Neurophysiology for Anaesthesia

Quick Answer

Cerebral blood flow (CBF) is normally 50 mL/100g/min (15% cardiac output). Cerebral metabolic rate for oxygen (CMRO₂): 3.5 mL/100g/min. Cerebral perfusion pressure (CPP) = MAP - ICP (or CVP, whichever higher), normal 70-90 mmHg. Autoregulation: Maintains constant CBF between MAP 60-150 mmHg (myogenic response). CO₂ reactivity: PaCO₂ 1 mmHg change → CBF 3-4% change (hypercapnia vasodilates, hypocapnia vasoconstrictes). O₂ reactivity: Minimal between PaO₂ 60-300 mmHg; <60 mmHg causes marked vasodilation. Brain compliance: Monro-Kellie doctrine (fixed intracranial volume - brain 80%, CSF 10%, blood 10%). Intracranial pressure (ICP): Normal 5-15 mmHg. Anaesthetic effects: Propofol/thiopental ↓CMRO₂ and ↓CBF; volatiles ↑CBF dose-dependently (vasodilation) but ↓CMRO₂; ketamine ↑CMRO₂ and ↑CBF; opioids have minimal direct effect (may ↓CBF secondary to ↓CMRO₂). [1-10]

Anatomy and Physiology

Cerebral Blood Flow

Normal Values:

• Global CBF: 50 mL/100g brain tissue/min
• Total cerebral blood flow: 700-1000 mL/min (15% cardiac output)
• Distribution: Grey matter 80 mL/100g/min, white matter 20 mL/100g/min
• Oxygen consumption: 3.5 mL/100g/min (20% total body O₂ consumption)
• Glucose consumption: 5 mg/100g/min (25% total body glucose, 100% aerobic in adults)

Cerebral Perfusion Pressure (CPP):

• Formula: CPP = MAP - ICP (or CVP, whichever is higher)
• Normal: 70-90 mmHg
• Critical thresholds:
  • <50 mmHg: Ischemia risk
  • <40 mmHg: Severe ischemia
  • <30 mmHg: Brain death

Regulation of Cerebral Blood Flow

1. Cerebral Autoregulation:

• Mechanism: Myogenic response of smooth muscle in cerebral vessels
• Range: MAP 60-150 mmHg (CBF maintained constant at ~50 mL/100g/min)
• Below 60 mmHg: CBF decreases linearly with pressure (ischemia risk)
• Above 150 mmHg: CBF increases (risk of hyperemia, edema)
• Impaired in:
  • Traumatic brain injury
  • Subarachnoid hemorrhage
  • Stroke
  • Severe hypoxia/hypercapnia
  • Hypotension
  • Vasodilating anaesthetics (high-dose volatile)
• Clinical importance: In impaired autoregulation, CBF becomes pressure-dependent
  • Must maintain adequate MAP (CPP >60-70 mmHg)
  • Hypotension causes ischemia
  • Hypertension may cause edema/hemorrhage

2. CO₂ Reactivity:

• Mechanism: CO₂ crosses blood-brain barrier → alters pH in perivascular space → vascular smooth muscle response
• Sensitivity: PaCO₂ change 1 mmHg → CBF change 3-4%
• Hypercapnia (PaCO₂ >45 mmHg): Vasodilation → ↑CBF → ↑ICP
  • PaCO₂ 80 mmHg: CBF doubles
• Hypocapnia (PaCO₂ <35 mmHg): Vasoconstriction → ↓CBF
  • PaCO₂ 20 mmHg: CBF reduced by 50% (ischemia risk)
• Clinical use: Mild hypocapnia (PaCO₂ 30-35 mmHg) to reduce ICP acutely
  • Do not use chronic hypocapnia (vasoconstriction causes ischemia)
• Loss of reactivity: Sign of poor prognosis in TBI

3. O₂ Reactivity:

• PaO₂ 60-300 mmHg: Minimal CBF change (plateau)
• PaO₂ <60 mmHg: Marked vasodilation → ↑CBF (protective response)
• PaO₂ >300 mmHg: Mild vasoconstriction (↓CBF)
• Clinical: Maintain normoxia (PaO₂ 100-300 mmHg)
• Hyperoxia: May be beneficial in focal ischemia (controversial)

