F. Della Corte – C. Maestrone

Intensive Care Unit – University of Novara -School of Medicine

Pathophysiology of Pathophysiology of brain injurybrain injury

F. Della Corte, MD

ObjectivesObjectives

-To describe which are the common pathophysiological features shared by head injury and stroke

-To define the mechanisms of hypoxic-ischaemic damage at neuronal level

-To stress the importance of ischemia in the determination of severity in the outcome in head injured patients

-To define the consequences of ischemic events in the adult

F. Della Corte, MD

Ischemic stroke vs Head injury

In most of the presentations molecular In most of the presentations molecular mechanisms are basically the same though mechanisms are basically the same though operating in:operating in:

-different sequences-different sequences-different time courses-different time courses-different intensities-different intensities

Peripheral penumbraPeripheral penumbra

Central coreCentral core

F. Della Corte, MD

Factors contributing to the increase of irreversibly damaged

brain parenchyma

Deterioration of CBF

due to progressive

damage of arterial

blood supply

Activation of cytotoxicActivation of cytotoxic

processes secondary toprocesses secondary to

formation and/or releaseformation and/or release

of neurotoxic mediators of neurotoxic mediators

compound and compound and

developmentdevelopment

of tissue acidosisof tissue acidosis

F. Della Corte, MD

• Inadequate Energy supplyInadequate Energy supply

Cellular injury during ischemiaCellular injury during ischemia

• Consequences of calcium overloadConsequences of calcium overload

• Deterioration of Ion GradientsDeterioration of Ion Gradients

F. Della Corte, MD

Mild to moderate ischemiaMild to moderate ischemiaSevere ischemiaSevere ischemiaAdvanced ischemiaAdvanced ischemia

Insufficient oxygenInsufficient oxygenand glucoseand glucose

Inadequate energyInadequate energysupplysupply

Failure of neuronal activityFailure of neuronal activityRegional brain dysfunctionRegional brain dysfunction

Influx of waterInflux of waterNaNa++ Cl Cl--

Loss of functionLoss of functioncauses accumulationcauses accumulation

of glutamate of glutamate and aspartateand aspartatewhich bind towhich bind to

NMDA receptorsNMDA receptorsInflux of CaInflux of Ca2+2+

Influx of waterInflux of waterNaNa++ Ca Ca2+2+

Destruction of cellDestruction of cell

componentscomponents

Formation of Formation of

free radicals,free radicals,

eicosanoids andeicosanoids and

leukotrienesleukotrienes

Accumulation of lactic acid and HAccumulation of lactic acid and H++

compromises neuronal integritycompromises neuronal integrity

AnaerobicAnaerobicmetabolismmetabolism

Cytotoxic edemaCytotoxic edema

Irreversible cellular injuryIrreversible cellular injury

F. Della Corte, MD

Cellular injury during ischemia - Inadequate energy Cellular injury during ischemia - Inadequate energy supplysupply

Ischemia Ischemia ( O( O22,glucose),glucose)

ATP ATP DepolarisationDepolarisation

Failed homeostatic Failed homeostatic mechanismsmechanisms

Lactic acidLactic acid

Free FeFree Fe2+2+

Free radicalsFree radicals

Glial injuryGlial injury

IRREVERSIBLE INJURYIRREVERSIBLE INJURY

ProteolysiProteolysiss

NO synthesisNO synthesisLipolysisLipolysis

GlutamateGlutamate

Arachidonic acidArachidonic acidAuto-oxidationAuto-oxidation

NA DANA DA

NeurotransmittersNeurotransmitters

[H[H++]][Na[Na++] ] ii [K[K++] ] ii [Cl[Cl--] ] ii

[Ca[Ca2+2+] ] ii

VCRVCR

LCRLCR

Free radicalsFree radicals

F. Della Corte, MD

Ischemia and brain injury

Prognosis in head injury has been strictly correlated with:Prognosis in head injury has been strictly correlated with:

-the degree-the degree-the duration of the ischemia-the duration of the ischemia

More than 90% of authopsies on HI pts showed ischemicMore than 90% of authopsies on HI pts showed ischemiclesions of different severitylesions of different severity

Graham D.I., Adams J.H. Ischemic brain damage in fatal head injuries. Lancet 1:265-266, 1971

F. Della Corte, MD

Posttraumatic cerebral ischemiaPosttraumatic cerebral ischemia

IntracranialIntracranial

hypertensionhypertensionArterial Arterial

hypotensionhypotension

Brain edema andBrain edema and

swellingswelling

Focal tissue compressionFocal tissue compression

from intracranial hematomasfrom intracranial hematomas

VasospasVasospasmm

F. Della Corte, MDMartin NA, Patwardhan RV, et al: Characterization of cerebral hemodynamic phases following severe head trauma: hypoperfusion, hyperemia, and vasospasm. J Neurosurg 87: 9-19, 1997

Day

0 1 2 3 4 5 6 7 8 9 10 11 12 13

CBFml/100g/min

CBFml/100g/min

25

35

40

50

30

45

. .... .

