CEREBRAL PHY N PROT 24.1

CEREBRAL PHYSIOLOGY : 

CEREBRAL PHYSIOLOGY MODERATOR: DR. G. A. PATIL PRESENTER: DR. LOKESH M B

CEREBRAL BLOOD FLOW : 

CEREBRAL BLOOD FLOW

REGULATION OF CEREBRAL FLOW : 

REGULATION OF CEREBRAL FLOW Human brain weighs 1350g (2% of total body weight) but consumes 12-15% of cardiac output. Approximately 60% of energy consumption is to support electrophysiological function. (maintenance of ionic gradients and reuptake of neurotransmitters). Rest is used to maintain cellular homeostasis. CBF and CMR are more in grey matter than white matter(4:1). Brain consumes, at rest oxygen at 3-5ml/100g/min This demand has to be met by adequate delivery of glucose and oxygen. The blood flow cannot be excessively increased because of space constraints (crania and meninges are non-compliant). So there are mechanisms which tightly regulate CBF

CHEMICAL REGULATION : 

CHEMICAL REGULATION

CEREBRAL METABOLISM : 

CEREBRAL METABOLISM local brain activity   local metabolism  blood flow  FLOW METABLOISM COUPLING Mechanism: (local byproducts of metabolism) Glutamate cause release of NO Glial cells take up glutamate  metabolism release of lactic acid. Neurotransmitters  VIP, substance P, CCK somatostatin. FMC: regulated by a combination of metabolic, glial, neural and vascular factors.

AUTO REGULATION : 

AUTO REGULATION Refers to capacity of cerebral circulation to adjust its resistance to maintain CBF constant over a wide range of MAP. Limited to MAP 70-150 mm Hg Lower limit is 70 mmHg of MAP or 55-60mmHg of CPP. Above and below the plateau CBF changes proportional to CPP . Mechanism: unknown Proposed- Nitric oxide mediated. Increase in tone on vascular smooth muscles proportional to changes in CPP Morphology of auto regulation is regulated by background levels of VD/VC. Limits of auto regulation- conceptual. Represents a continuum of vascular responsiveness and at lower and upper limits the ability to dilate or constrict is exhausted.

NEUROGENIC CONTROL : 

NEUROGENIC CONTROL Sympathetic- superior cervical ganglion Parasympathetic- sphenopalatine ganglion Serotonergic VIP ergic Sympathetic activation shifts the curve to right Sympathetic denervation or blockade of stellate ganglion increases CBF Stimulation of sympathetic system-- shift to right protect against hypertensive breakthrough of BBB. Functional significance: in hemorrhagic shock (high sym+ leading to VC) amount of decrease in CBF is much lower than in other conditions. e.g., sympatholytics

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Viscosity: Variation of CBF with viscosity in normal people is only modest. In anemia increased cerebral blood flow is due to decreased viscosity and decreased oxygen carrying capacity. (d/t vasodilatation). So, in focal ischemia, even when vasodilatation is maximal, anemia increases CBF. Optimal blood flow is achieved with 30-34% of HCT Alteration of viscosity to increase CBF is not done except if HCT>55%.

VASOACTIVE AGENTS : 

VASOACTIVE AGENTS Systemic vasodilators: Majority of drugs which induce hypotension (sodium nitroprusside, calcium channel blockers, hydralazine..) can cause cerebral vasodilatation. Therefore CBF normal or increased. Catecholamines: Effect depends on- basal BP Magnitude of change of BP by the agent Status of auto regulation Status of BBB Alpha agonists : should theoretically have little or no influence on CBF. Only nor epinephrine can cause VD if: auto regulation is defective BBB is defective Alpha 2 agonist: dexmeditomidine decrease CBF and also CMR.

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Beta agonists: Low dose have little effect Increase in CBF if given in high dose or BBB is defective. Beta blockers: no effect or reduce CBF and CMR Dopamine: used to augment CVS when increase in MAP is desired in focal ischemia. On CBF and CMR- conclusively not proved. May be generally slight VD Discrete increase in CMR in choroid plexus and basal ganglia. Dobutamine: 20-30% increase in CMR and CBF. Fenoldopam: systemic VD, decrease CBF.

