30

40

50

60

2. Predominant delta

3. Triphasic waves

4. Burst suppresssion

Young et al JCN 1992; Straver et al Neurol Res 1998

0

10

20

30

Normal Theta Delta Triphasic Burst

suppression

NORMAL MILD SEVERE

ELECTROENCEPHALOGRAM

• Sepsis: independent predictor of electrographicseizure (ESZs) or periodic epileptiform discharges(PEDs) : OR: 4.6, 95% CI 1.9–12.7, p = 0.002.(PEDs) : OR: 4.6, 95% CI 1.9–12.7, p = 0.002.

• Sepsis: poor outcome in 90% versus 55% inpatients with and without ESZs or PEDs. adjustedOR 10.4, 95% CI 3.0–50.7, p < 0.001.

Oddo et al Crit Care Med 2008

SENSORY EVOKED POTENTIALSSENSORY EVOKED POTENTIALS

1. Prolonged SEP subcorticaland cortical peak latenciesin 34% and in 84% of septicpatients

2. Cortical Peak latencycorrelated with APACHEIII.

3. SEP peak latency did notdiffer between sedated andnon-sedated patients

Zauner et al - CCM - 2000; Zauner et al - CCM - 2002

PATHOPHYSIOLOGY

Excessive inflammatory brain signalling

(Sickness behavior => Delirium)

MPL (Sharshar 2002)

Neuroinflammatory process CytokinesNeuroinflammatory process (Delirium => neurodegenerative)

Ischemic process

(Delirium/focal => vascular demantia)

(Sharshar 2007, Polito 2011)

(Sharshar 2007, Sharshar 2004)

Cytokines

NO

40% mortality

60% mortality

NEUROINFLAMMATORY

PROCESS

1. Endothelial activation

2. Alteration of blood-brain barrier

1. Role of TNFa

2. Role of complement

EXPERIMENTAL OR CLINICAL DEMONSTRATION

3. Brain expression of cytokines and iNOS

4. Microglial activation

1. Amplification of neuro-inflammatory process

5. Brain cells oxidative stress

6. Brain cell apoptosis

7. Alteration of neurotransmission

MICROGLIAL ACTIVATION

Van Gool et al – Lancet - 2010

Effect of rivastigmine as an adjunct to usual care with

haloperidol on duration of delirium and mortality in critically ill

patients: a multicentre, double-blind, placebo-controlled

randomised trial

Although a sample size of 440 patients was planned,

after inclusion of 104 patients with delirium, the trial

was halted becausewas halted because

1. Mortality in the rivastigmine group (n=12, 22%)

was higher than in the placebo group (n=4, 8%;

p=0·07).

2. Median duration of delirium was longer in the

rivastigmine group (5·0 days, IQR 2·7—14·2) than

in the placebo group (3·0 days, IQR 1·0—9·3;

p=0·06).

Van Eijk et al - Lancet - 2010

METABOLIC DISTURBANCES

• Liver dysfunction

• Kidney dysfunction

• Drugs toxicity• Drugs toxicity

• Drugs withdrawal

• Electrolytic disturbances

• Glycemia

…

GLUCOSE

HYPERGLYCEMIA NORMOGLYCEMIA

(INSULIN)

Microglial activation and apoptosis

(GLUT5)

Astrocytes inactivation

+ -

Polito et al – Crit Care – 2011; Sonneville et al – JCEM - 2012

CEREBRAL INFARCTSn=22 (39%)

Association with clotting disorder

ISCHEMIC PROCESSISCHEMIC PROCESS

Sharshar et al - ICM – 2007; Eischwald et al - Submitted

CYTOTOXIC EDEMA

Bozza et al – JCBFM - 2010

MICROCIRCULATION

Control

Septic

Taccone et al – Crit Care - 2010

CI: cardiac index

FCD: functional capillary density

ISCHEMIA

(100%) HEMORRHAGE

(30%) IDC

(30%)MICRO

ABSCESSES

(10%)

NEUROPATHOLOGY

Sharshar et al - Brain Pathology - 2004

CEREBRAL BLOOD FLOWCEREBRAL BLOOD FLOW

CONTROVERSIAL

Cerebral blood flow, cerebral vasomotor reactivity

and cerebral metabolic rates have been shown to beand cerebral metabolic rates have been shown to be

decreased or preserved in experimental sepsis and in

septic patients.

