1. F. Della Corte – C. Maestrone Intensive Care Unit – University of Novara -School of Medicine Pathophysiology of brain injury

2. F. Della Corte, MD 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

3. F. Della Corte, MD Ischemic stroke vs Head injury In most of the presentations molecular mechanisms are basically the same though operating in: -different sequences -different time courses -different intensities Peripheral penumbra Central core

4. 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 cytotoxic processes secondary to formation and/or release of neurotoxic mediators compound and development of tissue acidosis

5. F. Della Corte, MD Inadequate Energy supply Inadequate Energy supply Cellular injury during ischemia Consequences of calcium overload Consequences of calcium overload Deterioration of Ion Gradients Deterioration of Ion Gradients

6. F. Della Corte, MD Mild to moderate ischemia Severe ischemia Advanced ischemia Insufficient oxygen and glucose Inadequate energy supply Failure of neuronal activity Regional brain dysfunction Influx of water Na + Cl - Loss of function causes accumulation of glutamate and aspartate which bind to NMDA receptors Influx of Ca 2+ Influx of water Na + Ca 2+ Destruction of cell components Formation of free radicals, eicosanoids and leukotrienes Accumulation of lactic acid and H + compromises neuronal integrity Anaerobicmetabolism Cytotoxic edema Irreversible cellular injury

7. F. Della Corte, MD Cellular injury during ischemia - Inadequate energy supply Ischemia ( O 2,glucose) ATP Depolarisation Failed homeostatic mechanisms Lactic acid Free Fe 2+ Free radicals Glial injury IRREVERSIBLE INJURY Proteolysis NO synthesis Lipolysis Glutamate Arachidonic acid Auto-oxidation NA DA Neurotransmitters [H + ] [Na + ] i [K + ] i [Cl - ] i [Ca 2+ ] i VCR LCR Free radicals

8. F. Della Corte, MD 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

9. F. Della Corte, MD Posttraumatic cerebral ischemia Intracranialhypertension Arterialhypotension Brain edema and swelling Focal tissue compression from intracranial hematomas Vasospasm

10. 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 Day 0 1 2 3 4 5 6 7 8 9 10 11 12 13 CBF ml/100g/min CBF ml/100g/min 25 35 40 50 30 45.......... I IIIII Phase Time course and CBF in head injury

11. 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 20 25 30 35 0 10 20 30 40 hours after injury 6 12 18 24 30 36 42 48........        ..  CBF CBFml/100g/min ml/100g/min 40 %ischemia %ischemia Time course and CBF in head injury

12. 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     ..... AJDO 2 ml/100ml ml/100ml Time course and CBF in head injury

13. 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 Phase I 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 injury

14. F. Della Corte, MD SEQUENTIAL ACTIVATION OF CEREBROVASCULAR RESPONSES CBF (ml/100g/m) Survival Ischemic threshold Death 0 1 2 3 4 5 6 7 8 9 10 days post injury Bullock MR et Al J. Neurotrauma 1996; 13; 643-5 50 40 30 10 20

15. 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

16. F. Della Corte, MD % desaturations (SjO2 < 50% for ten minutes or more) Time course of jugular venous desaturations Gopinath SP: J Neurol,Neurosurg and Psy 1994; 57:717-723

17. 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

18. F. Della Corte, MD Oxygen and glucose metabolism after head injury 100 50 0 % Bergsneider: J Neurosurg 86; 241-251, 1997 Metabolic ratio = CMRO2/CMRglu Metabolic ratio = CMRO2/CMRglu

19. F. Della Corte, MD 29.3 + 16.4 Mc Laughlin, 1996 39.9 + 11.2 (Schroeder, 1995) 42.5 + 15.8 (Mc Laughlin, 1996) Vasoreactivity 0.4-9.1% Contusion Perilesional edema CT-normal tissue Cerebral Blood Flow

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

21. F. Della Corte, MD Glutamate MM Days after injury Yamamoto: Acta Neurochir S75: 31-34

22. F. Della Corte, MD Potassium mM hours Contusion  Contusion  No contusion Doppenber EMR: Determinants of cerebral extracellular potassium after severe human head injury. Acta Neurochir 1999; S75: 31-34 Potassium

23. F. Della Corte, MD Framework of stroke Stroke Infarction85% Hemorrhage15% Cerebrovasculardisease80% Cardiogenicembolism15% Otherunusual5% Intracerebral Subarachnoid

24. F. Della Corte, MD Atherosclerosis and thrombus formation Physiological subtypes of thrombotic-related ischemic stroke Thrombosis Primary large vessel occlusive disease Primary small vessel occlusive disease Embolism -arterial atherothrombosis -cardiogenic atrial fibrillation myocardial infarction/ mural thrombus cardiomyopathy prosthetic 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

25. 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 formation Recruit monocytes Inhibit macrophage egress Promote endothelial injury Cytotoxicity Scavenger receptor De Graba TJ in Barnett (eds): Stroke:Pathophysiology, Diagnosis and Management - New York - Churchill Davidson, 1992

26. F. Della Corte, MD 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

27. 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

28. F. Della Corte, MD Atherosclerosis and thrombus formation Potential outcome of plaque fissuring 1)fibrotic organization 2)intraintimal and intraluminal thrombosis 3)occlusive thrombosis

29. F. Della Corte, MD Evolution of Cerebral Atherothrombosis The ischemic penumbra

30. F. Della Corte, MD Cerebral Embolism formation III III Cardiac Sources

31. F. Della Corte, MD Any question from the floor ? Short !! Easy to understand!!! …and to be replied !!!! Please