4. Metabolic Coupling:

• Principle: CBF matches metabolic demand (neurovascular coupling)
• Mechanism: Local metabolites (adenosine, K⁺, CO₂, lactate) dilate vessels
• Functional imaging: PET, fMRI based on this principle
• Anaesthesia: CBF generally coupled to CMRO₂ (exception: volatile agents at high doses)

5. Neurogenic Regulation:

• Autonomic innervation: Sympathetic (constriction) and parasympathetic (dilation) fibers
• Effect: Modest compared to metabolic/autoregulatory factors
• Significance: May protect against severe hypertension (sympathetic)

6. Myogenic Response:

• Mechanism: Vascular smooth muscle responds to stretch
• Increased transmural pressure: Constriction
• Decreased transmural pressure: Dilation
• Basis of autoregulation

Intracranial Dynamics

Monro-Kellie Doctrine:

• Principle: Fixed intracranial volume (rigid skull)
• Components:
  1. Brain tissue: 80% (1400 mL) - fixed
  2. CSF: 10% (150 mL) - partly compressible
  3. Blood: 10% (150 mL) - most compressible
• Compensation:
  • CSF displacement to spinal subarachnoid space
  • CSF absorption increase
  • Venous blood reduction
  • Reduced CSF production
• Compliance curve: Non-linear
  • Initial: High compliance (small pressure rise with volume)
  • Decompensated: Low compliance (large pressure rise with small volume)

Intracranial Pressure (ICP):

• Normal: 5-15 mmHg (supine)
• Critical: >20 mmHg (requires treatment)
• Severe: >40 mmHg (poor prognosis)
• Cerebral perfusion: CPP = MAP - ICP

Intracranial Compliance:

• Compensatory reserve: CSF and venous blood can be displaced
• Exhaustion: Small volume increases cause large ICP rises
• Clinical: Little warning before catastrophic rise

Factors Increasing ICP:

• Mass lesions (tumor, hematoma)
• Cerebral edema (cytotoxic, vasogenic)
• CSF obstruction (hydrocephalus)
• Hypercapnia (vasodilation)
• Venous obstruction (neck flexion, PEEP, Trendelenburg)
• Hypertension (if autoregulation impaired)

Cerebral Metabolism

Cerebral Metabolic Rate for Oxygen (CMRO₂):

• Normal: 3.5 mL/100g/min (total ~50 mL/min, 20% body O₂ consumption)
• Grey matter: Higher than white matter
• Factors decreasing CMRO₂:
  • Hypothermia (7% per degree)
  • Anaesthetics (barbiturates, propofol, volatile agents)
  • Coma
  • Brain death
• Factors increasing CMRO₂:
  • Fever
  • Seizures
  • Pain/stress
  • Ketamine
  • Awake state

Cerebral Metabolic Rate for Glucose (CMRglc):

• Normal: 5 mg/100g/min
• 100% aerobic in adults (anaerobic metabolism inadequate)
• Hypoglycemia: Critical (neuroglycopenia <2.2 mmol/L)
• Hyperglycemia: Worsens ischemic injury (lactic acidosis)

Oxygen Extraction:

• Oxygen extraction fraction (OEF): 33% (venous O₂ saturation 65%)
• Reserve: Can increase to 80% (critical)
• Coupling: Normally CBF 3× metabolic demand

Blood-Brain Barrier (BBB)

Structure:

• Tight junctions: Between capillary endothelial cells
• Astrocyte foot processes: Surround capillaries
• Basement membrane: Support
• No fenestrations: Unlike systemic capillaries

Function:

• Selective permeability: Protects brain from toxins, maintains ionic environment
• Lipid-soluble: Cross easily (O₂, CO₂, volatile agents, thiopental, propofol, opioids)
• Water-soluble: Require transporters (glucose, amino acids) or don't cross (polar molecules, most drugs)
• Ions: Actively transported (Na⁺/K⁺-ATPase)

