Pathophysiology of

brain injury

F. Della Corte – C. Maestrone

Intensive Care Unit –

University of Novara -School of Medicine
 Objectives
-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
Central core

Peripheral penumbra

In most of the presentations molecular mechanisms are

basically the same though operating in:

-different sequences
-different time courses
F. Della Corte, MD
-different intensities
 Factors contributing to the
increase of irreversibly damaged
brain parenchyma

Deterioration of CBF Activation of cytotoxic

due to progressive processes secondary to

formation and/or release
damage of arterial
of neurotoxic mediators
blood supply
compound and development
of tissue acidosis

F. Della Corte, MD
 Cellular injury during ischemia

• Inadequate Energy supply

• Deterioration of Ion Gradients

• Consequences of calcium overload

F. Della Corte, MD
Mild to moderate ischemia Severe ischemia Advanced ischemia

Insufficient oxygen Influx of water Loss of function

and glucose Na+ Cl- causes accumulation
of glutamate
and aspartate
Cytotoxic edema which bind to
Inadequate energy Influx of Ca2+ NMDA receptors
supply

Irreversible cellular injury

Influx of water
Na+ Ca2+
Failure of neuronal activity
Regional brain dysfunction Anaerobic
metabolism Destruction of cell
components
Formation of
Accumulation of lactic acid and H+ free radicals,
compromises neuronal integrity eicosanoids and
leukotrienes

F. Della Corte, MD
Cellular injury during ischemia - Inadequate energy supply
Ischemia ( O2,glucose)

ATP
Depolarisation Lactic acid

[Na+] [K+] [Cl-] Failed homeostatic [H+]

i i i
mechanisms
VCR

Neurotransmitters [Ca2+] i
LCR Free Fe2+

NA DA Glutamate
Lipolysis NO synthesis Free radicals

Auto-oxidation Arachidonic acid Proteolysis Glial injury

Free radicals

F. Della Corte, MD
IRREVERSIBLE INJURY
 Ischemia and brain injury

Prognosis in head injury has been strictly correlated with:

-the degree
-the duration of the ischemia

More than 90% of authopsies on HI pts showed ischemic

lesions 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
 Vasospasm
Intracranial Arterial
hypertension hypotension

Posttraumatic cerebral ischemia

Brain edema and Focal tissue compression

swelling from intracranial hematomas

F. Della Corte, MD
 CBF
ml/100g/min

50
Time course and CBF in head injury

.
. .
45

40 .
. . .
35

. . .
30

Phase
25
I II III
Day
0 1 2 3 4 5 6 7 8 9 10 11 12 13

Martin NA, Patwardhan RV, et al: Characterization of cerebral

F. Della Corte, MD
hemodynamic phases following severe head trauma: hypoperfusion,
hyperemia, and vasospasm. J Neurosurg 87: 9-19, 1997
 CBF
%
ml/100g/min
Time course and CBF in head injury ischemia
. .
40 40

 
.
35
. . . . 30

.
30
. 20

 10
25

.    
20
  0

6 12 18 24 30 36 42 48
hours after injury
Bouma GJ, Muizelaar JP, Choi SC, et al: Cerebral circulation and
F. Della Corte, MD
metabolism after severe traumatic brain injury: the elusive role
of ischemia. J Neurosurg 75: 685-693, 1991
 AJDO2 Motorscore
9.0
ml/100ml
Time course and CBF in head injury  = 1,2
8.0

. = 3,4,5

7.0

.
6.0
.

5.0
. . .
4.0  
3.0
hours

Bouma GJ, Muizelaar JP, Choi SC, et al: Cerebral circulation and
metabolism after severe traumatic brain injury: the elusive role F. Della Corte, MD
of ischemia. J Neurosurg 75: 685-693, 1991
 Time course and CBF in head injury

%
100
90
80 CBF
70 (ml/100g/min)
60
50 > 55
40
30
35 to 55
20 < 35
10
0
I II III Phase

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

F. Della Corte, MD
 SEQUENTIAL ACTIVATION OF
CEREBROVASCULAR RESPONSES
Survival

CBF (ml/100g/m) Ischemic threshold

Death
50
40
30
20
10
0 1 2 3 4 5 6 7 8 9 10 days post injury

Bullock MR et Al J. Neurotrauma 1996; 13; 643-5 F. Della Corte, MD

 SEQUENTIAL ACTIVATION
OF INJURY PROCESSES

ICP mechanisms Cytotoxic edema

Vascular engoargement

Vasogenic edema

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

Bullock MR et Al J. Neurotrauma 1996; 13; 643-5 F. Della Corte, MD
Time course of jugular venous desaturations
Gopinath SP: J Neurol,Neurosurg and Psy 1994; 57:717-723