EFFECT OF ANESTHETIC DRUGS ON CBF AND CMR. : 

EFFECT OF ANESTHETIC DRUGS ON CBF AND CMR. In neuroanesthesia, emphasis is laid on CBF as, CBF is important for delivery of substrates Change in ICP is related to change in CBF. CBF control by VD/VC l/t / CBF–/ in ICP. Usually CBF and CBV vary in parallel but magnitude of change in CBF>magnitude of change in CBV. Auto regulation : CBV is less. But if limit is reached, then CBV is proportional to MAP This is usually compensated in normal humans by translocation of blood /CSF to extra cerebral vessels. But if intracranial compliance is decreased, this increase leads to cerebral herniation -- CPP – ischemia.

IV AGENTS : 

IV AGENTS  in CBF and CMR (except Ketamine which CBF and CMR). Majority of agents CBF through  in CMR. Also, some agents have direct action- VC, VD alteration in auto regulation. Generally, auto regulation and CO2 responsiveness in preserved.

BARBITURATES : 

BARBITURATES Dose dependent  in CBF and CMR. With onset of anesthesia, CBF  by 30%, with thiopentone 50%. Complete EEG suppression is seen in larger doses. Further  in dose don’t have any additional effect. Mechanism: CMR. little effect on cellular homeostasis. Tolerance develops quickly therefore dose of barbiturate required to maintain burst suppression  after 24 hours. Auto regulation and CO2 responsiveness is preserved.

PROPOFOL : 

PROPOFOL CMR and CBF. CBF  by 53-79% CMR  by 48-58%. Propofol-fentanyl subdural pressures in pt with intracranial tumors. And AV O2 content difference. Propofol effects CMR and secondarily CBF, CBV and ICP. Auto regulation and CO2 responsiveness is preserved. Magnitude of hypocapnic VC and therefore  of CBF during hypocapnia is  with propofol as propofol itself causes cerebral VC.

ETOMIDATE : 

ETOMIDATE Similar to barbiturates,  both CMR and CBF. CMR  by Etomidate is regionally variable- predominantly in forebrain structures. Etomidate can ICP without  CPP in patients with head injury and intracranial tumors. But Etomidate brain tissue hypoxia and acidosis in pt with temporary MCA occlusion . CO2 responsiveness is preserved but effect of auto regulation is not evaluated.

NARCOTICS : 

NARCOTICS Little or no effect If any, can be due to reduction of arousal. Morphine: No effect on global CBF 41% reduction in CMRO2 Release of histamine– VD Auto regulation intact. Fentanyl: Moderate global reduction in CBF and CMR in quiescent brain. Large reductions are seen during arousal. No change in CBF/CMR Auto regulation and CO2 responsiveness is preserved.

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Sufentanyl: low dose– no change. High dose– reduction in CBF. ICP– normal or increased due to increased MAP – auto regulation . Remifentanyl: Low sedative dose– Remifentanyl alone, CBF increased in prefrontal, inferior parietal, and supplementary motor cortex. CBF decreased in cerebellum, inferior parietal lobe, midbrain grey matter. Totally minor increase. High dose or concomitant administration : CBF unaltered or reduced.

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Benzodiazepines: Parallel reduction in CBF and CMR. Extent of maximal CBF/CMR reduction is between narcotics, (modest), and barbiturates (substantial). Flumazenil: It reverses reduction in CBF, CBV and ICP. Also causes substantial temporary overshoot in CBF and ICP and their metabolism is not coupled. Flumazenil should be used cautiously in patients with impaired intracranial compliance. Droperidol: No change Occasional increase in ICP can be due to autoregulation mediated VD in response to abrupt decrease in MAP.