Crit Care - 2010; Siami et al - Crit Care Clin - 2008

Should we monitor and “optimize” cerebral blood

flow in patients with septic shock?

Pandharipande et al – CC - 2010

TREATMENT

No specific treatment other than control of sepsisNo specific treatment other than control of sepsis

Persistence or reappearance of delirium often indicates Persistence or reappearance of delirium often indicates

that the sepsis is uncontrolledthat the sepsis is uncontrolled

Cerebral effects of accepted treatments of septic shockCerebral effects of accepted treatments of septic shock

1.1. Activated protein C ? (Effect on endothelial activation)Activated protein C ? (Effect on endothelial activation)

2.2. Corticosteroids? (decrease in PTSD, effect on BBB)Corticosteroids? (decrease in PTSD, effect on BBB)

3.3. Insulin? (Insulin? (neuroprotectiveneuroprotective?)?)

MECHANISMS OF LONG-TERM

COGNITIVE DECLINE IN SEPSIS

Psychological

disorders

BEHAVIOR

(AmygadalDELIRIUM

Cognitive

disorders

HIPPOCAMPUS, AMYGDALA, LIMBIC SYSTEM…

CONCEPT OF BRAINSTEM

DYSFUNCTIONDYSFUNCTION

NEUROLOGICAL EXAMINATION

OF SEDATED PATIENTSOF SEDATED PATIENTS

NEUROLOGICAL ASSESSMENT

BRAINSTEM RESPONSESFOCAL SIGNS

Comparison between right

Verbal responseEyes response Motor response

GLASGOW COMA SCALE

1. Eyes spontaneous movement

2. Eyes position

3. Oculocephalogyre response

4. Pupillar size

5. Pupillar light reflex

6. Corneal reflex

7. Grimace

8. Cough reflex

Comparison between right

and left body

1. Motor responses to order

or painful stimulation

2. Limbs tone

3. Tendon reflexes

4. Plantar reflex

Fitting set

n = 72

Validation set

n = 72

Women (%) 24 (33) 28 (39)

Age (years) 58 (46 to 74) 69 (51 to 80)

Surgical admission (%) 16 (22) 22 (31)

CHARACTERISTICS AND OUTCOME

Surgical admission (%) 16 (22) 22 (31)

SAPS-II at admission 50 (37 to 61) 57 (45 to 67)

Duration of sedation (days) 5 (2 to 8) 3 (2 to 6)

Confusion/delirium at awakening (%) 26 (43) 26 (53)

Coma (%) 11 (18) 14 (23)

Altered mental status (%) 34 (57)* 34 (55)**

Mortality rate at day 28 (%) 22 (31) 21 (29)

* 60 and ** 62 patients


12-24H OF SEDATION Fitting set Validation set

Number of patients 72 72

Midazolam (mg/kg) 0.9 (0.6 to 1.8) 1.3 (0.8 to 2.0)

Subfentanyl (µg/kg) 2.0. (0.8 to 4.0) 2.0 (0.7 to 4.6)

sedation to inclusion (hours) 12 (12-24) 12 (12-24)

ATICE (from 0 to 20) 9 (9 to 10) 9 (9 to 10)

RASS Not tested -4 (-4 to -2)RASS Not tested -4 (-4 to -2)

Blinking to strong light (%) 31 (43) 28 (39)

Absent eye movement (%) 66 (93) 67 (93)

Myosis (%) 45 (63) 38 (54)

Pupillary light response (%) 51 (71) 58 (82)

Corneal reflex (%) 65 (90) 66 (92)

Oculocephalic response (%) 32 (47) 33 (46)

Cough response (%) 36 (51) 60 (83)

Grimacing (%) 41 (57) 48 (69)

Myo

91

0

Cluster Dendrogram

Crn: corneal reflex

Blk: blinking

Gmg: grimace

Cgh: cough


SYSTEMATIZED ALTERATION OF BRAINSTEM REFLEXES BY SEDATION

Gm

g

Cg

h

Ocr B

lk

Myo

Eyp

Crn Lid

Lig

ht

56

78

agnes (*, "ward")

t(x)

Heig

ht

Cgh: cough

Light: pupillar reflex

Moi: miosis

EyP: eye position

Ocr: oculocephalogyre

Septic shock with ARDS and

severe liver and renal failure

in a aplasic 82 years old man.