.

.

..

I II IIIPhase

Time course and CBF in head injuryTime course and CBF in head injury

F. Della Corte, MDBouma GJ, Muizelaar JP, Choi SC, et al: Cerebral circulation and metabolism after severe traumatic brain injury: the elusive role of ischemia. J Neurosurg 75: 685-693, 1991

20

25

30

35

0

10

20

30

40

hours after injury6 12 18 24 30 36 42 48

.

..

....

.

. .

CBFCBFml/100g/minml/100g/min

CBFCBFml/100g/minml/100g/min

40

%%ischemiaischemia

%%ischemiaischemiaTime course and CBF in head injuryTime course and CBF in head injury

F. Della Corte, MD

Bouma GJ, Muizelaar JP, Choi SC, et al: Cerebral circulation and metabolism after severe traumatic brain injury: the elusive role of ischemia. J Neurosurg 75: 685-693, 1991

hours

3.0

4.0

5.0

6.0

7.0

9.0

8.0

.Motorscore

= 1,2

= 3,4,5

.

...

.

AJDOAJDO22

ml/100mlml/100ml

AJDOAJDO22

ml/100mlml/100ml Time course and CBF in head injuryTime course and CBF in head injury

F. Della Corte, MD

Martin NA, Patwardhan RV, et al: Characterization of cerebral hemodynamic phases following severe head trauma: hypoperfusion, hyperemia, and vasospasm. J Neurosurg 87: 9-19, 1997

PhaseI II III

%

CBF(ml/100g/min)

> 55

35 to 55

< 35

0

10

20

30

40

50

60

70

80

90

100

Time course and CBF in head injuryTime course and CBF in head injuryTime course and CBF in head injuryTime course and CBF in head injury

F. Della Corte, MD

SEQUENTIAL ACTIVATION OF SEQUENTIAL ACTIVATION OF CEREBROVASCULAR CEREBROVASCULAR

RESPONSESRESPONSES

CBF CBF (ml/100g/m)(ml/100g/m)

SurvivalSurvival

Ischemic thresholdIschemic threshold

DeathDeath

0 1 2 3 4 5 6 7 8 9 10 days post injury0 1 2 3 4 5 6 7 8 9 10 days post injury

Bullock MR et Al J. Neurotrauma 1996; 13; 643-Bullock MR et Al J. Neurotrauma 1996; 13; 643-55

5050

4040

3030

1010

2020

F. Della Corte, MD

SEQUENTIAL ACTIVATION SEQUENTIAL ACTIVATION OF INJURY PROCESSESOF INJURY PROCESSES

ICP ICP mechanismsmechanisms

Cytotoxic edemaCytotoxic edema

Vascular engoargementVascular engoargement

Vasogenic edemaVasogenic edema

0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 days post injurydays post injuryBullock MR et Al J. Neurotrauma 1996; 13; 643-Bullock MR et Al J. Neurotrauma 1996; 13; 643-55

F. Della Corte, MD

0

5

10

15

20

25

30

35

40

24h day 2 day 3 day 4 day 5 day >5

%desaturations(SjO2 < 50% for ten minutes or more)

Time course of jugular venous desaturationsTime course of jugular venous desaturationsGopinath SP: J Neurol,Neurosurg and Psy 1994; 57:717-723

F. Della Corte, MD

CBF and incidence of jugular venous desaturations

43

44

45

46

47

48

49

50

51

52

None One Multiple

Gopinath SP: J Neurol,Neurosurg and Psy 1994; 57:717-723

ml/100g/min

F. Della Corte, MD

Oxygen and glucose metabolism after head injury

0

3

6

9

12

CMRO2 CMRglu Metabolic Ratio

Head injuryNormal values

100

50

0

%

Bergsneider: J Neurosurg 86; 241-251, 1997

Metabolic ratio =CMRO2/CMRglu

Metabolic ratio =CMRO2/CMRglu

F. Della Corte, MD

29.3 + 16.4Mc Laughlin, 1996

39.9 + 11.2 (Schroeder, 1995)