Clinical Implications:

• Drug entry: Lipophilic drugs enter brain rapidly
• Edema: BBB disruption allows protein/fluid extravasation (vasogenic edema)
• Inflammation: BBB breakdown in meningitis, encephalitis

CSF Physiology

Production:

• Rate: 500 mL/day (20 mL/hour)
• Site: Choroid plexus (lateral, 3rd, 4th ventricles)
• Mechanism: Active secretion (Na⁺/K⁺-ATPase)

Circulation:

• Lateral ventricles → foramen of Monro → 3rd ventricle → aqueduct of Sylvius → 4th ventricle → foramina of Luschka & Magendie → subarachnoid space
• Arachnoid villi: Absorption into venous sinuses

Volume:

• Total: 150 mL (50 mL intracranial, 100 mL spinal)
• Turnover: 3-4 times per day

Composition:

• Similar to plasma but low protein, different electrolyte concentrations
• Pressure: 5-15 mmHg (CSF production rate relatively constant, absorption pressure-dependent)

Effects of Anaesthetic Agents

Intravenous Agents

Propofol:

• CMRO₂: ↓ 30-50% (dose-dependent)
• CBF: ↓ (coupled to CMRO₂ reduction)
• ICP: ↓ (useful for neurosurgery)
• Autoregulation: Preserved
• CO₂ reactivity: Preserved
• Cerebral protection: Used for burst suppression (metabolic suppression)
• Disadvantage: Hypotension (reduces CPP if not managed)

Thiopental:

• CMRO₂: ↓ 40-50%
• CBF: ↓ (coupled)
• ICP: ↓
• Neuroprotection: Barbiturate coma for refractory ICP, temporary clipping in aneurysm surgery
• Burst suppression: High doses reduce CMRO₂ to 50% of baseline (electrical silence)

Etomidate:

• CMRO₂: ↓ 30-40%
• CBF: ↓
• ICP: ↓
• Advantage: Hemodynamically stable (preserves CPP)
• Disadvantage: Adrenal suppression (avoid prolonged infusion)

Ketamine:

• CMRO₂: ↑ (increases metabolic activity)
• CBF: ↑ (vasodilation)
• ICP: ↑ (historically contraindicated in TBI)
• Modern view: May be safe in ventilated patients with ICP monitoring (doesn't increase ICP if ventilation controlled)
• Advantages: Sympathomimetic (maintains MAP), analgesic, neuroprotective in some models

Dexmedetomidine:

• CMRO₂: ↓ mildly
• CBF: ↓ mildly
• ICP: Neutral/minimal effect
• Advantages: Awake craniotomy (sedation without respiratory depression)

Opioids (Fentanyl, Morphine, Remifentanil):

• Direct effect: Minimal on CBF and CMRO₂
• Indirect: ↓CMRO₂ if reduce arousal/pain
• Side effect: Respiratory depression → CO₂ retention → ↑CBF/ICP (if spontaneous ventilation)
• Fentanyl: May cause rigidity (mimics seizure activity on EEG)

Benzodiazepines (Midazolam, Diazepam):

• CMRO₂: ↓ mildly
• CBF: ↓ mildly
• ICP: ↓ mildly
• Anticonvulsant: Useful for seizure prophylaxis

Volatile Agents

Dose-Dependent Effects:

Low Dose (<0.5 MAC):

• CBF: Minimal change or slight ↓
• CMRO₂: ↓
• ICP: Minimal change
• Autoregulation: Preserved

Moderate Dose (0.5-1.0 MAC):

• CBF: Slight ↑ (vasodilation begins)
• CMRO₂: ↓ 20-30%
• Coupling: Uncoupling begins (CBF > metabolic demand)

High Dose (>1.0 MAC):

• CBF: ↑↑ (marked vasodilation)
• CMRO₂: ↓ 40-50%
• ICP: ↑ (can increase significantly)
• Autoregulation: Impaired at high doses
• CBV: ↑ (cerebral blood volume increases)

Agent-Specific Differences:

Sevoflurane:

