CEREBRAL BLOOD FLOW & ITS REGULATION Dr. Shahnawaz.

INTRODUCTION Cerebral circulation refers to the movement of blood through the network of blood vessels supplying the brain. The amount of blood that the cerebral circulation carries is known as cerebral blood flow.

Blood supply of brain

WHY UNDERSTANDING OF CBF IMPORTANT? Delivery of energy substrates is dependent on CBF, and in the setting of ischemia, modest alterations in CBF can substantially influence neuronal outcome Control and manipulation of CBF are central to management of ICP because CBV and CBF usually vary almost in parallel fashion. The magnitude of change in CBV is less than the magnitude of change in CBF ; for a given increase in CBF, the increase in CBV is considerably less.

CEREBRAL BLOOD FLOW: Varies with metabolic activity CBF can vary from 10 -300ml/100 g/min Approx 15% of total cardiac output Gray matter: 80ml/100g/min White matter: 20ml/100g/min Total CBF: on an average 50 ml/100g/min OR 750ml/min CBF < 20 – 25 ml/100 g/min - cognitive impairment CBF < 15 – 20 ml/100 g/min - isoelectric EEG CBF < 1o ml/100 g/min – irreversible brain damage

FACTORS EFFECTING CBF: Myogenic : Autoregulation/ MAP (CPP) Chemical/ Metabolic/ Humoral: CMR – depends on : Anesthetic agents Temperature & Seizures PaCO₂ PaO₂ Vasoactive drugs: Vasopressors & vasodilators Rheologic: Blood viscosity Neurogenic : Extracranial sympathetic and parasympathetic pathways , Intra-axial pathways

CEREBRAL PERFUSION PRESSURE: (CPP) CPP = difference b/w mean arterial pressure (MAP) and intracranial pressure (ICP) or central venous pressure (CVP) , whichever is greater. MAP – ICP (or CVP) = CPP Normally CPP = 80- 100 mm Hg ICP normally is ≤ 10 mm Hg, so , CPP depends primarily on MAP

CEREBRAL PERFUSION PRESSURE: (CPP) Moderate to severe ↑ ICP (≥ 30 mm Hg) - impairs CPP and CBF even in presence of normal MAP. CPP ≤ 50 mm Hg – slowing on EEG CPP 25 - 40 mm Hg – flat EEG CPP ≤ 25 mm Hg – irreversible brain damage

AUTOREGULATION: Normally, brain tolerates wide swings in BP Cerebral vasculature adapts rapidly (10-60 sec) to change in CPP. But , abrupt changes in MAP, even with intact autoregulation, lead to transient changes in CBF. ↓ CPP- cerebral vasodilation ↑ CPP- cerebral vasoconstriction CBF nearly remains constant b/w MAP of about 60- 160 mm Hg beyond these limits, CBF becomes pressure dependent MAP ↑ 150-160 mm Hg – disruption of BBB & cerebral edema

AUTOREGULATION:

AUTOREGULATION: Ex. H⁺, NO, adenosine, prostaglandins etc. Autoregulation curve, in chronic hypertension – shifted to right Flow more pressure dependent at low normal pressures Long term antihypertensive Rx - restores cerebral autoregulation limits towards normal Mechanism of autoregulation: Myogenic- intrinsic response of smooth muscle cells in arterioles, to changes in MAP Metabolic- tissue demand exceeds CBF → release of tissue metabolites determines arteriolar tone Ex. H⁺, NO, adenosine, prostaglandins etc.

PaCO₂ : Most imp. extrinsic influences on CBF – PaCO₂ CBF directly proportional to PaCO₂ b/w tensions of 20-80 mm Hg Depends on pH changes in ECF of brain. CBF changes 1-2 ml/100g/min/mmHg change in PaCO2. Change is almost immediate Results from CO₂ readily crossing BBB The effect is not sustained CBF normalises over 6 to 8 hrs pH of CSF returns to normal due to adjustment in HCO3 .

PaCo2: The CBF to changes in Paco2 appears to be positively correlated with resting levels of CBF. Anesthetic drugs that alter resting CBF cause changes in the response of the CBF to CO2. The magnitude of the reduction in CBF caused by hypocapnia is greater when resting CBF is high . When resting CBF is low, the magnitude of the hypocapnia-induced reduction in CBF is decreased.

PaO₂ : Changes in PaO₂ B/W 60 – 300mm of Hg – Little influence on CBF. Severe hypoxemia (PaO₂ < 60mm Hg) – profound ↑ in CBF Hypoxia induced hyperpolarisation and Neurogenic effects initiated by peripheral and central chemoreceptors. Stimulation of the RVM by hypoxia results in an increase in CBF (but not CMR) High PaO₂ values – ↓ CBF minimal.