42.5 + 15.8 (Mc Laughlin, 1996)Vasoreactivity 0.4-9.1%

ContusionContusion

Perilesional edemaPerilesional edema

CT-normal tissueCT-normal tissue

Cerebral Blood FlowCerebral Blood Flow

F. Della Corte, MD

Brain oxygen tension

Van den Brink, Neurosurgery 46; 868-878, 2000

F. Della Corte, MD

Glutamate

0

2

4

6

8

10

12

14

16

Day 1 Day 2 Day 3 Day 4

M

Days after injury

Yamamoto: Acta Neurochir S75: 31-34

F. Della Corte, MD

Potassium

0

0,5

1

1,52

2,5

3

3,5

4

0 20 40 60 80

mM

hours

ContusionContusion No contusionNo contusion

Doppenber EMR: Determinants of cerebral extracellular potassium after severe human head injury. Acta Neurochir 1999; S75: 31-34

PotassiumPotassium

F. Della Corte, MD

Framework of stroke

Stroke

InfarctionInfarction85%85%

HemorrhageHemorrhage15%15%

CerebrovascularCerebrovasculardiseasedisease

80%80% Cardiogenic Cardiogenic embolismembolism

15%15%Other Other

unusualunusual5%5%

IntracerebralIntracerebral

SubarachnoidSubarachnoid

F. Della Corte, MD

Atherosclerosis and thrombus formation

Physiological subtypes of thrombotic-related ischemic strokePhysiological subtypes of thrombotic-related ischemic stroke

ThrombosisThrombosis

Primary large vesselPrimary large vesselocclusive diseaseocclusive disease

Primary small vesselPrimary small vesselocclusive diseaseocclusive disease

EmbolismEmbolism

-arterial atherothrombosis-cardiogenic

atrial fibrillationmyocardial infarction/mural thrombuscardiomyopathyprosthetic valves

-”paradoxical” (deep vein thrombosis)

-atherothrombosis-dissection-arteritis-migraine-drug-induced-etc

-”lacunar” (i.e. microatheroma/lipoyalinosis-arteritis-eclampsia-drug-induced-antiphospholipid antibodies

Rotthrock JF In Hemostasis and Thrombosis:Philadelphia, JB Lippincott Company, 1994

F. Della Corte, MD

Atherosclerosis and thrombus formation

Oxydation of LDL cholesterolOxydation of LDL cholesterol

Monocyte/MacrophageMonocyte/Macrophage Endothelial cellsEndothelial cells Smooth muscle cellsSmooth muscle cells

Free radical releaseFree radical release

Oxidize LDL cholesterolOxidize LDL cholesterol

Foam cell Foam cell formationformation

Recruit monocytesRecruit monocytesInhibit macrophage egressInhibit macrophage egress

Promote endothelialPromote endothelialinjuryinjury

Cytotoxicity

Scave

nger rece

ptor

De Graba TJ in Barnett (eds): Stroke:Pathophysiology, De Graba TJ in Barnett (eds): Stroke:Pathophysiology, Diagnosis and Management - New York - Churchill Davidson, 1992Diagnosis and Management - New York - Churchill Davidson, 1992

F. Della Corte, MD

Atherosclerosis and thrombus formationAtherosclerosis and thrombus formation

Minimal endothelial injuryMinimal endothelial injury

Role of Monocytes and T Lymphocytes Role of Monocytes and T Lymphocytes in the transformation to foam cellsin the transformation to foam cells

Smooth muscle cell migration Smooth muscle cell migration and proliferationand proliferation

Platelets adhesionPlatelets adhesion

F. Della Corte, MD

Atherosclerosis and thrombus formation (2)Atherosclerosis and thrombus formation (2)

Plaque fissuring and Formation Plaque fissuring and Formation of platelet thrombusof platelet thrombus

I - Platelets activationII - Platelets adhesionIII - Activation of coagulation cascade

Thrombus formationThrombus formation

F. Della Corte, MD

Atherosclerosis and thrombus formationAtherosclerosis and thrombus formation

Potential outcome of plaque fissuringPotential outcome of plaque fissuring

1)fibrotic organization1)fibrotic organization

2)intraintimal and intraluminal thrombosis2)intraintimal and intraluminal thrombosis

3)occlusive thrombosis3)occlusive thrombosis

F. Della Corte, MD

Evolution of Evolution of Cerebral AtherothrombosisCerebral Atherothrombosis

The ischemic penumbraThe ischemic penumbra

F. Della Corte, MD

Cerebral Embolism formationCerebral Embolism formation

I II III

Cardiac SourcesCardiac Sources

F. Della Corte, MD

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