• CBF: ↑ dose-dependently
• CMRO₂: ↓ dose-dependently
• ICP: ↑ at >1 MAC
• Advantage: Rapid emergence for neuro assessment
• Seizures: Can cause epileptiform activity (especially at 1.5-2 MAC)

Isoflurane:

• CBF: ↑ less than halothane
• CMRO₂: ↓ most of all volatiles
• Cerebral protection: Preconditioning effect (controversial)
• Coronary steal: Less than other agents

Desflurane:

• CBF: ↑ dose-dependently
• CMRO₂: ↓
• Emergence: Fastest (good for neurosurgery)
• Airway irritation: Limits use for inhalational induction

Nitrous Oxide:

• CBF: ↑ 20-30% (sympathetic stimulation, direct vasodilation)
• CMRO₂: ↑ slightly
• ICP: ↑
• Use in neurosurgery: Generally avoided (increases CBF, PONV, expands air spaces)

Muscle Relaxants

Non-Depolarizing:

• Direct CNS effect: None (ionized, don't cross BBB)
• Indirect: ↓CMRO₂ if reduce movement/bucking

Succinylcholine:

• Fasciculations: May ↑ICP transiently (muscle activity)
• Clinical significance: Minimal, brief
• Use in neurosurgery: Can be used if defasciculated (small dose of non-depolarizer first)

Vasopressors and Inotropes

Effect on CBF depends on:

1. Autoregulation integrity:
   • Intact: Little effect on CBF (vessels constrict/dilate to maintain flow)
   • Impaired: CBF pressure-dependent (vasopressors ↑CBF, vasodilators ↓CBF)
2. Blood pressure change:
   • Within autoregulatory range: No change
   • Outside range: Change in CBF

Specific Agents:

• Phenylephrine: ↑MAP, may ↓HR, generally preserves CBF if autoregulation intact
• Noradrenaline: ↑MAP, maintains CPP in TBI (recommended if vasopressors needed)
• Adrenaline: ↑MAP, ↑CO, may ↑CBF
• Dopamine: Dose-dependent; high dose vasoconstricts cerebral vessels
• Vasopressin: Cerebral vasodilation at low doses, vasoconstriction at high doses

Clinical Applications

Neurosurgical Anaesthesia

Goals:

1. Brain relaxation: Facilitate surgical access
2. Hemodynamic stability: Maintain CPP >60-70 mmHg
3. Rapid emergence: For neurological assessment
4. Cerebral protection: If ischemia risk (temporary clipping, hypotension)

Technique:

• Induction: Propofol/thiopental (↓ICP), avoid ketamine
• Maintenance: TIVA (propofol/remifentanil) preferred (↓CBF, rapid emergence)
  • Volatile acceptable <1 MAC (sevoflurane or isoflurane)
• Ventilation: Normocapnia (PaCO₂ 35-40 mmHg), avoid hypocapnia (ischemia)
• Positioning: Head elevation 30° (promotes venous drainage)
• Fluid: Isotonic, avoid hypotonic (cerebral edema)

Traumatic Brain Injury

Principles:

• CPP >60-70 mmHg: Avoid hypotension (single most important factor for outcome)
• ICP <20 mmHg: If monitored, treat if elevated
• Normocapnia: PaCO₂ 35-40 mmHg (avoid chronic hypocapnia)
• Normothermia: Avoid fever
• Anaesthesia: Propofol infusion (sedation, ↓CMRO₂, ↓ICP)

Cerebral Protection

Strategies:

1. Pharmacological:
   • Barbiturates (thiopental): Burst suppression
   • Propofol: High doses
   • Etomidate: Hemodynamically stable
   • Volatile: Preconditioning effect (controversial)
2. Physiological:
   • Mild hypothermia (32-34°C): Reduces CMRO₂ 7% per degree
   • Normoglycemia: Avoid hyper/hypoglycemia
   • Normocapnia: Avoid extremes

ANZCA Primary Exam Focus

Key Equations and Values

Must Know:

• CBF: 50 mL/100g/min (global), 15% cardiac output
• CMRO₂: 3.5 mL/100g/min (20% body O₂ consumption)
• CPP: MAP - ICP (or CVP), normal 70-90 mmHg
• Autoregulation range: MAP 60-150 mmHg
• CO₂ reactivity: 3-4% CBF change per 1 mmHg PaCO₂ change
• ICP: Normal 5-15 mmHg, critical >20 mmHg

Mechanisms

Autoregulation:

• Myogenic response to pressure changes
• Maintains constant CBF 60-150 mmHg
• Impaired in TBI, SAH, stroke

CO₂ Reactivity:

• CO₂ crosses BBB → pH change → smooth muscle response
• Hypercapnia vasodilates, hypocapnia vasoconstricts
• Clinical: Use mild hypocapnia acutely, avoid chronic

Monro-Kellie:

• Fixed intracranial volume
• Brain 80%, CSF 10%, blood 10%
• Compensation via CSF displacement, venous compression

Drug Effects

Propofol:

• ↓CMRO₂, ↓CBF, ↓ICP, preserves autoregulation

Volatile agents:

• Dose-dependent: ↓CMRO₂ but ↑CBF (vasodilation)
• At >1 MAC: Uncoupling, ↑ICP, impaired autoregulation

Ketamine:

• ↑CMRO₂, ↑CBF, ↑ICP (historically avoided in TBI)

Opioids:

• Minimal direct effect; indirect ↓via sedation
• Can ↑ICP if cause CO₂ retention (spontaneous ventilation)

Common Exam Questions

"Explain cerebral autoregulation."

• Definition: Maintenance of constant CBF despite changes in MAP
• Mechanism: Myogenic response of vascular smooth muscle
• Range: 60-150 mmHg (CBF constant)
• Below 60: CBF decreases (ischemia)
• Above 150: CBF increases (hyperemia, edema)
• Impaired in: TBI, SAH, stroke, severe hypoxia
• Clinical importance: CPP must be maintained in brain-injured patients

"How does CO₂ affect cerebral blood flow?"

• CO₂ crosses blood-brain barrier easily
• Changes pH in perivascular space
• Hypercapnia → acidosis → vasodilation → ↑CBF
• Hypocapnia → alkalosis → vasoconstriction → ↓CBF
• Sensitivity: 3-4% CBF change per 1 mmHg PaCO₂
• Clinical use: Mild hypocapnia (30-35 mmHg) to acutely reduce ICP
• Risk: Chronic hypocapnia causes ischemia (don't maintain <35 long-term)

"Compare the effects of propofol and sevoflurane on cerebral physiology."

"What is the Monro-Kellie doctrine?"

• Principle: Intracranial volume is fixed (rigid skull)
• Components: Brain 80%, CSF 10%, blood 10%
• Implication: Adding volume requires compensatory decrease in other components
• Compensation: CSF displacement, reduced CSF production, venous compression
• Exhaustion: Once compensatory mechanisms exhausted, small volume increase causes large ICP rise
• Clinical: Little warning before catastrophic herniation

References

1. ANZCA. Primary Examination Syllabus. Physiology Section - Neurophysiology.
2. Lassen NA. Cerebral blood flow and oxygen consumption. Physiol Rev. 1959;39(2):183-238.
3. Drummond JC et al. The effect of high dose sodium nitroprusside on cerebral blood flow. Anesthesiology. 1985;62(4):439-444.
4. Matta BF et al. The effects of sevoflurane on cerebral haemodynamics. Anesth Analg. 1995;81(4):785-790.
5. Cottrell JE et al. Intracranial pressure and brain monitoring. In: Cottrell and Patel's Neuroanesthesia. 6th ed. Elsevier; 2017:63-82.
6. Strebel S et al. The impact of ketamine on cerebral hemodynamics. Can J Anaesth. 2014;61(9):806-815.
7. Artru AA et al. Cerebral blood flow responses to hypocapnia during anesthesia. J Cereb Blood Flow Metab. 1989;9(3):309-316.
8. Gupta AK et al. Anaesthesia for neurosurgery. BJA. 2020;125(6):900-911.