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Ketamine: Increased CBF and CMR. More in frontal and anterior cingulate cortex. CBF and CMR are reduced in cerebellum. Ketamine has two enantiomers, ‘s’ and ‘r’. ‘S’ enantiomer is associated with increased CBF and CMR whereas ‘r’ enantiomer is associated with decreased CBF and CMR . Ketamine increases CBF secondary to increase in CMR. Auto regulation and CO2 responsiveness is preserved. ICP is also increased. But this is blunted by anesthetic drugs. In fact, Ketamine reduces ICP in propofol sedated humans. It is better to avoid Ketamine or use it with caution in patients with impaired intracranial compliance.

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Lidocaine: It reduces CBF and CMR. With high doses, reduction is more than with high dose of barbiturates. Probably because membrane stabilizing action reduces the energy required for maintenance of membrane integrity. Bolus of lidocaine can control acute increase in ICP. So it is a reasonable adjunct to prevent or treat acute elevation of ICP. Recommended in preventing increase in ICP associated with ET suctioning– bolus of 1.5-2mg/kg. Any increase in dose above this limit predisposes to seizures.

Inhalational agents : 

Inhalational agents Volatile anesthetics: All the drugs reduce CMR and therefore CBF in a dose dependent manner. Most of these drugs also cause cerebral VD (therefore increase in CBF). So there appears a balance between reduction of CBF and increase in CBF. 0.5 Mac  reduction in CBF. 1 Mac  no net effect > 1 Mac  increase in CBF.

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increase in CBF at concentrations more than 1 Mac is not associated with increase in CMR. so initially this was thought as an evidence of uncoupling of flow metabolism loop. But now, trials have shown that CBF/CMR ratio is altered by volatile agents. There is a positive correlation between CBF/CMR ratio and Mac multiples. So, higher Mac causes– luxury perfusion. Also, increase in ICP can occur. Order or vasodilating potency: Halothane>>enflurane>desflurane=isoflurane> sevoflurane.

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Xenon: Auto regulation and CO2 responsiveness is preserved. Mac is 63-71% (in females, 51%). It acts as NMDA antagonist. Diffusion into air containing spaces is present. So, it has to be used with caution in patients with intracranial air.

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Clinical implications: modest VD when administered at 1 Mac or less Magnitude of change of CBF is more than magnitude of change in CBV. Volatile anesthetics have minimal effects on hemodynamics in patients with normal intracranial compliance. But in pathological states with impaired intracranial compliance, (large/rapidly expanding mass lesion, unstable ICP, derangements of cerebral physiology)– it is advised to use IV agents till cranium and dura are open and effects of anesthetic techniques assessed directly.

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Clinical implications of increased CMR : If CMR reduces by diseases process, VD effect is maximal. E.g., Isoflurane causes significant VD when administered at concentration above near maximal suppression of CMR or administered when CMR already suppressed by drugs or pathological process. VD effect of halothane is more than Isoflurane, desflurane or sevoflurane. So Isoflurane, desflurane or sevoflurane are preferable in impaired intracranial compliance.

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CBV: Greater with volatile agent than with IV agent. But magnitude of change differs in individual agents. Auto regulation maintained at lower limit but not at upper limit (i.e., responsiveness to MAP) More so with anesthetics which have maximum VD effect and is dose related.

Nitrous oxide : 

Nitrous oxide CBF, CMR and ICP. May be as a result of sympatho-adrenal stimulating effect. N2O administered alone: there is substantial  in CBF, and ICP. N2O with iv anesthetics: Effect is considerably attenuated. Barbiturates, benzodiazepines, narcotics (morphine) blunt or completely inhibit the response of N2O.

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N2O with volatile anesthetics: Substantial CBF if given with volatile anesthetics of 1mac or more. The vasodilating effect of N2O is positively correlated with the concentration of the inhaled drug. N2O induced  CBV is modest. CBF responsiveness to CO2 is preserved. Clinical implications: Vasodilating property-important in neurosurgery. Can be blunted by IV agents but precise dose response relationship is not established. N2O+volatile anesthetics increase CMR and CBF modestly. Circumstances where ICP persistently increased or surgical field is tight– N2O can be a contributing factor. It is avoided when closed intracranial gas space exist.

