Cerebral Blood Flow and how it is regulated in the body

1. Cerebral Blood Flow
and its Regulation
Presenter: Dr Kaushal Deep Singh
MCh Senior Resident
Department of Neurosurgery
Sher-i-Kashmir Institute of Medical Sciences
Srinagar

2. INTRODUCTION
• Skull is a closed structure
• Most of it's content is
brain tissue while some
of it is blood and CSF
• Brain comprises 80%
• Cerebral blood volume
12%
• CSF contribute to 8% of
the space inside the skull
vault
Monro – Kellie doctrine

3. ANATOMY
Circulation of brain
was first described
by WILLIS in 1664
1. Anterior circulation
and Posterior
circulation via circle
of Willis
2. Collateral arterial
inflow channels
3. Leptomeningial
collaterals- pial to
pial anastomoses

4. ANATOMY
Circulation via circle of
Willis:
Anterior circulation: via
2 carotid arteries and
their derivations
Posterior circulations:
via 2 vertebral
arteries joining to
form basilar artery
It lies in subarachnoid
space and encircles
pituitary gland
Willisian channels:
anterior
communicating artery,
posterior
communicating artery
ophthalmic artery via
external carotid
artery

5. CIRCLE OF WILLIS WITH ITS
COLLATERALS

6. COLLATERAL CIRCULATION
In a normal individuals
there is no net flow of
blood across these
communicating arteries
But to maintain patency
and prevent thrombosis
there is to-and-fro flow
of blood
Their importance
appears when a
pressure gradient
develops
Second collateral flow
appears in surface
connections that
bridge pial arteries.
They bridge major
arterial territories (
ACA – PCA, ACA-
MCA, MCA – PCA)
They are called
leptomeningial
pathways or equal
pressure
pathways.

7. CEREBRAL
MICROCIRCULATION
• Capillary density in grey matter is 3 times higher
than white matter
• Pre-capillary vessels divide and reunite to form
anastomotic circle called as circle of Duret
• They are highly tortuous and irregular
• Velocity of RBC’s is higher in these capillaries
• To facilitate transfer of substrate and nutrients
RBC’s have to traverse longer distance via these
capillaries

8. CEREBRAL
MICROCIRCULATION
Fast capillaries: These are the ones which do not
take part in transfer of substrate.
BUT
• During cerebral hypoperfusion they have a
decrease in blood velocity , diverting blood to
slower functional capillaries.

9. VENOUS DRAINAGE
3 set of veins drain
from brain
1. Superficial cortical
vein
2. Deep cortical veins
3. Dural sinuses
• All ultimately drain
into right and left
IJV

10. CEREBRAL BLOOD SUPPLY
Physiological considerations:
• Brain accounts for 2% of
body weight yet
requires 20% of resting
oxygen consumption
• O2 requirement of brain is
3 – 3.5 ml/100gm/min
• And in children it goes
higher up to 5 ml/100gm/min
Brain has high metabolic rate
That’s why brain requires
higher blood supply
55ml/100gm/min is the
rate of blood supply
requires
more
substrate
lacks of
storage of
energy
substrate

11. CEREBRAL BLOOD SUPPLY
• Brain is having the highest energy requirement by mass.
• Even though brain constitutes less than 2% of body
weight, the adult brain receives 25% of cardiac output at
rest and uses 20% of the total energy produced by the
body.
• In children, up to 50% of the energy consumption of the
body is being accounted for by the brain.
• Much of this energy allocation is devoted to activities
connected to neural signalling.

12. CEREBRAL BLOOD SUPPLY
Cortical grey matter
75 – 80 ml/100gm/min
Subcortical white matter
20ml/100gm/min
CMRO2: 5.5 ml/100gm/min
Functional requirement is
3.3 ml/100gm/min
Integrity required O2 is
2.2 ml/100gm/min
60% functional
40 %
integrity

13. CEREBRAL BLOOD FLOW
HEMODYNAMICS
• Analogy between blood flow in an arterial system and
current flow in an electrical circuit.
• Ohm’s Law: I = ΔV/Re 1
• Blood Flow, Q = ΔP/Rv 2
• CBF = CPP/CVR 3
• CPP = MAP − ICP 4
• MAP = [1 3× (SP −DP)] + DP 5
• Laminar flow is described by the following Hagen-
Poiseuille law:
Q = (π.r4. ΔP)/(8.η.L) 6