%
desaturations
(SjO2 < 50%
for ten minutes 40
or more) 35
30
25
20
15
10
5
0
24h day 2 day 3 day 4 day 5 day >5

F. Della Corte, MD
 CBF and incidence of jugular
venous desaturations
Gopinath SP: J Neurol,Neurosurg and Psy 1994; 57:717-723
ml/100g/min
52
51
50
49
48
47
46
45
44
43
None One Multiple

F. Della Corte, MD
Oxygen and glucose metabolism
after head injury
12 100 %

6 50 Head injury
Normal values

0 0 Metabolic ratio =
CMRO2 CMRglu Metabolic Ratio
CMRO2/CMRglu

F. Della Corte, MD
Bergsneider: J Neurosurg 86; 241-251, 1997
Cerebral Blood Flow

39.9 + 11.2 (Schroeder, 1995)

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

29.3 + 16.4
Mc Laughlin, 1996
Contusion

Perilesional edema

CT-normal tissue

F. Della Corte, MD
 Brain oxygen tension

Van den Brink, Neurosurgery 46; 868-878, 2000 F. Della Corte, MD

 Glutamate
Days after injury
16
14
mM
12
10
8
6
4
2
0
Day 1 Day 2 Day 3 Day 4

Yamamoto: Acta Neurochir S75: 31-34 F. Della Corte, MD

 Potassium
4
Potassium
3,5  Contusion
 No contusion
mM3
2,5
2
1,5
1
0,5
0
0 20 40 60 hours 80

Doppenber EMR: Determinants of cerebral extracellular potassium after severe

human head injury. Acta Neurochir 1999; S75: 31-34
F. Della Corte, MD
 Framework of stroke
Stroke

Infarction Hemorrhage
85% 15%
Cerebrovascular
disease Intracerebral
80% Cardiogenic
embolism
15% Subarachnoid
Other
unusual
5%
F. Della Corte, MD
 Atherosclerosis and thrombus formation
Physiological subtypes of thrombotic-related ischemic stroke

Primary large vessel Embolism

occlusive disease

-atherothrombosis -arterial atherothrombosis

-dissection -cardiogenic
-arteritis Thrombosis atrial fibrillation
-migraine myocardial infarction/
-drug-induced mural thrombus
-etc cardiomyopathy
Primary small vessel prosthetic valves
-”paradoxical”
occlusive disease (deep vein thrombosis)
-”lacunar” (i.e. microatheroma/lipoyalinosis
-arteritis Rotthrock JF In Hemostasis and Thrombosis:
-eclampsia Philadelphia, JB Lippincott Company, 1994
-drug-induced
-antiphospholipid antibodies F. Della Corte, MD
 Atherosclerosis and thrombus formation
Oxydation of LDL cholesterol

Monocyte/Macrophage Endothelial cells Smooth muscle cells

Free radical release

Oxidize LDL cholesterol

Foam cell Promote endothelial

formation injury
Recruit monocytes
Inhibit macrophage egress
De Graba TJ in Barnett (eds): Stroke:Pathophysiology, F. Della Corte, MD
Diagnosis and Management - New York - Churchill Davidson, 1992
 Atherosclerosis and thrombus formation

Minimal endothelial injury

Role of Monocytes and T Lymphocytes

in the transformation to foam cells

Smooth muscle cell migration

and proliferation

Platelets adhesion

F. Della Corte, MD
 Atherosclerosis and thrombus formation (2)

Plaque fissuring and Formation

of platelet thrombus

I - Platelets activation
II - Platelets adhesion
III - Activation of coagulation cascade

Thrombus formation

F. Della Corte, MD
 Atherosclerosis and thrombus formation

Potential outcome of plaque fissuring

1)fibrotic organization
2)intraintimal and intraluminal thrombosis
3)occlusive thrombosis
F. Della Corte, MD
 Evolution of
Cerebral Atherothrombosis

The ischemic penumbra

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 Cerebral Embolism formation

I II III

Cardiac Sources

F. Della Corte, MD
Any question from the floor ?
Please

• Short !!

• Easy to
understand!!!

• …and to be
replied !!!!

F. Della Corte, MD