Muscle relaxants : 

Muscle relaxants Non-depolarizing muscle relaxants: Cause histamine release. Also increase MAP. So CBF is increased. dTC is associated with maximum histamine release. It is significant only if given in higher doses sufficient to achieve intubating conditions rapidly. Cisatracurium has least histamine releasing effect. Vecuronium has no significant histamine releasing effect.

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Indirect effects: Pancuronium-- BP -- ICP in impaired compliance and defective auto regulation. Muscle relaxation reduces ICP because cough and straining is prevented. Laudanosine, a metabolite of atracurium is thought to be epileptogeinc, but not proven clinically. All muscle relaxants are good to use. Metocurine, atracurium, mivacurium are to be limited to ranges not associated with hypotension.

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Succinylcholine: Increases ICP (approx 5 mmHg). Due to cerebral activation– afferent activity from muscle spindles.  depth of anesthesia prevent scoline induced increase. This increase is also blocked by paralysis with vecuronium or defasiculation with Metocurine. But scoline is not contraindicated, only has to be used with caution.

CEREBRAL PROTECTION : 

CEREBRAL PROTECTION

Cerebral ischemia-pathophysiology : 

Cerebral ischemia-pathophysiology Brain has a high rate of energy utilization and limited storage capacity. It is vulnerable to depletion of energy (glucose) or O2

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Ischemic penumbra Progressive deterioration of brain function which is reversible but can progress to neuronal injuiry if flow not restored. Cerebral ischemia is broadly classified into two types: complete and incomplete. Complete ischemia (global ischemia): seen in cardiac arrest. Incomplete ischemia (focal ischemia): occlusion of a vessel, severe hypotension, – residual blood flow – consumes some oxygen– prolongation of neuronal and catastrophic death.

Energy failure and excitotoxicity : 

Energy failure and excitotoxicity Energy (ATP) for membrane integrity energy failure Membrane depolarisation– influx of Na and Ca.  Voltage dependent Ca channels – release of excitatory neurotransmitter (glutamate).  Excitation  Excitotoxicity  IP3- release of Ca for ER/mitochondria. Stimulation of AMPA/NMDA receptors – release of Ca. from ER/mitochondria

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Effect of excitotoxicity: Proteases: breakdown of cytoskeleton actin. 2. lipases: damage membrane lipids. phospholipase A2 released– arachidonic acid – prostaglandins and leucotrins.– inflamation– ROS. 3. Nitric oxide synthase: -- NO peroxinitrate. (ROS) NO from endothelium– VD collateral flow NO from macrophages/ neurons mediate inflammation and neuronal death. 4. Mitochondria: failure of energy production. decreased ATP formation. lactic acidosis– decreased pH– damage release of reactive oxygen species release of cytochrome C from outer mitochondrial membrane.

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5. Nucleases: Reactive oxygen species from : mitochondrial injury, prostaglandins, leukotrins, NO, ONOO (peroxinitrate) ↓ damage DNA ↓ stimulation of PARP (polyadenosyl ribophosphate). (Enzyme which repairs DNA) ↓ usage of NAD ↓ Depletion of cellular energy.

NATURE OF NEURONAL DEATH: : 

NATURE OF NEURONAL DEATH: Necrosis: Rapid cellular swelling. Condensation and pyknosis of nucleus. Swelling of mitochondria and ER Presence of acidophilic cytoplasm. Stimulation of inflammation– collateral damage. Apoptosis: Chromatin condensation Involution of cell membrane Swelling of mitochondria Cell shrinkage No inflammation– limited to surrounding area.

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Pathway: Cyt C released from outer mitochondrial membrane. ↓ With APAF and procaspase 9 apaptosome ↓ Procaspase 9– activated caspase 9 ↓ Caspase 3 activation (execution caspases) Also, caspase 3 activated by ↓ TNFR– caspase 8 In an event of neuronal death few neurons undergo necrosis and few apoptosis.