14. CEREBRAL BLOOD FLOW
HEMODYNAMICS
• Contrary to the key assumptions behind the
Hagen-Poiseuille law, it is not strictly followed –
• normal blood flow is not continuous but pulsatile,
• blood vessels are not rigid and branchless tubes,
• if the rate of flow is continuously increased, there
comes a point when resistance to flow increases
sharply and the flow ceases to be laminar, instead
forming a turbulent pattern,
• cerebrovascular autoregulation

15. CEREBRAL BLOOD FLOW
HEMODYNAMICS
• CVR = (8.η.L)/(π.r4)
• Resistance of the cerebral circulation is subject to
dynamic changes in the contractile state of vascular
smooth muscle (VSM)
• Most resistance at the level of the penetrating precapillary
arterioles.
• However, up to 50% of total CVR arises from smaller pial
arteries (150 to 200 μm in diameter) and arteries of the
circle of Willis.

16. CEREBRAL BLOOD FLOW
HEMORHEOLOGY
• Principal influence on the flow behaviour of a liquid is viscosity.
• Sir Isaac Newton was the first to propose that for a liquid
undergoing perfectly laminar flow, the shear stress (ƫ) between
the laminae is proportional to the shear rate or velocity
gradient (δu/δz) in the direction perpendicular to the laminae
by a constant of proportionality, ε.
ε = ƫ + η.δu/δz
• For a typical Newtonian fluid such as water, ε is properly called
the coefficient of viscosity but can be equated with fluid
viscosity and is a constant that is dependent only on
temperature.
• In contrast, the viscosity of a non-Newtonian fluid can undergo
large variations as the shear rate changes.

17. CEREBRAL BLOOD FLOW
HEMORHEOLOGY
• Blood viscosity is not only a function of plasma viscosity
but also depends on the concentration of cells
(haematocrit).
• Blood of normal hematocrit approximates Newtonian
behaviour reasonably well.
• Non-Newtonian behavior of blood is best demonstrated in
its passage through the microcirculation.
• In large arteries, where the shear rate is low, calculations
using Poiseuille’s equation yield an “apparent” viscosity
that is much higher than expected.

18. CEREBRAL BLOOD FLOW
HEMORHEOLOGY
• With the higher shear rates typically found in the
microvasculature, the apparent viscosity falls.
• When blood flows through progressively diminishing
arterioles or capillaries with a diameter of 300 μm or
smaller, there is a linear fall in apparent viscosity known
as the Fahraeus-Lindqvist effect.
• When blood reaches capillaries with a diameter that is
less than that of an erythrocyte (6 to 8 μm), a steep rise in
blood viscosity and an inversion phenomenon (i.e.,
reversal of the Fahraeus-Lindqvist effect) take place.

19. CEREBRAL BLOOD FLOW
HEMORHEOLOGY
• Blood viscosity becomes even more critical to cerebral
perfusion in pathologic states of low blood flow.
• This is the theoretical basis for the clinical use of
hemodilution techniques as a means of attempting to
improve cerebral perfusion in conditions such as ischemic
stroke and cerebral vasospasm.

20. FACTORS REGULATING
CEREBRAL BLOOD FLOW
• Hemodynamic autoregulation
• Metabolic mediators and chemoregulation
• Neural control
• Circulatory peptides

21. AUTOREGULATION
• Proposed mechanisms include intrinsic changes in VSM tone
(myogenic hypothesis) and the release of a variety of
vasoactive substances from the endothelium (endothelial
hypothesis - NO, PGI2, and EDHF) or periadventitial nerves
(neurogenic hypothesis) in response to changes in transmural
pressure.
• Cerebral blood flow (CBF) closely follows cerebral
perfusion pressure (CPP)
• Within the range of 50 to 150 mm Hg of CPP, blood flow
remains constant.
• Pure changes in perfusion pressure involve myogenic
response in vascular smooth muscles (Bayliss effect).

23. AUTOREGULATION
Venous physiology:
Venous system contains
most of the cerebral
blood volume
Slight change in vessel
diameter has profound
effect on intracranial
blood volume
But evidence of their role is
less
Less smooth
muscle content
Less innervations
than arterial
system

24. AUTOREGULATION
• Pulsatile perfusion:
Fast and slow components of myogenic
response bring a change in perfusion pressure
• Cardiac output:
Cardiac output may be responsible for improved
cerebral blood flow
They are indirectly related via central venous
pressure and large cerebral vessel tone.

25. AUTOREGULATION
• Rheological factors: Related with blood viscosity.
• Hematocrit has main influence on blood
viscosity.
• Flow is inversely related with haematocrit.

