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Regulation of cerebral blood flow

Created 16/05/2023, last revision 18/05/2023

  • the regulation of cerebral blood flow (CBF) is critical because it allows the brain to receive a steady supply of nutrients and oxygen despite changes in systemic blood pressure
  • the brain weighing ∼ 1400 g  (∼2% of total body weight) consumes:
    • 20% of basal oxygen demand (~ 3.5 mL O2/100g brain tissue/min)  (Rink, 2011)
    • 25% of basal glucose demand (~ 75-100 mg/min; ~5.6 mg glucose/100 g brain tissue/min) (Mergenthaler, 2013)
    • 14-20% of cardiac output (CBF is ~ 700-800 mL in total per minute for standard 1400g brain; 50ml/100g brain tissue/min)
      • ∼ 70% in the anterior circulation
      • ∼ 30% in the posterior circulation
  • the brain is supplied with blood by the two internal carotid arteries (ICA) and two vertebral arteries, which anastomose intracranially and form the circle of Willis   → Anatomy of cerebral arteries
  • the intracranial vascular compartment has an arterial (high-pressure) part with active autoregulation and a venous (low-pressure, relatively passive) part; both can change their volume
  • CBF decreases with age

Cerebral blood flow (CBF) definition

CBF = CPP / CVR

CPP = MAP – ICP (or CVP if higher than ICP)
MAP = CO x SVR

cerebral resistance (R)  = (8 x l x η) / πr4
l = length of the vessel, η = viscosity of the blood, r = vessel radius

CPP – Cerebral Perfusion Pressure, MAP – Mean Arterial Pressure, CVR – Cerebral Vascular Resistance, SVR – Systemic Vascular Resistance, CO – Cardiac Output

  • in stable CPP, changes in cerebral blood flow (CBF) are regulated by cerebrovascular resistance (CVR), most commonly by changes in the diameter of intracranial arteries and arterioles
    • narrowing of arterioles leads to an increase in CVR and a decrease in blood flow velocity in the proximal segment of the artery
    • CVR also increases with increased blood viscosity (polyglobulia, leukocytosis, increased plasma protein content, etc.)
  • Cerebral Perfusion Pressure (CPP) is the difference between mean arterial pressure (MAP) and intracranial pressure (ICP = 10 mmHg under physiologic circumstances) or CVP
    • normal CPP ∼ 70-90 mm Hg
    • CPP< 50 mm Hg leads to hypoperfusion (irreversible at CPP < 30mmHg)
    • the higher the ICP (or CVP), the lower the CPP, if the MAP remains stable
  • CBF is constant at MAP in the range of 60(70)-160 (170) mmHg (different values were reported); outside this range, it already responds passively (see autoregulation curve below)
    • MAP < 50-70 mmHg (i.e. CPP < 50 mm Hg) leads to hypoperfusion
    • MAP > 160-170  mmHg (i.e., CPP > 150 mm Hg) leads to hyperperfusion, impaired HEB, and the development of edema or bleeding (e.g., post-CEA hyperperfusion syndrome)
    • the exact range is not clear and probably indivudlaa
  • normal CBF
    • gray matter 70-80 mL/100g/min
    • white matter 20-40 mL/100g/min
  • pathologic CBF values:
    • penumbra ∼12-20 mL/100g/min
    • ischemia < 12 mL/100g/min
  • in healthy individuals, CBF decreases by up to 28% during REM sleep but increases by up to 40% during non-REM sleep. These hemodynamic changes are accompanied by corresponding metabolic changes, changes in oxygen extraction from the blood, etc.

Regulation of cerebral circulation

Regulation ensures constant cerebral blood flow despite changes in systemic blood pressure and, to some extent, local drops in perfusion pressure (distal to the stenosis)

Neurogenic regulation

  • a complement to autoregulation and metabolic regulation mediated by baroreceptors (nerve endings sensitive to blood pressure changes)
  • baroreceptors are located in the ascending aorta and carotid sinuses and are connected to the medullary cardiovascular center (cardioaccelerator, cardioinhibitor, and vasomotor)
  • it protects the brain against sudden elevations or drops in systemic blood pressure
  • other neural mechanisms can also significantly impact cardiovascular function (such as the limbic system linking the physiological responses to psychological stimuli, etc.)