1. Coma plus abolition of all

brainstem reflexes

DISCREPANCY

brainstem reflexes

2. After discontinutaion of

sedation, recovery of

cough and oculocephalic

repsonses but not of

corneal reflex and

grimace.

ALTERED MENTAL STATUS

(after discontinuation of sedation)

Fitting set Validation set

RESPONSES ASSESSED BETWEEN THE 12Th AND 24th H OF SEDATION

Multiple logistic model


Criteria Confusion or coma Delirium or coma

OR (95%CI) P OR (95%CI) P

SAPS-II at inclusion 1.04 (1.00 to 1.07) 0.058 1.03 (0.99 to 1.08) 0.10

Absent oculocephalic response 4.49 (1.34 to 15.1) 0.015 5.64 (1.63 to 19.5) 0.006

Sharshar et al – Crit Care Med - 2011

Multiple logistic model

28-DAYS MORTALITY


RESPONSES ASSESSED BETWEEN THE 12Th AND 24th H OF SEDATION

Sharshar et al – Crit Care Med - 2011


OR (95%CI) P OR (95%CI) P

SAPS-II at inclusion 1.06 (1.02 to 1.09) 0.003 1.03 (1.00 to 1.07) 0.051

Absent cough response 7.80 (2.00 to 30.4) 0.003 5.44 (1.35 to 22.0) 0.017

C-index (SE) 0.836 (0.055) 0.743 (0.067)

CONCEPT OF BRAINSTEM

DYSFUNCTION

Oculocephalic response

Apoptosis LC

RAAS dysfunctionDELIRIUM

CRITICAL

ILLNESS

Apoptosis LC

Effect of DEX

DEATHAutonomic dysfunction

Cough reflex

HR/BP variability

Immune control

IMMUNO

DEPRESSION

Inappropriate Sympathetic Activation at Onset of

Septic Shock: A spectral Analysis approach

Annane et al - AJRCCM - 1999

NEURO-IMMUNE MODULATION

ΣΣΣΣ PARAΣΣΣΣ

αααα2 ββββ2ββββ1 αΑαΑαΑαΑ7

(CMganglion)

DYSFUNCTION

HPA axis

Splenic AR

INFLAMMATION

+ _

EXPERIMENTAL SEPSIS-RVLM

LPS IV

oligodendrocytes

Superoxide (O2-)

iNOS

neurons

astrocytes

microglia

Apoptosis

T1

Cytochrome C

Apoptosis

Arterial hypotension

Chan et al-Free Rad-2005

T2 T3

T4

PROJECT

Clinical and neurophysiological assessment ofClinical and neurophysiological assessment of

relationships between brainstem response and

delirium and death in critically ill patients with and

without brain damages

SEDATION

(C’est la confusion!)

BZD

(Dose/durée)

DXM Interruption

quotidienne

DELIRIUM0

-+

Physiothérapie

-

Absence

sédation

+

Confort/amnésie ?

Faux souvenirs

BE CAREFULBE CAREFUL

In a 65 years old man lightlysedated for a hypoxemicpneumonia:

+ no response of the leftarm to painful stimuli

+ a greater hypotonia of theleft arm and leg

Facial Facial

palsypalsy

left arm and leg

+ a decreased contraction ofthe right face to painfulstimulation

+ Claude-Bernard Hornersign

FOCAL NEUROLOGICAL SIGNS IN A CRITICALLY ILL PATIENT

WITH CEREBROVASCULAR RISK FACTORS AND TREATED BY HEPARIN

WeaknessWeakness


Accounts for all neurological signs


Three days after discontinuation of sedation, the patient

developed agitation and delirium. General and neurological

examination was not changed. EEG was normal. Agitation and

delirium was ascribed to discontinuation of sedation. Three days

later, patient complained of pain of the legs and ankles that

turned to be due to bacterial and ischemic myositis.turned to be due to bacterial and ischemic myositis.