26. METABOLIC AND CHEMICAL
REGULATION
• CO2 is considered to be the most important physiologic
variable in chemoregulation.
• The arterial partial pressure of CO2 (PaCO2) exerts
profound effects on CBF, particularly across the
physiologic range of 30 to 50 mm Hg.
• At normal conditions CBF has linear relationship with
CO2 between 20-80 mm Hg.
• For every mm Hg change of PaCO2 CBF changes by
2–4%.
• When alterations in PCO2 have been sustained for 3 to 5
hours, there is an adaptive return of CBF toward baseline
levels.

28. CO2 Induced Vasodilatation

29. CARBON DIOXIDE : HOW IT
WORKS
ADULT
NO
Ca2+
↓Ca2+
Channel
↓Ca2+
K+ Channel
C GMP
Smooth Ms
Relaxation
↑CO2
↑H+ ions
↑K+
↑nNOS

30. ↓Ca2+
Ca 2+ Channel
↓Ca2+
K+ Channel
C AMP
Smooth Ms
Relaxation
↑CO2
↑H+ ions
↑K+
↑COX
endothelium
PG
CARBON DIOXIDE : HOW IT
WORKS
NEONATES

31. METABOLIC AND CHEMICAL
REGULATION
Oxygen
• Elevated inspired oxygen concentrations elicit CVR and
decrease CBF. Conversely, a fall in Pao2 results in
vasodilation.
• Within physiological range PaO2 has no effect on CBF.
• Hypoxia is a potent stimulus for arteriolar
dilatation.
• At PaO2 50 mmHg, CBF starts to increase and at PaO2 30
mm Hg, it doubles.
• Hypoxia elicits VSM relaxation by inhibiting sarcoplasmic
Ca2+ uptake and stimulating the production of EDRF.

34. METABOLIC AND CHEMICAL
REGULATION
Temperature
• Like other organs cerebral metabolism
decreases with temperature.
• For every 1˚C fall in core body temperature
CMRO2 decreases by 7 %.
• At temperature < 18 ˚C EEG activity ceases.

35. TEMPERATURE

36. FLOW METABOLISM COUPLING
• Flow metabolism/Cerebral Neurovascular
coupling (Roy and Sherrington): Mediators
involved are: H+, K+, adenosine, glycolytic
intermediate and phospholipid metabolites
along with GABAnergic neurons, VIP and NO.
• Nitric oxide controls the smooth muscles tone.

37. PHARMACOLOGY AND
AUTOREGULATION
Vasoactive agents:
Drugs that do not cross blood brain barrier do not affect
CBF

38. PHARMACOLOGY AND
AUTOREGULATION
Dexmedetomidine:
Causes 25% reduction in CBF primarily by
reducing CMR
ACE inhibitors, Angiotensin receptor antagonists,
β blockers…….. Do not reduce CBF or alter
autoregulation

39. NEUROGENIC EFFECTS
Neurogenic effects: sympathetic tone shift the curve
to right

40. CIRCULATORY PEPTIDES
Vasoactive peptides like angiotensin II do affect
CBF.
Reactive oxygen molecules
Alteration to vasomotor function
Vascular remodeling
De silva et al: effects of angiotensin II on cerebral circulation: role of oxidative stress;
review article – front physiology ; Jan 2013

42. CLINICAL MEASUREMENT OF
CEREBRAL BLOOD FLOW
• Laser Doppler flowmetry, transcranial Doppler, and
electroencephalography provide qualitative
assessment of CBF.
• Quantitative CBF measurement techniques can be
divided into two principal groups that use either a
diffusible or non-diffusible tracer and rely on entirely
different mathematical models.

43. CLINICAL MEASUREMENT OF
CEREBRAL BLOOD FLOW
• The former group involves calculation of the uptake of inert
and highly diffusible tracers by the brain via some modification
of the Fick equation.
• Because these tracers are freely diffusible in the brain
parenchyma, the CBF values obtained reflect cerebral
perfusion.
• The remaining techniques are based on the central volume
theorem and require the construction of a time-density curve
after the injection of nondiffusible contrast agents.
• Because these agents are confined to the vasculature, the
values obtained reflect intravascular flow rather than perfusion.

44. CLINICAL MEASUREMENT OF
CEREBRAL BLOOD FLOW
• The ideal clinical technique should be based on widely available and
relatively inexpensive technology, be non-invasive, not require
anesthesia, and permit accurate and reproducible measurements
with a high degree of spatial and temporal resolution.
• Stable xenon–enhanced computed tomography (Xe-CT) comes
closest to meeting these criteria for CBF, but its availability is
constrained by equipment and gas requirements.
• Positron emission tomography (PET) has the benefit of allowing both
CBF and metabolic measurements but has largely been confined to
the research setting because of the requirement for an in-house
cyclotron.
• By comparison, the equipment and materials needed for CBF
measurement by single-photon emission computed tomography
(SPECT) and intracarotid 133Xe studies are relatively accessible to
clinicians, thus making these the current modalities of choice in most
centers.