Effect of chemical factor on CBF

TEMPERATURE: CBF changes 5-7% per 1° change in temp Hypothermia decreases both CBF and CMR Hyperthermia increases both CBF and CMR EEG isoelectric at 20 °C B/w 17°C - 37°C, Q10 for humans – approx 2 i;e for every 10 ° ↑ in temp – CMR doubles Conversely, CMR ↓ by 50% , if temp of brain falls by 10 In contrast with anesthetic drugs, temperature reduction beyond that at which EEG suppression first occurs does produce a further decrease in CMR.

INTRACRANIAL PRESSURE: (ICP) Monro-Kellie Doctrine: “The Total Volume of Intracranial Contents Must Remain Stable” ↑ In one component - offset by equivalent ↓in another, to prevent rise in ICP

Increase in volume is initially well tolerated Further increase cause precipitous ↑ ICP. Major compensatory mechanisms include: Displacement of CSF from cranium to spinal compartment ↓ CBV (primarily venous) ↑ CSF absorption ↓ CSF production

EFFECT OF ANESTHETIC AGENTS ON CEREBRAL PHYSIOLOGY

INTRAVENOUS ANESTHETICS: Generally, CMRO₂ and CBF decrease KETAMINE is an exception. Changes in CBF generally parallel those in CMR Cerebral autoregulation and CO₂ responsivenes- preserved with all agents

BARBITURATES: 4 major actions on CNS: Hypnosis Depression of CMR ↓ CBF, due to ↑ cerebral vascular resistance Anticonvulsant activity make thiopental ‘the most commonly used’ induction agent in neuroanesthesia Dose dependent reduction in CBF& CMR, until EEG becomes isoelectric max. reduction of nearly 50% is observed

BARBITURATES: CMR reduction is uniform – throughout the whole brain CMR decreased more than CBF So, supply exceeds demand barbiturate induced cerebral vasoconstriction occurs only in normal areas Vasculature in ischemic areas remain maximally dilated & unaffected by barbiturates Net result is : redistribution of blood flow From normal to ischemic areas Called as – ROBIN HOOD or REVERSE STEAL phenomenon

PROPOFOL: Reduce CMR, CBF & ICP CO2 responsiveness preserved Autoregulation preserved Short elimination half life Excessive hypotension & cardiac depression – in elderly/ unstable pts can compromise CPP

PROPOFOL AND SEIZURE INCIDENCE: dystonic & choriform movements, opisthotonus etc have been reported with its use, SYSTEMATIC STUDIES FAILED TO CONFIRM THAT PROPOFOL IS PROCONVULSANT Appears to be anticonvulsant in animals

ADRENOCORTICAL SUPPRESSION ETOMIDATE : Parallel reductions in CBF, CMR & ICP Effect on CMR variable: more in cortex than brainstem May be responsible for greater hemodynamic stability in unstable pts. ↓ CSF production & ↑ absorption Concerns ………… ADRENOCORTICAL SUPPRESSION

OPIOIDS: In general, little effects in normal brain When occur, modest reduction in CBF& CMR, unless PaCO₂ ↑ 2° to respiratory depression Morphine, generally not considered optimal, due to poor lipid solubility and prolonged sedation

BENZODIAZEPINES: Modest reduction in CBF The reduction attained is intermediate b/w that caused by opioids (modest) barbiturates (substantial) Midazolam preferred- short half life Useful as anticonvulsant also Remember they can produce respiratory depression increase in paCO2 If we avoid this… BENZODIAZEPINES appear safe

KETAMINE: Only IV agent to cause VASODILATAION ↑CBF (50-60%) Effect is regionally variable limbic system & reticular formation are activated Somatosensory & auditory areas are depressed Total CMR doesn’t change Seizure activity in thalamus and limbic area.