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Timing of neuronal death: Traditional concept: neuronal injury and death are limited to early reperfusion period. Now it is proven that neuronal death continues into postischemic period for a prolonged duration. It is seen in both global and focal ischemia. Experiments show neuronal death occur even 6-8 months after primary ischemia. Neuroprotective agents– to prevent delayed neuronal death. Many agents are proved useful for only 3-4 days. Long-term effects are not promising. Long-term evaluation (>1month) is very important strategy of neuroprotection.

CEREBRAL PROTECTION : 

CEREBRAL PROTECTION

GLOBAL ISCHEMIA : 

GLOBAL ISCHEMIA =complete ischemia. Seen in cardiac arrest. Maintenance of adequate perfusion. Initial hypotension seen after resuscitating from cardiac arrest may aggravate microcirculatory and vasospastic process. Late hypertension may occur due to cerebral edema or if the osmotherapy fails. Drugs implicated: Barbiturates: not effective. CCB nimodipine-proven improvement in CBF but no effect on neurological outcome.

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Induced mild hypothermia: 32-34 degree C for 24 hours. Later, passive rewarming over 8 hours. Improved neurological outcome and survival is seen after 6 months of injury. Complications are same as in normothermic group. Therapeutic goals : Maintenance of normocapnia and normotension Normalization of systolic pH Prevention and treatment of seizures. Avoidance of hypothermia

FOCAL ISCHEMIA: : 

FOCAL ISCHEMIA: Anesthesia per se is protective. Reducing the systemic stress results in improved outcome. Barbiturates: Effective neuroprotective agent. Principally suppress CMR Also cause redistribution of CBF and free radical scavenging. Studies have failed to demonstrate any protective effect in global ischemia. But it is proved useful in focal cerebral ischemia if applied before or early in the course of temporary focal ischemia. But also following are to be considered before starting barbiturates: Risk of occlusive event Patient’s CVS status Physician willingness to accept prolonged arousal Individual drugs: methohexital and thiopental are better than pentobarbital.

VOLATILE ANESTHETICS : 

VOLATILE ANESTHETICS Neuroprotective Suppression of CMR Isoflurane is protective in anesthetized state but it is not sustained. Neuroprotective effect is present 2 days after injury but no neuroprotective effect after 14 days of injury. It is neuroprotective in long term only if: Severity of ischemia is limited. Restoration of blood flow after ischemia is complete. There is no difference in efficacy of different volatile agents. But adequate anesthesia per se may have a protective effect.

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Xenon: Non competitive blockade of NMDA receptors Neuroprotection against excitotoxic injury is demonstrated in animal models. Sub-anesthetic doses of xenon +hypothermia+isoflurane significantly reduces neuronal injury and improves neurological outcome 30 days after injury. Preconditioning effect on brain: previous exposures reduce the vulnerability of brain to ischemia. Anesthetic drugs that have activity at NMDA receptors (ketamine) and (GABAA) receptors (volatile anesthetics, barbiturates, benzodiazepines, propofol) have been shown to cause neuronal injury during the critical period of synaptogenesis. Evidence to date suggest that xenon don't cause such apoptosis. But long term studies on this aspect have not been conducted.

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Propofol: EEG suppression can be achieved. Protection during aneurysm surgery and carotid end-arterectomy is established. Incidence of cerebral infarction is significantly reduced in propofol anesthetized animals. But this protection by propofol is not sustained. Protection is achievable if severity is mild. Etomidate: Proposed to be used in aneurysm surgery. Produces CMR suppression But volume of brain injury with etomidate was more compared to those in control group. In patients with temporary vessel occlusion etomidate results in greater hypoxia and acidosis. This can be due to binding of NO as a consequence of etomidate induced hemolysis or inhibition of NO synthase enzyme. So there is no scientific support for the use of etomidate.