45. CLINICAL MEASUREMENT OF
CEREBRAL BLOOD FLOW
• Computed tomographic perfusion (CTP) imaging has
emerged as a promising means of rapidly evaluating
cerebral perfusion in various clinical scenarios, although
the accuracy, reproducibility, and reliability of the
quantitative results are still in question.
• At the present time, MRI is not routinely used for
perfusion imaging because of the difficulty of obtaining
absolute quantification of perfusion parameters.

46. CLINICAL CONSIDERATIONS
Hypertensive patients:
• Autoregulatory curve shifts to right.
• Protection from breakthrough but at the cost of
risk of ischemia.
• May suffer cerebral ischemia during hemorrhage,
shock or hypotension.

47. CLINICAL CONSIDERATIONS
• Elderly patients: With age CBF decreases
• Younger people have increased blood flow in
frontal areas…. Frontal hyperaemia
• But with age this increased flow reduces
• Flow in other areas are well maintained hence
blood is more uniformly distributed
• Autoregulatory failure occurs in morel elderly

48. AUTO REGULATORY FAILURE
For auto regulatory failure to occur vasomotor
paralysis is the end point
• Acute ischemia
all lead to
vasomotor
paralysis
• Mass lesions
• Inflammation
• Prematurity
• Neonatal asphyxia
• Diabetes mellitus

49. AUTOREGULATORY FAILURE
Hyperperfusion
leads to circulatory
breakthrough
Fluid from capillaries seep
into the extracellular
space leading to edema
e.g. AVM
Right sided heart failure Left sided heart failure
Hypoperfusion

Ischemia
Na˖ and Ca 2˖ influx with
water and K+ efflux
leads to cytotoxic
edema and infarction
e.g. ischemic stroke

50. AUTOREGULATORY FAILURE
• Symon and coauthors reported their observations of three
zones of flow disturbance in a baboon model of middle
cerebral artery occlusion (MCAO):
• A peripheral zone of only mildly reduced blood flow without
discernible adverse cellular effect;
• an intermediate zone of moderate reduction of blood flow
to below 20 mL/100 g per minute, in which an isoelectric
electroencephalogram and absent evoked potentials
indicated “electrical failure”; and
• an inner “core” zone of severe reduction of blood flow to
below 6 to 10 mL/100 g per minute, in which the signs of
“electrical failure” were accompanied by a dramatic
increase in the extracellular K+ concentration, indicative of
“membrane failure.”

51. AUTOREGULATORY FAILURE
Two stages before infarction:
a. Penlucida at flow 18 – 23 ml/100gm/min
brain becomes inactive but function can be
restored at any time by reperfusion
b. Penumbra at lower flow rates brain
function can be restored by reperfusion
but only within a time limit

53. HEMODYNAMIC
CONSIDERATIONS
• Cerebral steal: it means blood is diverted from one
area to another if pressure gradient exists between
the two circulatory beds.
• Vasodilatation in ischemic brain takes blood from
ischemic areas to normal areas causing more
ischemia.
• Vasoconstriction results in redistribution of blood
from normal to ischemic areas leading to inverse
steal or ROBIN HOOD EFFECT.

54. HEMODYNAMIC
CONSIDERATIONS
Vessel length and viscosity
• At breakthrough point flow depends on vessel
length and viscosity
• Autoregulation has failed and it behaves like
fluid in a rigid tube
• Pressure gradient across the ends are now same
so distal area have the lowest flow
• This makes watershed areas more vulnerable to
ischemic changes

55. CONSIDERATIONS FOR
ISCHEMIA
Consideration relevant
to global ischemia
• Prevent and treat
hypotension as well as
vasogenic & cytotoxic
edema
• Induction of mild
hypothermia for 24 hrs
Consideration relevant
to focal ischemia
• Barbiturate coma, volatile
anesthetics (xenon),
calcium channel
antagonists
• PaCO2 and temperature

56. THERAPIES FOR ENHANCING
PERFUSION
• Induced hypertension
• Inverse steal
• Hypocapnea
• Hemodilution
• Pharmacological agents
• Barbiturates, propofol
• Intra arterial delivery of drugs. Like mannitol
and vasodilators

57. THANK
YOU