KETAMINE: May impede absorption of CSF ↑CBF, CBV & CSF volume : ↑ ICP (potentially) Better to avoid as sole agent… Diazepam , Midazolam ,Isoflurane /N2O, Propofol …. They blunt its effects Reasonable to use it along with the above drugs… cautiously

LIDOCAINE: Reduce CMR, CBF & ICP, but to a lesser degree Decreases CBF without other major hemodynamic effects Rx & prevention of acute rise in ICP, also during laryngoscopy , intubation & ETT suctioning Risk of systemic toxicity and seizures – limit the usefulness of repeated dosing

VOLATILE AGENTS…. Reduce CMR . Cerebral vasodilation augment CBF

VOLATILE AGENTS & CBF: Dilate blood vessels & impair auto regulation - in a dose dependent manner Greatest effect – halothane Conc >1%- nearly abolishes auto regulation Blood flow increase - generalized throughout brain At equivalent MAC – halothane ↑ CBF 200%, compared to 20% for isoflurane. Isoflurane increases blood flow mainly in subcortical areas & hindbrain (unlike halothane) Qualitatively & quantitatively – des/sevoflurane closest to isoflurane

VOLATILE AGENTS & CMR: ↓ CMR- dose dependent Max depression – isoflurane (about 50%) Least effect – halothane (less than 25%) No further decrease in reduction in CMR is observed once EEG is isoelectric. (Unlike hypothermia) Reduction in CMR – not uniform Mainly in neocortex

EFFECTS @ DIFFERENT MACs: CMR suppression predominates So net CBF decreases @ 1 MAC CMR suppression = vasodilation CBF unchanged Dose beyond 1 MAC CMR reduced; but vasodilatory effect predominates CBF increases

VOLATILE AGENTS: The vasodilator effect usually appear rapidly than the effects on CMR. The CBF also appears to be time dependent Returns to almost normal after continued admn (2-5 hrs) If antecedent lowering of CMR by drugs/disease, then vasodilator effect may predominate ↑ in CBV (10-12%) generally parallels CBF But relation is not necessarily linear

VOLATILE AGENTS & PaCO₂: CO2 responsiveness of vasculature - preserved Hyperventilation can therfore abolish/blunt the effects on CBF Timing is important Effect is observed only if hyperventilation is initiated prior to administration of halothane In contrast, simultaneous hyperventilation with iso/sevoflurane- can prevent ↑ in ICP

Altered Coupling of Cerebral Metabolic Rate & Blood Flow Volatile agents alter but do not uncouple the normal relationship of CBF and CMR. The combination of a decrease in neuronal metabolic demand with an increase in CBF (metabolic supply) has been termed luxury perfusion.

In contrast to this potentially beneficial effect during global ischemia, a detrimental circulatory steal phenomenon is possible with volatile anesthetics in the setting of focal ischemia. Volatile agents can increase blood flow in normal areas of the brain but not in ischemic areas, where arterioles are already maximally vasodilated. The end result may be a redistribution of blood flow away from ischemic to normal areas.

NON DEPOLARIZING RELAXANTS: Lack direct action, but have 2° effects Main effect is via Histamine release Cerebral vasodilation increase ICP d-Tubocurarine is the most potent histamine releaser among available muscle relaxants. Metocurine, atracurium, and mivacurium also release histamine in lesser quantities.

NDMR: Pancuronium- large bolus : abrupt increase in BP if autoregulation defective - increase ICP metabolite of atracurium- Laudanosine: epileptogenic properties in trials But” it appears highly unlikely that epileptogenesis will occur in humans with atracurium”

SUCCINYLCHOLINE: Increases ICP in lightly anaesthetized Possibly result of cerebral activation Enhanced muscle spindle activity Prevention by: Adequate dose of inducing agent- deep plane Institute hyperventilation at induction Defasciculating dose of non depolarizing NMBA

VASOPRESSORS: With normal autoregulation & intact BBB vasopressors ↑ CBF, only when MAP <50-60 mmHg or >150-160 mm Hg In absence of autoregulation – vasopressors ↑ CPP → ↑ CBF. β adrenergic agents → (+) central β-1 receptors → ↑ CMR and blood flow. Show greater effect when BBB is disrupted. β blockers have no effect on CMR or CBF α2 agonists produce cerebral vasoconstriction.

VASODILATORS: In absence of hypotension: cause cerebral vasodilation and ↑ CBF in a dose related fashion When they ↓ systemic BP: CBF either maintained or increases (d/t autoregulation) Can significantly ↑ ICP in pt with ↓ intracranial compliance

VASODILATORS: Only trimethaphan has no or little effect on CBF But it constricts pupils May interfere with neurological examination No longer available in USA

BLOOD VISCOSITY Hematocrit – most imp determinant of blood viscosity. ↑ Hct can reduce CBF. ↓ Hct → improve CBF in ischemic area More obvious during focal cerebral ischemia May ↓ the O2 carrying capacity of blood → impair O2 delivery (potentially) A Hct of 30 – 34 % is optimal for patients with focal cerebral ischemia.

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