Brain Protection Ahmad N. Hamdy, MD

Objectives (IOLs) Cerebral physiology 1 Explain cerebral ischemia 23 Algorithm for brain protection 4 Strategies to protect the brain from cerebral ischemia

Cerebral Physiology  BRAIN 1350 gm- 2% of total adult body wt  Receives 12 to 15 % of cardiac output  Global cerebral blood flow 45-55ml/100 gm / min Cortical Subcortical 75-80ml /100gm/min 20ml /100gm/min

 CMRO 2 3 to 3.5 ml/100gm/min  Whole brain O 2 consumption 50ml/min (20% of total body O 2 consumption)  Cerebral glucose utilization 5.5 gm/100gm of brain tissue (1ry energy source)  ICP ( supine) 5 to 15 mm Hg  CPP= MAP- ICP or (CVP), whichever is greater ( mm Hg) Cerebral Physiology

Factors Influencing CBF  Chemical/Metabolic /Humoral  Cerebral metabolic rate  Anaesthetics  Temperature  PaCO 2 (20-80 mmHg)  PaO 2  Vasoactive drugs - Anaesthetics,Vasodilators, Vasopressors  Myogenic / Autoregulation  Blood viscosity  Neurogenic

Cerebral Ischemia  It is the potentially reversible altered state of brain physiology and biochemistry that occurs when substrate delivery is cut off or substantially reduced by vascular stenosis or occlusion  Metabolic demands > substrate delivery Company Logo

Pathophysiology GLOBAL Cardiac arrest Resp. Failure Shock Hypoglycemia Asphyxia Cerebral Ischemia FOCAL Head injury Vascular Stenosis Occlusion Spasm

Biochemical & Pathophysiological changes Inadequate blood flow ↓↓ O 2 delivery Ischaemia Excitotoxic ApoptoticInflammationcell death

Strategies for Brain Protection Strategies CMRO2 Oxygen CBF&CPP Future concepts Glucose Specific

Oxygen & Glucose  In the absence of oxygen, glucose undergoes anaerobic glycolysis resulting in intracellular acidosis  Patients with higher blood glucose concentrations have worse outcomes from stroke, TBI, etc.  More rapid expansion of ischemic lesion in hyperglycemic, compared with normoglycemic patients  For all of this reasons, it is rational to maintain normoglycemia in all patients at risk for,or recovering from acute brain injury

CMRO 2  Hypothermia  Anesthetics

Body Temperature Hyper Hypo Ischaemic Injury

Temperature  Hypothermia  Reduce CMR in a temperature-dependent fashion  Mild hypothermia(32-35 ℃ ) ; negliable effect on CMR But, in several studies mild hypothermia produce major protection ; provides scientific basis of using off-bypass hypothermia to provide meaningful neuroprotection  Deep hypothermia(18-22 ℃ ) ; highly neuroprotective In normothermic brain ; only a few minutes of complete global ischemia cause neuronal death In deep hypothermia before circulatory arrest ; brain can tolerate over 40 min and completely or near-completely recover

Temperature  Hyperthermia  In animal studies, spontaneous post- ischemic hyperthermia is common and intra-ischemic or even delayed post-ischemic hyperthermia dramatically worsen outcome  Advocate frequent temperature monitoring in patients with cerebral injuy  Aggressive treatment of hyperthermia should be considered

Anesthetics  Volatile anesthetics  Protect against both focal and global ischemia Transient improvement in global ischemia Persistent improvement in focal ischemia  Suppression of energy requirements Inhibition of excitatory neurotransmission Potentiation of inhibitory receptors Regulation of intracellular calcium response during ischemia  Isoflurane, sevoflurane ;  Desflurane ; insufficiently studied

Anesthetics  Barbiturates have major actions on CNS: hypnosis depression of CMR anticonvulsant activity.  These properties make barbiturates, particularly thiopental, the most commonly used induction agents in neuroanesthesia. Company Logo

Anesthetics  Propofol  Suppression of CMR  Free radical scavenging  Anti-inflammatory properties  Appears efficacy similar to barbiturates  Etomidate  Paradoxically exacerbate ischemic injury  Cannot use for neuroprotection  Lidocaine  Suppress CMR  Inhibition of apoptosis  No long-term outcome studies  Ketamine  Inhibition of glutamate at NMDA receptor  Little or no protection against global insult  Substantial protection against focal insult  However, no human data

CPP  More than 65-70mmHg  Elevation of MAP  Decrease ICP  Decrease blood viscosity

Specific  CCBs as nimodipine (SAH)  Na CBs as lamotrigine (SDH)  NMDA antagonist  Steroids (Brain tumors)

Preconditioning  Ischaemic Preconditioning Homeothermic mammal Elicits “an evolutionary conserved endogenous response to decreased blood flow and oxygen limitation such as seen during hibernation”

Clinical methods of preconditioning  Pre - op hyperbaric oxygen  Normobaric 100 % oxygen  Electroconvulsive shock  K + channel opener → Diazoxide  Erythropoietin (EPO)

Erythropoietin  Cytokine growth hormone -↓ apoptosis - ↑ erythrocyte production ↑↑ haematocrit Deleterious effect on ischaemia

Intravenous recombinant erythropoietin Once daily for 3 days fold ↓ glial markers ↓ infarct ↑ of EPO in CNS of cerebral size & injury improved (S 100)recovery

Astrocytes in ischaemic penumbra produces EPO in mammalian brain Stimulates protein Stimulates of repair neurogenesis & angiogenesis ↓ neural apoptosis ↓↓ neural ↓ inflammatoin excitotoxicity

Magnesium  Membrane stabilizer  Suggested protective mechanism: Reduction of presynaptic release of glutamate Blockade of NMDA receptors Smooth muscle relaxation Improved mitochondrial Ca 2+ buffering Blockage of Ca 2+ entry  Protection depends on: Time of treatment initiation Type of cerebral ischemia  Benefit in neocortical stroke

Strategies for Brain Protection O2 HCT: % PaO2 Levels GL mg/dl CMRO2 Hypothermia Anesthetics

Strategies of Brain Protection (Cont.) CBF CPP: ≥ 70 mmhg MBP: Elevated Viscosity: Decresed ICP: Decrease Future NO Cerebral preconditioning Apoptosis Specific CCBs Na CBs NMDA antagonist

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