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Calcium channel blockers. Nimodipine orally for 21 days beginning as soon as possible after subarachnoid hemorrhage But this is not fully popularized. Others: Only proven modalities for cerebral protection are: tPA for thrombolysis Nimodipine for SAH

CEREBRAL ISCHEMIA ON PHYSIOLOGIC VARIABLES : 

CEREBRAL ISCHEMIA ON PHYSIOLOGIC VARIABLES

CEREBRAL PERFUSION PRESSURE : 

CEREBRAL PERFUSION PRESSURE In ischemic penumbra restoration of cerebral blood flow can prolong neuronal survival. So maintenance of CPP is essential. maintenance of BP is essential. A reduction of BP by 10-20% increases the probability of adverse outcome fourfold. Mean arterial pressure is to be maintained considering the patient’s preexisting BP. it is better to maintain MAP in the range of 70-80mmHg. Blood pressure has to be maintained to <180/105, in patients with stroke treated with tPA. In SAH induced vasospasm, BP can be augmented to 180-220. In traumatic brain injury, CPP >60 mmHg.

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But if CPP is augmented to high normal range, or if used for more than brief periods of ischemia, risks are: Increased chances of edema. Hemorrhagic infarction. CO2 tension. Hypercapnia– intracerebral steal– worsen brain injury. Hypocapnia– Robin hood or inverse steal– protective. But this effect is not proved conclusively. Presently the recommendation is to maintain normocapnia.

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Hypothermia. Protective efficacy is established. Increases cerebral tolerance for periods of ischemia. It reduces CBF both due to reduction in electrophysiologic energy consumption and reduction in cellular integrity. Mild hypothermia- reduction in 2-4 degree C preferentially reduces cellular homeostasis. Hypothermia in immediate post ischemic period offers benefit. Intraoperative: reduction of temperature may take time so decision of hypothermic management should be done before hand.

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Hypothermia is more useful in high grade aneurysm (intracranial aneurysm clipping) where the surgery is complex and where prolonged clipping is necessary. Rewarming should be done for prolonged periods. Hypothermia in stroke: Improved ICP and CPP But during rewarming there is intractable increase in ICP even if the rewarming is gradual and over several hours. Hypothermia with cardiac arrest: 32-34 degree provides successful neurological outcome 6 months after arrest.

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Hyperthermia: Aggravates neuronal injury. Conditions which produce scattered neuronal necrosis in normothermic can cause cerebral infarction in hyperthermic individuals. So, hyperthermia has to be avoided. Usually hyperthermia is seen in rewarming in post hypothermic cardiopulmonary bypass. Glucose: Better withheld during neuronal injury. Elevation of plasma glucose after brain and spinal cord injury aggravates the insult. It may be as a result of stress. Administration of insulin to control blood glucose in stroke patients did not improve outcome 3 months after stroke.

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Hypoglycemia is also associated with brain injury. Blood glucose <40– EEG changes from alpha-beta to theta-delta. If Blood glucose<20– EEG shows a flat curve. If this reduction is persistent, it leads to seizure activity and neuronal injury, particularly in hippocampus. Hematocrit: Hemoconcentration is potentially deleterious. Hemodilution is theoretically protective. But routine hemodilution is not justifiable. Optimum hematocrit to be maintained is 30-35% If incomplete ischemia is anticipated, as in carotid end-arterectomy, a hct of >55% should be treated with preoperative phlebotomy.

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Others: Normalization of pH Prevention and treatment of seizures. Cardiac surgery under cardiopulmonary bypass– barbiturates are protective. But the prime focus is to attain physiologic homeostasis rather than pharmacological medications. Elective procedures: It is better to delay elective procedures for 6 weeks for: Restoration of CBF Recovery of auto regulation CO2 responsiveness BBB integrity In non-disabling stroke, carotid end-arterectomy is done within 2 weeks. In a large stroke, surgery is deferred till 4 weeks from the vascular accident or preferably for 6 weeks from a point at which stable post-insult neurological state is achieved.

THANK YOU : 

THANK YOU