Baroreceptors

  • baroreceptors are specialized stretch receptors located within blood vessels and heart chambers that respond to stretch
  • they send impulses to the cardiovascular center to regulate blood pressure
  • vascular baroreceptors are located in the sinuses of the aorta and carotid arteries
    • aortic sinuses in the wall of the ascending aorta just above the aortic valve
    • carotid sinuses  at the origin of the internal carotid arteries

Increased blood pressure 

  • the baroreceptors are stretched and initiate action potentials at a higher rate
  • cardiac output decreases
  • sympathetic stimulation of the peripheral arterioles decreases, resulting in systemic vasodilation (inhibition of the vasomotor center)
  • these actions cause blood pressure to fall

Decreased blood pressure 

  • the degree of stretch is lower, and the rate of baroreceptor firing is slower
  • this triggers an increased sympathetic stimulation of the heart, which increases cardiac output
  • it also triggers sympathetic stimulation of the peripheral vessels, resulting in systemic vasoconstriction
  • these activities cause blood pressure to rise

Brainstem cardiovascular center

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Metabolic regulation

CBF changes in response to PaCO2

  • ↓PaCO2 (hypocapnia, e.g., due to hyperventilation) – CBF decreases (vasoconstriction → ↑peripheral resistance → decreased velocity in MCA, detectable by TCCD)
    • ↓pCO2 by 1kPa leads to ↓CBF by 15 mL/100g of brain tissue/min
  • ↑PaCO2  (hypercapnia) – CBF increases (vasodilation → ↓peripheral resistance → increased velocity in MCA, detectable by TCCD)
    • 5% CO2 inhalation causes an increase in cerebral blood flow by 50%
    • increase in flow is ∼ 1-2ml/100g/min for every 1mmHg increase in CO2
  • hypercapnia alters the normal autoregulatory relationship between MAP and blood flow  Hypercapnia alters autoregulatory relationship between MAP and CBF

CBF changes in response to reduced oxygen supply

  • acute hypoxia (PaO2 <50 mmHg) is a potent dilator and leads to exponentially increased CBF
    • opening of KATP channels in smooth muscle ⇒ hyperpolarization and vasodilation
    • hypoxia increases nitric oxide and adenosine production ⇒ vasodilation

The increase in flow is by about 1-2ml/100g/min for every 1mmHg increase in CO2

Intracranial flow changes during apnoe and hyperpnoe

Autoregulation

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Pathophysiologic conditions which can impair the autoregulation

  • hypercapnea
  • stroke
  • traumatic brain injury (TBI)
  • global hypoxic brain injury
  • regionally, surrounding a space-occupying lesion or a hematoma
  • infection, eg. meningitis or encephalitis
  • malignant hypertension
  • diabetic microangiopathy (after many years of uncontrolled diabetes)
  • hepatic encephalopathy
  • septic encephalopathy

Relationship between perfusion and regional metabolism

Overview of measurable parameters

  • in general, locally increased cerebral metabolic activity (regional Cerebral Metabolic Rate – rCMR) leads to ↑ regional CBF (rCBF)
  • AVDO2 – Arterio-Venous oxygen Difference
    • CaO2-CvO2
    • increases with increasing brain activity or decreasing CBF
  • OEF (Oxygen Extraction Fraction) or OER (Oxygen Extraction Ratio)
    • (CaO2-CvO2)/CaO2
    • when CBF decreases due to ischemia, ↑OEF occurs
    • when CBF decreases due to lower metabolism, OEF remains unchanged
  • CMRO2 (Cerebral Metabolic Rate of Oxygen consumption)
    • CMRO2 = (AVDO2 x CBF) (mL/100g/min) = CBF x OEF x CaO2
    • decrease in CBF due to occlusion is transiently compensated by increased oxygen extraction from the blood
  • rCBF, OEF, and CMRO2 can be measured with PET and MRI  [Lin, 2017]

Consequences of a decrease in perfusion pressure

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Regulation of cerebral blood flow
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