DELIRIUM WITHOUT (new) FOCAL NEUROLOGICAL SIGN

IN A RECENTLY NON SEDATED PATIENT

DIFFERENTIATING

ENCEPHALOATHY FROM ENCEPHALOATHY FROM

SICKNESS BEHAVIOR

CONCEPT OF SICKNESS BEHAVIOR

• Behavior is a major, highly preserved and adaptivecomponent of response to stress.

• The behavioral response to stress is variable, ranging fromaggressiveness, anxiety or hyperalertness to lethargy and isaggressiveness, anxiety or hyperalertness to lethargy and ismainly controlled by the amygdala and hippocampus,which are vulnerable to hemodynamic and metabolicinsults.

• Changes in behavior are therefore not easily interpretablebecause they can be adaptive or maladaptive, physiologicor pathophysiologic.

Dantzer et al – Nat Neurosci Rev

PHYSIOLOGICAL BRAIN SIGNALLINGSickness behavior

Adapted neurovegetetative and neuroendocine response

Vagal nerve

Dantzer et al – Nat Rev Sci - 2008

Circumventricular organs

(no BBB)

Vagal nerve

Delirium+

NE NE

BHV

(Amygadal DELIRIUM

IMMUNE

Psychological

disorders

NE

NV

(Brainstem

NE

COMA

IMMUNE

SYSTEMCognitive

disorders

CONCLUSION

SEPSIS ASSOCIATED ENCEPHALOPATHY IS

1. A FREQUENT AND SEVERE COMPLICATION

2. HAS TO BE DETECTED ROUTINELY

3. HIS ASSESSMENT IS MAINLY CLINICAL, EEG OR MRI BEING

UNDERTAKEN UPON NEUROLOGICAL ARGUMENT

4. REQUIRES A SYSTEMATIC APPROACH THAT TAKE INTO ACCOUNT

MENGITIS, UNCONTROLLED SEPSIS AND DRUG NEUROTOXICITY

5. SECONDARY TO ISCHEMIC AND INFLAMMATORY PROCESSES,5. SECONDARY TO ISCHEMIC AND INFLAMMATORY PROCESSES,

INVOLVING BRAIN PERFUSION, MICROCIRCULATION AND BBB AND

MICROGLIAL CELLS

6. ASSOCIATED WITH LONG TERM COGNITIVE DYSFUNTION

ITS TREATMENT IS:

1. CONTROL OF SEPSIS,

2. AVOID NEUROTOXICITY,

3. NEUROPROTECTIVE AGENTS OR STRATEGY?

Raymond Poincaré

Service de Réanimation

MERCI

Institut Pasteur

Fabrice Chrétien

Histopathologie Humaine et Modèles Animaux

ACKNOWLEDGEMENTS

Institut PasteurRaymond Poincaré

Dr Romain Sonneville

Dr Nicolas Weiss

Dr Andréa Polito

DrShidasp Siami

Dr Juliette Bailly-Salin

Dr Anne-Laure le Maho

Beaujon

Dr Jeremy Allary

Dr Stanilas candlemanDr Nicolas Weiss

Pr Fabrice Chretin

Pr Mervyn Singer

Dr Anne-Laure le Maho

Dr Aurelien Mazeraud

Dr Eric Azabou

Pr Geoffroy Lorin

Pr Djillali Annane

Pr Tarek Sharshar

Dr Stanilas candleman

Pr Jean Mantz

UCL

Pr Greet van den Berghe

Leuven

Jan-Pieter Konsman

Bordeaux

Non sedated

EXAMINATION Normal

LUMBAR PUNCTURE IF ANY DOUBT

Sedated

Discontinuation of sedation

What

strategy?

Sedation necessary

Monitoring

Focal sign

Delirium

Agitation

Coma

Myoclonus

Brain imaging

EEG - Biochemistry - Drugs Brain imaging

EEG - Biochemistry - Drugs Brain imaging

Biochemistry - Drugs Brain imagingEEG

UNCONTROLLED SEPSIS?

Antagonist?

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Raymond Poincaré

Service de Réanimation

MERCI

Institut Pasteur

Fabrice Chrétien

Histopathologie Humaine et Modèles Animaux

brain dysfunction during sepsis - cnerea.fr · concept of sickness behavior • behavior is a...

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